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Clostridioides difficile, a gram-positive, toxin-producing, spore-forming anaerobe, is a major cause of antibiotic-associated diarrhoea. The bacterium's intrinsic drug resistance limits current treatment options to fidaxomicin and vancomycin for initial episodes, with anti-toxin B monoclonal antibody or faecal microbiota transplantation recommended for complicated or recurrent cases. This underscores the urgent need for novel therapeutics. In this study, we screened the MMV Pathogen Box at a 10 µM concentration against C. difficile R20291. Primary hits were evaluated for minimum inhibitory concentrations (MIC), killing kinetics, and biofilm inhibition. Bacterial cytological profiling (BCP) and transmission electron microscopy (TEM) were employed to study the mode of action. MMV676558 was further tested in a mouse model to assess survival, histopathology, and gut microbiota effects. We identified nineteen hits that inhibited over 50 % of C. difficile growth. MIC assays revealed three hits with MICs below 16 µg/mL: MMV676558, MMV688755, and MMV690027. These hits were effective against various C. difficile ribotypes. Killing kinetics were comparable or superior to vancomycin and fidaxomicin, and biofilm assays showed inhibitory effects. BCP and TEM analyses suggested membrane function disruption as the mode of action. Furthermore, MMV676558 demonstrated a protective effect in mice, with favourable histopathology and gut microbiota profiles. Given the urgent threat posed by C. difficile antibiotic resistance, discovering new treatments is a top priority. Our study identified three promising hits from the MMV Pathogen Box, with MMV676558 showing significant in vivo potential for further evaluation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This paper explores the intricate relationship between depression, gut dysbiosis, and Clostridioides difficile infections, collectively termed "The 3 Ds". Depression is a widespread mental disorder increasing in prevalence. It is recognized for its societal burden and complex pathophysiology, encompassing genetic, environmental, and microbiome-related factors. The consequent increased use of antidepressants has led to growing concerns about their effects on the gut microbiome. Various classes of antidepressants and antipsychotics show antimicrobial activity, potentially leading to shifts in the gut microbiome and contributing to the development of dysbiosis. Dysbiosis, in turn, can predispose individuals to opportunistic infections like C. difficile, a significant healthcare concern due to its high recurrence rates and severe impact on patients' quality of life. Further, the link between antidepressant use and an increased risk of C. difficile infection (CDI) is explored and, finally, the emergence of live biotherapeutic products as novel treatment options for recurrent CDI is discussed., (© 2024. The Author(s).)

Objectives: 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., Methods: 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., Results: 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])., Discussion: Our analysis confirms current changes in guidelines, as it supports the superiority of vancomycin compared with metronidazole across all severity levels., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The medical treatment of ulcerative colitis (UC) includes the use of biological agents such as vedolizumab, a gut-selective alpha4beta7 (ɑ4β7) antagonist. The mechanism of action of vedolizumab involves interfering with leukocyte trafficking into the gut vasculature, which halts inflammation. Due to this mechanism of action, concerns have arisen regarding an increased risk of gut infections, specifically, clostridium difficile infection (CDI). The aim is to provide clarity regarding the association between the use of vedolizumab as a therapy for ulcerative colitis and the risk of developing CDI., Methods: A systematic literature review was conducted, starting with the scoping search, followed by backward snowballing parallel with keyword-based search to identify related articles. A quality assessment was conducted on the initially selected articles and excluded low-quality papers., Results: Pooled analyses indicated that there was no significant association between the use of vedolizumab and the risk of developing CDI (effect size = 0.03 [-0.02, 0.07])., Conclusions: Vedolizumab does not increase the risk of CDI in patients with UC. Further studies are needed to confirm these findings., (Copyright © 2024 Copyright: © 2024 Saudi Journal of Gastroenterology.)

Up to 25% of patients recovering from antibiotic-treated Clostridioides difficile infection (CDI) develop functional symptoms reminiscent of Post-Infectious Irritable Bowel Syndrome (PI-IBS). For patients with persistent symptoms following infection, a clinical dilemma arises as to whether to provide additional antibiotic treatment or to adopt a conservative symptom-based approach. Here, we review the literature on CDI-related PI-IBS and compare the findings with PI-IBS. We review proposed mechanisms, including the role of C. difficile toxins and the microbiota, and discuss implications for therapy. We suggest that gut dysfunction post-CDI may be initiated by toxin-induced damage to enteroglial cells and that a dysbiotic gut microbitota maintains the clinical phenotype over time, prompting consideration of microbiota-directed therapies. While Fecal Microbial Transplant (FMT) is currently reserved for recurrent CDI (rCDI), we propose that microbiota-directed therapies may have a role in primary CDI in order to avoid or mitigate futher antibiotic treatment that further disrupts the microbiota and thus prevent PI-IBS. We discuss novel microbial transfer therapies and as they emerge, we recommend clinical trials to determine whether microbial transfer therapy of the primary infection prevents both rCDI and CDI-related PI- IBS., Competing Interests: Conflict of interest The authors have no conflict of interest to declare., (Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: Antibiotic exposure is a known risk factor for Clostridioides difficile infection (CDI) and recurrence and can lead to infection with specific C. difficile strains. In this study, we sought to explore the relationship between antecedent antibiotic exposure and C. difficile antimicrobial resistance, and the impact of resistance on clinical outcomes., Methods: This was a single center retrospective study evaluating patients with CDI between 2011 and 2021. A logistic regression model was used to evaluate the relationship between antecedent antibiotics in the 30 days prior to CDI and resistance among isolates. In addition, an exploratory analysis using a cause-specific Cox proportional hazards model evaluated the association between resistance and a composite outcome of clinical failure, relapse at 30 days or CDI-related death., Results: we analyzed one isolate from 510 patients; resistance was noted in 339 (66.5 %) of the isolates. Exposure to fluoroquinolones and macrolides was associated with 2.4 (95 % CI 1.4-4.4) and 4.7 (95 % CI 1.1-20.5) increased odds of having resistance compared to other antibiotic class exposure, respectively. There were 58 (17.0 %) patients in the resistance group who developed the composite outcome and 24 (14.2 %) patients who lacked resistance who developed the composite outcome (HR 1.32, 95 % CI 0.81-2.14)., Conclusion: These findings suggest that fluoroquinolone and macrolide exposure were significantly associated with isolating a resistant strain, but we did not find significant differences in clinical outcomes based on the presence of antimicrobial resistance., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: DSR has research contracts at Tufts Medical Center from Prolacta, Summit Therapeutics, Seres Health and Merck. He is also a consultant to Prolacta and Merck. MA has grant funding from CARB-X. JC has research contracts at Tufts Medical Center from Merck and Kamada. All other authors do not have any conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

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.

Background: Clostridium difficile infection (CDI) is a debilitating nosocomial infection. C. difficile produces toxins A and B, which cause inflammation. Existing therapies have issues with recurrence, cost, and safety. We aim to discover a safe, effective, and economical nonmicrobiological therapeutic approach against CDI., Methods: We included human primary peripheral blood mononuclear cells (PBMCs), fresh human colonic explants, and humanized HuCD34-NCG mice. Toxin A+B+ VPI 10463 and A-B+ ribotype 017 C. difficile strains were used. We used single-cell RNA profiling and high-throughput screening to find actionable toxin B-dependent pathways in PBMCs., Results: Histamine 1 receptor-related drugs were found among the hit compounds that reversed toxin-mediated macrophage inflammatory protein (MIP) 1α expression in PBMCs. We identified loratadine as the safest representative antihistamine for therapeutic development. Loratadine inhibited toxin B-induced MIP-1α secretion in fresh human colonic tissues. Oral loratadine (10 mg/kg/d) maintained survival, inhibited intestinal CCl3 messenger RNA expression, and prevented vancomycin-associated recurrence in the VPI 10463-infected mice and ribotype 017-infected hamsters. Splenocytes from loratadine-treated mice conferred anti-inflammatory effects to the VPI 10463-infected T/B-cell--deficient Rag-/- mice. Oral loratadine suppressed human MIP-1α expression in monocytes/macrophages in toxin B-expressing ribotype 017-infected humanized HuCD34-NCG mice., Conclusions: Loratadine may be repurposed to optimize existing therapies against CDI., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: Potential conflicts of interest. Both authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Ciaran Kelly has acted as a paid consultant to: Facile Therapeutics, Ferring Pharma, Finch, Fzata, Merck, Milkyway Life Sciences, Pfizer, Recursion, RVAC Medicines, Seres Therapeutics, Summit Therapeutics and has acted as a study investigator for: Milkyway Life Sciences and Merck.

Japanese guidelines recommend metronidazole (MNZ) and vancomycin (VCM) for non-severe and severe cases of Clostridioides difficile infection (CDI), respectively. In the present study, we investigated the use of CDI antimicrobials and evaluated their clinical efficacy and validity using four severity classifications. A retrospective chart review was conducted using the data of 137 inpatients with initially positive C. difficile toxin test results and the initiation of CDI antimicrobials between April 2015 and March 2019. Patients treated with VCM or oral MNZ were included for clinical efficacy analysis of CDI antimicrobials and validation of severity classifications. The endpoints were CDI recurrence, 30-day mortality, and diarrhea cure rates. No significant differences were found between the VCM and oral MNZ groups in the CDI recurrence rate (10.4% vs. 12.7%, P = 0.707), 30-day mortality rate (12.5% vs. 5.6%, P = 0.162), and diarrhea cure rate (61.9% vs. 72.7%, P = 0.238), regardless of severity. Treatment with oral MNZ for non-severe cases was promising, confirming its usefulness according to Japanese guidelines. Further investigation of the clinical efficacy of oral MNZ in patients with first-episode CDI and evaluation of the preferred severity classification are warranted.

Clostridioides difficile infection (CDI) is a common healthcare-associated infection and the leading cause of gastroenteritis-related deaths worldwide. To investigate the effects of peptide composition of different protein products on CDI, we analyzed and compared the peptide sequences and compositions from Engraulis japonicus and Glycine max using Ultra High Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). An animal model of CDI was also established to investigate the potential therapeutic effects of these peptides in vivo. The peptide compositions of E. japonicus and G. max differed, with only 11% of the peptide sequences being identical. Oral administration of the tested peptides could reduce intestinal inflammation, repair the intestinal barrier, increase the proportion of beneficial bacteria, and reduce the proportion of harmful bacteria, providing a therapeutic effect against CDI. However, the peptides may differ considerably in some aspects. E. japonicus peptides were superior to G. max peptides in promoting colon epithelial cell proliferation and repairing tight intestinal cell junctions. Interestingly, the two sources of peptides have different effects on the cecal microbiome. E. japonicus peptides can effectively restore the diversity and richness of intestinal microbiota, while G. max peptides have poor regulatory effects on the intestinal microbiota structure. Overall, E. japonicus peptides showed better results than G. max peptides in treating CDI. This study supports the potential treatment of CDI with natural peptides and promotes the development of specialty foods for CDI enteritis. Clostridioides difficile infection (CDI) is a common healthcare-associated infection and the leading cause of gastroenteritis-related deaths worldwide. To investigate the effects of peptide composition of different protein products on CDI, we analyzed and compared the peptide sequences and compositions from Engraulis japonicus and Glycine max using Ultra High Performance Liquid Chromatography Tandem Mass Spectrometry (UPLC-MS/MS). An animal model of CDI was also established to investigate the potential therapeutic effects of these peptides in vivo. The peptide compositions of E. japonicus and G. max differed, with only 11% of the peptide sequences being identical. Oral administration of the tested peptides could reduce intestinal inflammation, repair the intestinal barrier, increase the proportion of beneficial bacteria, and reduce the proportion of harmful bacteria, providing a therapeutic effect against CDI. However, the peptides may differ considerably in some aspects. E. japonicus peptides were superior to G. max peptides in promoting colon epithelial cell proliferation and repairing tight intestinal cell junctions. Interestingly, the two sources of peptides have different effects on the cecal microbiome. E. japonicus peptides can effectively restore the diversity and richness of intestinal microbiota, while G. max peptides have poor regulatory effects on the intestinal microbiota structure., (© 2024. The Author(s).)

Background: Clostridioides difficile infection (CDI), a leading cause of nosocomial deaths, is a microbiota-mediated disease. As such, the use of broader spectrum antibiotics, such as vancomycin and metronidazole, can prime the gastrointestinal tract to become more prone to CDI recurrences. Fidaxomicin, a narrow-spectrum antibiotic, has been demonstrated to be superior in preventing recurrence and in preserving the intestinal microbiota; however, widespread employment worldwide has been hindered due to high acquisition costs., Objectives: To integrate the currently available guidelines on the management of CDI and to shed light on the timeliest employment of fidaxomicin., Methods: An expert panel was gathered to obtain consensus using Delphi methodology on a series of statements regarding the management of CDI and on appropriate antibiotic use., Results: Consensus was reached on 21 of the 25 statements addressing the management of CDI., Conclusions: Delphi methodology was used to achieve consensus on the management of CDI, on the identification of patients at risk of recurrences or severe infection, and on the most appropriate use of fidaxomicin, with the final aim of fostering clinical practice application of treatment algorithms proposed by previous guidelines, in absolute synergy. It could be an important tool to promote more appropriate and cost-effective CDI treatments in European settings with limited resources, like Italy., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

The development of new biological agents and small molecules has revolutionized the treatment of Inflammatory Bowel Disease (IBD). However, many patients do not respond or gradually lose their response, necessitating the search for other therapeutic strategies (1). In this clinical case, we describe the evolution of a patient with difficult-to-manage Crohn's Disease (CD) who was treated with oral vancomycin.

Clostridioides difficile infection (CDI) poses a significant health threat due to high recurrence rates. Antimicrobial agents are commonly used to manage CDI-related diarrhoea; however, by aggravating intestinal dysbiosis, antibiotics enable C. difficile spores germination and production of toxins, the main virulence factors. Therefore, the binding of exotoxins using adsorbents represents an attractive alternative medication for the prevention and treatment of relapses. In this study, we provided evidence that the natural insoluble polysaccharides, named ABR119, extracted by plant cell cultures, effectively trap C. difficile toxins. In our experiments, ABR119 exhibited no cytotoxicity in vitro and was safely administered in vivo. In the animal model of C. difficile-associated colitis, ABR119 (50 mg/kg body weight) significantly reduced the colonic myeloperoxidase activity and severity of inflammation, preventing body weight loss. These effects were not evident when we treated animals with wheat bran polysaccharides. We did not detect bacterial killing effects of ABR119 against C. difficile nor against bacterial species of the normal gut microbiota. Moreover, ABR119 did not interfere in vitro with the antimicrobial activities of most clinically used antibiotics. In summary, ABR119 holds promise for treating and preventing C. difficile colitis by trapping the bacterial toxins, warranting further studies to assess the ABR119 potential in human infections caused by C. difficile., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Objective: To review the efficacy, safety, and role of live biotherapeutic products (LBPs) in the prevention of recurrent Clostridioides difficile infection (rCDI)., Data Sources: A literature search was performed using PubMed and Google Scholar (through February 2024) with search terms RBX2660, SER-109, and fecal microbiota. Other resources included abstracts presented at recent conferences, national clinical practice guidelines, and manufacturers' websites., Study Selection and Data Extraction: All relevant studies, trial updates, conference abstracts, and guidelines in the English language were included., Data Synthesis: Two LBPs were recently approved by the Food and Drug Administration for the prevention of recurrence in adults following antibiotic treatment for rCDI. Fecal microbiota, live-jslm is administered rectally as a retention enema, whereas fecal microbiota spores, live-brpk is given orally after bowel preparation. Several phase 2 and phase 3 clinical trials have established the safety and efficacy of these LBPs in reducing rates of rCDI compared with placebo. Patients with severe immunosuppression and those with inflammatory bowel disease were largely excluded from these trials., Relevance to Patient Care and Clinical Practice in Comparison With Existing Drugs: Live biotherapeutic products offer a similar mechanism to conventional fecal microbiota transplant (FMT) in preventing rCDI through microbiota restoration. The primary advantages of LBPs over FMT are their standardized composition and donor stool screening processes for transmissible pathogens. Bezlotoxumab is also available for the prevention of Clostridioides difficile infection; however, there are no clinical data available to compare the efficacy of LBPs with bezlotoxumab, and the benefit of simultaneous use of these preventative therapies is unclear., Conclusions: Live biotherapeutic products provide a safe and effective option for the prevention of rCDI and represent an improvement over conventional FMT. Additional studies are needed to further determine their place in therapy relative to bezlotoxumab and in the setting of immunosuppression and inflammatory bowel disease., Competing Interests: Declaration of Conflicting InterestsThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: NNP and KMS have nothing to disclose. EBC served on the speakers’ bureau of Seqirus.

Clostridioides difficile is a toxin-producing bacteria that is a main cause of antibiotic-associated diarrhea. Clostridioides difficile infections (CDI) are associated with disruptions within the gastrointestinal (GI) microbiota which can be further exacerbated by CDI-targeted antibiotic treatment thereby causing recurrent CDI (rCDI) and compounding the burden placed on patients and the healthcare system. Treatment of rCDI consists of antibiotics which can be paired with preventative therapeutics, such as bezlotoxumab or fecal microbiota transplants (FMTs), if sustained clinical response is not obtained. Newer preventative strategies have been recently approved to assist in restoring balance within the GI system with the goal of preventing recurrent infections., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Purpose: To compare the efficacy, recurrence rate, adverse event rate and mortality of fidaxomicin compared with vancomycin in treating different types of Clostridium difficile infection (CDI)., Methods: A systematic search was conducted on PubMed, Embase, Web of Science, Cochrane Library and clinical trial registration databases for research on fidaxomicin versus vancomycin in the treatment of CDI and the retrieval period extended from the establishment of the database to July 22, 2022. A total of 15 studies were included, including 8 RCTs and 7 retrospective cohort studies., Results: Results showed that there was no significant difference in the overall efficacy of the treatment between fidaxomicin and vancomycin, and results in the subgroups of CDI hypervirulent strains and recurrent CDI were obtained, but vancomycin was more effective than fidaxomicin in the treatment of severe CDI (RR = 0.94, 95% CI: 0.90-0.98, P < .01). Results showed that fidaxomicin is superior to vancomycin in terms of 40-day recurrence rate (RR = 0.52, 95% CI: 0.38-0.70, P < .01), 60-day recurrence rate (RR = 0.38, 95% CI: 0.21-0.69, P < .01) and 90-day recurrence rate (RR = 0.62, 95% CI: 0.50-0.77, P < .01). For the recurrence rate of the treatment in CDI hypervirulent strains, severe CDI and recurrent CDI, there was no significant difference between the 2 groups. In addition, there was no significant difference in the incidence of clinical adverse reactions, and same outcomes appeared in all-cause mortality at 40-day, severe CDI and recurrent CDI, but fidaxomicin was superior to vancomycin in all-cause mortality over 60-day (RR = 0.57, 95% CI: 0.34-0.96, P = .03)., Conclusion: There were no significant differences between fidaxomicin and vancomycin in the treatment of CDI in therapeutic effectiveness and adverse reactions, while fidaxomicin was superior to vancomycin in terms of recurrence rate and long-term mortality, and vancomycin is more effective in treating severe CDI., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Clostridioides difficile infection (CDI) is a significant public health threat, associated with antibiotic-induced disruption of the normally protective gastrointestinal microbiota. CDI is thought to occur in two stages: acquisition of asymptomatic colonization from ingesting C. difficile bacteria followed by progression to symptomatic CDI caused by toxins produced during C. difficile overgrowth. The degree to which disruptive antibiotic exposure increases susceptibility at each stage is uncertain, which might contribute to divergent published projections of the impact of hospital antibiotic stewardship interventions on CDI. Here, we model C. difficile transmission and CDI among hospital inpatients, including exposure to high-CDI-risk antibiotics and their effects on each stage of CDI epidemiology. We derive the mathematical relationship, using a deterministic model, between those parameters and observed equilibrium levels of colonization, CDI, and risk ratio of CDI among certain antibiotic-exposed patients relative to patients with no recent antibiotic exposure. We then quantify the sensitivity of projected antibiotic stewardship intervention impacts to alternate assumptions. We find that two key parameters, the antibiotic effects on susceptibility to colonization and to CDI progression, are not identifiable given the data frequently available. Furthermore, the effects of antibiotic stewardship interventions are sensitive to their assumed values. Thus, discrepancies between different projections of antibiotic stewardship interventions may be largely due to model assumptions. Data supporting improved quantification of mechanistic antibiotic effects on CDI epidemiology are needed to understand stewardship effects better., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mitchell et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

In contrast to the epidemiology 10 years earlier at our hospital when the epidemic restriction endonuclease analysis (REA) group strain BI accounted for 72% of Clostridioides difficile isolates recovered from first-episode C. difficile infection (CDI) cases, BI represented 19% of first-episode CDI isolates in 2013-2015. Two additional REA group strains accounted for 31% of isolates (Y, 16%; DH, 12%). High-level resistance to fluoroquinolones and azithromycin was more common among BI isolates than among DH, Y, and non-BI/DH/Y isolates. Multivariable analysis revealed that BI cases were 2.47 times more likely to be associated with fluoroquinolone exposure compared to non-BI cases (95% confidence interval [CI]: 1.12-5.46). In addition, the odds of developing a CDI after third- or fourth-generation cephalosporin exposure was 2.83 times for DH cases than for non-DH cases (95% CI: 1.06-7.54). Fluoroquinolone use in the hospital decreased from 2005 to 2015 from a peak of 113 to a low of 56 antimicrobial days/1,000 patient days. In contrast, cephalosporin use increased from 42 to 81 antimicrobial days/1,000 patient days. These changes correlated with a decrease in geometric mean MIC for ciprofloxacin (61.03 to 42.65 mg/L, P = 0.02) and an increase in geometric mean MIC for ceftriaxone (40.87 to 86.14 mg/L, P < 0.01) among BI isolates. The BI strain remained resistant to fluoroquinolones, but an overall decrease in fluoroquinolone use and increase in cephalosporin use were associated with a decrease in the prevalence of BI, an increased diversity of C. difficile strain types, and the emergence of strains DH and Y., Competing Interests: A.M.S. has served as a consultant for Bio-K+, Recursion Pharmaceuticals, and Ferring Pharmaceuticals and has received research funding from Paratek Pharmaceuticals (paid to institution). D.N.G. licensed technology the treatment of CDI to Destiny Pharma plc and is a consultant for Destiny, Sebela, and AstraZeneca. S.J. has served as a consultant for Acurx Pharmaceuticals, Inc, Bio-K+ International, and Ferring Pharmaceuticals. S.J. has received research funding from Paratek Pharmaceuticals (paid to institution). J.T.W., A.C., L.A.P., V.W.S., and L.M.W. have no disclosures.

Background: Advanced age has been widely identified as a risk factor for recurrent Clostridioides difficile infection (CDI), but most related studies were performed before the introduction of novel therapies. The aim of this study was to compare CDI characteristics and outcomes in patients over and under 80 years old with CDI and their outcomes in the era of new treatments., Methods: This was a retrospective cohort study of patients diagnosed with CDI from January 2021 to December 2022 in an academic hospital. We compared recurrence and mortality at 12 weeks after the end of treatment. An extension of the Fine and Grey model adjusted for competing events was used to assess the effect of age on recurrence., Results: Four hundred seventy-six patients were considered to have CDI (320 in patients <80 years and 156 in ≥80 years). CDI in older patients was more frequently healthcare-associated and was more severe. Although the Charlson index was almost identical between populations, comorbidities clearly differed. New treatments (bezlotoxumab, fidaxomicin and faecal microbiota transplantation) were more frequently used in older patients without statistical significance (41.3% vs. 33.4%, P = .053). There were 69 (14.5%) recurrences, with no differences by age group after adjusting for competing events. Mortality was greater in the oldest (35.3%) than in the youngest (13.1%); P < .001., Conclusions: No differences in CDI recurrence rates were found between age groups. However, there was a high mortality rate in patients ≥80 years old, which emphasises the urgent need to improve the prevention and treatment of CDI in this group., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: Clostridioides difficile has emerged as a major cause of life-threatening diarrheal disease. Conventional antibiotics used in current standards of care exacerbate the emergence of antibiotic-resistant strains and pose a risk of recurrent C. difficile infection (CDI). Thus, there is an urgent need for alternative therapeutics that selectively eliminate C. difficile without disturbing the commensal microbiota. This study aimed to explore the potential of endolysins as an alternative therapeutic agent to antibiotics. Endolysin is a bacteriophage-derived peptidoglycan hydrolase that aids in the release of phage progeny during the final stage of infection., Methods: In order to exploit endolysin as a therapeutic agent against CDI, the bactericidal activity of 23 putative endolysins was compared and ΦCD27 endolysin CD27L was selected and modified to CD27L&#95;EAD by cleaving the cell-wall binding domain of CD27L., Results: CD27L&#95;EAD exhibited greater bacteriolytic activity than CD27L and its activity was stable over a wide range of salt concentrations and pH conditions. CD27L&#95;EAD was added to a co-culture of human gut microbiota with C. difficile and the bacterial community structure was analyzed. CD27L&#95;EAD did not impair the richness and diversity of the bacterial population but remarkably attenuated the abundance of C. difficile. Furthermore, the co-administration of vancomycin exerted synergistic bactericidal activity against C. difficile. β-diversity analysis revealed that CD27L&#95;EAD did not significantly disturb the composition of the microbial community, whereas the abundance of some species belonging to the family Lachnospiraceae decreased after CD27L&#95;EAD treatment., Conclusions: This study provides insights into endolysin as a prospective therapeutic agent for the treatment of CDI without damaging the normal gut microbiota., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Abstract: Infections from Clostridioides difficile (often called C. diff) have long presented challenges for both patients and clinicians. Traditionally, C. diff has been considered a nosocomial infection, but in recent years, a noticeable spike in community-acquired cases has occurred. C. diff infection (CDI) testing is often complicated, as various testing options with differing sensitivity and specificity for active infection are available. Also, recent guideline changes have altered the recommended treatment of infection. This article discusses recent changes to both the diagnosis and management of CDI and how they can be applied to everyday NP practice., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Clostridioides difficile is an enteric pathogen that can cause a range of illnesses from mild diarrhea to pseudomembranous colitis and even death. This pathogen often takes advantage of microbial dysbiosis provoked by antibiotic use. With the increasing incidence and severity of infections, coupled with high recurrence rates, there is an urgent need to identify innovative therapies that can preserve the healthy state of the gut microbiota. In this study, we screened a microbial metabolite library against C. difficile . From a collection of 527 metabolites, we identified 18 compounds with no previously identified antimicrobial activity and metabolites that exhibited potent activity against C. difficile growth. Of these 18 hits, five drugs and three metabolites displayed the most potent anti- C . difficile activity and were subsequently assessed against 20 clinical isolates of C. difficile . These potent agents included ecteinascidin 770 (minimum inhibitory concentration against 50% of isolates [MIC 50 ] ≤0.06 µg/mL); 8-hydroxyquinoline derivatives, such as broxyquinoline and choloroquinaldol (MIC 50 = 0.125 µg/mL); ionomycin calcium salt, carbadox, and robenidine hydrochloride (MIC 50 = 1 µg/mL); and dronedarone and milbemycin oxime (MIC 50 = 4 µg/mL). Unlike vancomycin and fidaxomicin, which are the standard-of-care anti- C . difficile antibiotics, most of these metabolites showed robust bactericidal activity within 2-8 h with minimal impact on the growth of representative members of the normal gut microbiota. These results suggest that the drugs and microbial metabolite scaffolds may offer alternative avenues to address unmet needs in C. difficile disease prevention and treatment., Importance: The most frequent infection associated with hospital settings is Clostridioides difficile , which can cause fatal diarrhea and severe colitis, toxic megacolon, sepsis, and leaky gut. Those who have taken antibiotics for other illnesses that affect the gut's healthy microbiota are more susceptible to C. difficile infection (CDI). Recently, some reports showed higher recurrence rates and resistance to anti- C. difficile , which may compromise the efficacy of CDI treatment. Our study is significant because it is anticipated to discover novel microbial metabolites and drugs with microbial origins that are safe for the intestinal flora, effective against C. difficile , and reduce the risk of recurrence associated with CDI., Competing Interests: The authors declare no conflict of interest.

Background: Epidemiologic studies have shown decreasing vancomycin susceptibility among clinical Clostridioides difficile isolates, but the impact on patient outcomes is unknown. We hypothesized that reduced vancomycin susceptibility would be associated with decreased rates of sustained clinical response (SCR)., Methods: This multicenter cohort study included adults with C. difficile infection (CDI) treated with oral vancomycin between 2016 and 2021. Clostridioides difficile isolates underwent agar dilution vancomycin susceptibility testing, ribotyping, and Sanger sequencing of the vancomycin resistance vanR gene. Reduced susceptibility was defined as vancomycin minimum inhibitory concentration (MIC) >2 μg/mL. The primary outcome was 30-day SCR; secondary outcomes were 14-day initial cure, 30-day recurrence, and 30-day mortality. Exploratory analysis assessed the association between the VanR Thr115Ala polymorphism, susceptibility, and outcomes., Results: A high proportion (34% [102/300]) of C. difficile isolates exhibited reduced vancomycin susceptibility (range, 0.5-16 μg/mL; MIC50/90 = 2/4 μg/mL). Ribotype 027 accounted for the highest proportion (77.4% [41/53]) of isolates with reduced vancomycin susceptibility. Overall, 83% (249) of patients achieved 30-day SCR. Reduced vancomycin susceptibility was associated with lower rates of 30-day SCR (76% [78/102]) than vancomycin-susceptible strains (86% [171/198]; P = .031). A significantly lower rate of 14-day initial cure was also observed among individuals infected with strains with reduced vancomycin susceptibility (89% vs 96%; P = .04). Reduced susceptibility remained an independent predictor of 30-day SCR in multivariable modeling (odds ratio, 0.52 [95% confidence interval, .28-.97]; P = .04)., Conclusions: Reduced vancomycin susceptibility in C. difficile was associated with decreased odds of 30-day SCR and lower 14-day initial cure rates in the studied patient cohort., Competing Interests: Potential conflicts of interest. K. W. G. and A. J. G.-L. have received research funding from Merck. K. W. G. has received additional research funding from Acurx Pharmaceuticals. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Clostridioides difficile infection is the most common healthcare-associated infection in the United States, with potential life-threatening complications and a significant impact on the costs of care. Antibiotic stewardship as well as discontinuation of chronic acid suppressive therapy are key for its prevention and treatment. Effective infection management requires appropriate interpretation of diagnostic tests, as well as the use of vancomycin and fidaxomicin as first-line treatment. Novel treatments such as Bezlotoxumab, fecal microbiota transplant, and live biotherapeutic products are proven effective in recurrent C. difficile infection and address dysbiosis., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

The growing incidence of Clostridium difficile associated diarrhea (CDAD) underscores the urgency for potent treatments. This research delves into the therapeutic potential of Scutellaria baicalensis Georgi (Lamiaceae) root (SR) in addressing CDAD and its influence on gut microbiota. Using a CDAD mouse model and fidaxomicin as a control, SR's impact was measured through diarrhea symptoms, colonic histopathology, and C. difficile toxin levels. Employing the PacBio platform, 16S rRNA full-length gene sequencing analyzed the gut microbial composition and the effect of SR. Results revealed SR considerably alleviated diarrhea during treatment and restoration phases, with a marked decrease in colonic inflammation. C. difficile toxin levels dropped significantly with SR treatment (P < 0.001). While SR didn't augment gut microbiota's overall abundance, it enhanced its diversity. It restored levels of Proteobacteria and Bacteroidetes, reduced Akkermansia spp. and Enterococcus spp. proportions, and modulated specific bacterial species' abundance. In essence, SR effectively mitigates CDAD symptoms, curtails inflammatory reactions, and beneficially restructures gut microbiota, suggesting its potential in advanced CDAD clinical intervention., Competing Interests: Declaration of competing interest The authors declare that they have no known financial or interpersonal conflicts that might have looked to have influenced the research presented in this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Clostridioides difficile (formerly Clostridium difficile) has been regarded as an 'urgent threat' and a significant global health problem, as life-threatening diarrhoea and refractory recurrence are common in patients with C. difficile infection (CDI). Unfortunately, the available anti-CDI drugs are limited. Recent guidelines recommend fidaxomicin and vancomycin as first-line drugs to treat CDI, bezlotoxumab to prevent recurrence, and faecal microbiota transplantation for rescue treatment. Currently, researchers are investigating therapeutic antibacterial drugs (e.g. teicoplanin, ridinilazole, ibezapolstat, surotomycin, cadazolid, and LFF571), preventive medications against recurrence (e.g. Rebyota, Vowst, VP20621, VE303, RBX7455, and MET-2), primary prevention strategies (e.g. vaccine, ribaxamase, and DAV132) and other anti-CDI medications in the preclinical stage (e.g. Raja 42, Myxopyronin B, and bacteriophage). This narrative review summarises current medications, including newly marketed drugs and products in development against CDI, to help clinicians treat CDI appropriately and to call for more research on innovation., (Copyright © 2024 Elsevier Ltd and International Society of Antimicrobial Chemotherapy. All rights reserved.)

Background: Antibiotics with extended anaerobic coverage are used commonly to treat aspiration pneumonia, which is not recommended by current guidelines., Research Question: In patients admitted to hospital for community-acquired aspiration pneumonia, does a difference exist between antibiotic therapy with limited anaerobic coverage (LAC) vs antibiotic therapy with extended anaerobic coverage (EAC) in terms of in-hospital mortality and risk of Clostridioides difficile colitis?, Study Design and Methods: We conducted a multicenter retrospective cohort study across 18 hospitals in Ontario, Canada, from January 1, 2015, to January 1, 2022. Patients were included if the physician diagnosed aspiration pneumonia and prescribed guideline-concordant first-line community-acquired pneumonia parenteral antibiotic therapy to the patient within 48 h of admission. Patients then were categorized into the LAC group if they received ceftriaxone, cefotaxime, or levofloxacin. Patients were categorized into the EAC group if they received amoxicillin-clavulanate, moxifloxacin, or any of ceftriaxone, cefotaxime, or levofloxacin in combination with clindamycin or metronidazole. The primary outcome was all-cause in-hospital mortality. Secondary outcomes included incident C difficile colitis occurring after admission. Overlap weighting of propensity scores was used to balance baseline prognostic factors., Results: The LAC and EAC groups included 2,683 and 1,316 patients, respectively. In hospital, 814 patients (30.3%) and 422 patients (32.1%) in the LAC and EAC groups died, respectively. C difficile colitis occurred in five or fewer patients (≤ 0.2%) and 11 to 15 patients (0.8%-1.1%) in the LAC and EAC groups, respectively. After overlap weighting of propensity scores, the adjusted risk difference of EAC minus LAC was 1.6% (95% CI, -1.7% to 4.9%) for in-hospital mortality and 1.0% (95% CI, 0.3%-1.7%) for C difficile colitis., Interpretation: We found that extended anaerobic coverage likely is unnecessary in aspiration pneumonia because it was associated with no additional mortality benefit, only an increased risk of C difficile colitis., Competing Interests: Financial/Nonfinancial Disclosures None declared., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: In the last two decades, a significant increase in the number of Clostridioides difficile infection (CDI) cases has been observed. It is understandable to attempt to determine the factors that can predict the severity of the course of the infection and identify patients at risk of death. This study aimed to analyze the factors affecting the incidence and mortality of CDI in inpatient treatment at the University Clinical Hospital in Wrocław in 2016-2018., Methods: Statistical analysis of data obtained from patients' medical records was performed. Only patients with symptoms of infection and infection confirmed by laboratory tests were enrolled in the study. When analyzing the number of deaths, only adult patients who died in hospital wards were included. The quantitative data including laboratory tests, used antibiotics and Nutritional Risk Screening (NRS) were assessed. Also, the qualitative data such as sex, year of hospitalization, occurrence of diarrhoea on admission to the hospital, presence of additional diseases, as wee ad the use of antibacterial drugs or proton pump blockers and ranitidine during hospitalization were analyzed., Results: A total of 319 adult CDI patients (178 women and 141 men) were enrolled of which 80 people died (50 women and 30 men). The mean age of the patients was 72.08 ± 16.74 years. Over the entire period studied, the morbidity was 174 cases per 100,000 hospitalizations while mortality was 25.08%. The group of deceased patients was characterized by: older age (by 9.24 years), longer duration of hospitalization (by 10 days), reduced albumin levels (Rho = -0.235, p < 0.001), higher urea levels, use of more antibiotics, higher risk of malnutrition in NRS (Rho = 0.219, p < 0.001), higher incidence of sepsis, heart failure, stroke, hypothyroidism. Pneumonia was diagnosed twice as often. It was also shown that deceased patients were significantly more likely to take penicillin and fluoroquinolones., Conclusions: In this study, the morbidity was lower, but mortality was higher compared to similar hospitals in Poland. CDI patients were characterized by older age, multimorbidity, extended hospitalization, and the use of broad-spectrum antibiotics. Risk factors for death included advanced age, prolonged hospital stays, lower albumin, higher urea, malnutrition, and comorbidities like heart failure, stroke, pneumonia, sepsis, and hypothyroidism. Increased antibiotic use, particularly penicillin and fluoroquinolones, was associated with a higher mortality risk., (© 2024. The Author(s).)

The aryl hydrocarbon receptor (AhR) is a transcription factor that regulates the immune system through complicated transcriptional programs. Genistein, an AhR ligand, exhibits anti-inflammatory properties. However, its role in modulating immune responses via the AhR signaling pathway remains unclear. In this study, 360 male Arbor Acre broilers (1-day-old) were fed a basal diet supplemented with 40 or 80 mg/kg genistein and infected with or without Clostridium perfringens ( Cp ). Our results demonstrated that genistein ameliorated Cp -induced intestinal damage, as reflected by the reduced intestinal lesion scores and improved intestinal morphology and feed-to-gain ratio. Moreover, genistein increased intestinal sIgA, TGF-β, and IL-10, along with elevated serum IgG, IgA, and lysozyme levels. Genistein improved intestinal AhR and cytochrome P450 family 1 subfamily A member 1 (CYP1A1) protein levels and AhR + cell numbers in Cp -challenged broilers. The increased number of AhR + CD163 + cells in the jejunum suggested a potential association between genistein-induced AhR activation and anti-inflammatory effects mediated through M2 macrophage polarization. In IL-4-treated RAW264.7 cells, genistein increased the levels of AhR, CYP1A1, CD163, and arginase (Arg)-1 proteins, as well as IL-10 mRNA levels. This increase was attenuated by the AhR antagonist CH223191. In summary, genistein activated the AhR signaling pathway in M2 macrophages, which enhanced the secretion of anti-inflammatory cytokines and attenuated intestinal damage in Cp -infected broilers Cp ., Competing Interests: The authors declare no conflicts of interest.

Background: Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective drugs that treat CDI and perpetuate dysbiosis are associated with rCDI, in part due to loss of microbiome-derived secondary bile acid (SBA) production. Ridinilazole is a highly selective drug designed to treat CDI and prevent rCDI., Methods: In this phase 3 superiority trial, adults with CDI, confirmed with a stool toxin test, were randomized to receive 10 days of ridinilazole (200 mg twice daily) or vancomycin (125 mg 4 times daily). The primary endpoint was sustained clinical response (SCR), defined as clinical response and no rCDI through 30 days after end of treatment. Secondary endpoints included rCDI and change in relative abundance of SBAs., Results: Ridinilazole and vancomycin achieved an SCR rate of 73% versus 70.7%, respectively, a treatment difference of 2.2% (95% CI: -4.2%, 8.6%). Ridinilazole resulted in a 53% reduction in recurrence compared with vancomycin (8.1% vs 17.3%; 95% CI: -14.1%, -4.5%; P = .0002). Subgroup analyses revealed consistent ridinilazole benefit for reduction in rCDI across subgroups. Ridinilazole preserved microbiota diversity, increased SBAs, and did not increase the resistome. Conversely, vancomycin worsened CDI-associated dysbiosis, decreased SBAs, increased Proteobacteria abundance (∼3.5-fold), and increased the resistome., Conclusions: Although ridinilazole did not meet superiority in SCR, ridinilazole greatly reduced rCDI and preserved microbiome diversity and SBAs compared with vancomycin. These findings suggest that treatment of CDI with ridinilazole results in an earlier recovery of gut microbiome health. Clinical Trials Registration.Ri-CoDIFy 1 and 2: NCT03595553 and NCT03595566., Competing Interests: Potential conflicts of interest. K. W. G. received grants paid to his institution from Acurx, Paratek, Cidara, Therapeutics, and Seres Health. P. C. O. received faculty grant/research support from Merck, Sharp and Dohme, Deinove Pharmaceuticals, Summit Pharmaceuticals, Melinta Pharmaceuticals, the National Institutes of Health (NIH) National Institute of Allergy and Infectious Diseases (NIAID), Kieberg Foundation, and Napo Pharmaceutical; is a consultant to Napo Pharmaceutical, Ferring Pharmaceutical, Summit Pharmaceutical, SNIPR Biome Company, Haleon, and SNIPR; received payment for speaking from Colegio Mexicano de Medicina Interna; participated on a Scientific Advisory Board for Napo Pharmaceuticals; and has stock or stock options from Moderna, Pfizer, Haleon, Biontech, GSK, Novavax, AstraZeneca, Beam, and Johnson & Johnson. T. L. attended advisory board meetings for Summit, Inc, and received payments for the conduct of clinical trials for Seres Therapeutics, Finch Therapeutics, and Rebiotix/Ferring. E. D. and D. J. were employees of Summit, Inc, and owned stock options in Summit Therapeutics (parent company) at the time of manuscript submission. J. G. M. is a part-time employee and owns stock options in Summit, Inc. E. R. D. has received grants paid to his institution from Theriva Biologics and Ferring and consulting fees from Pfizer, Merck, Seres, Abbott, AstraZeneca, Summit, GSK, and Ferring. M. W. has received consulting fees from AiCuris, Bayer, Crestone, Da Volterra, Deinove, EnteroBiotix, The European Tissue Symposium, Ferring, GSK, Menarini, Merck, Nestlé, Paion, Paratek, Pfizer, Phico Therapeutics, Qpex Biopharma, Seres, Surface Skins, Summit, Tillotts, Vaxxilon/Idorsia, and Vedanta; lecture fees from GSK, Merck, Pfizer, Seres, and Tillotts; and grant support from Almirall, Da Volterra, EnteroBiotix, GSK, Merck, MicroPharm, Nabriva, Paratek, Pfizer, Seres, Summit, The European Tissue Symposium, and Tillotts. J. L., B. Y. C., J. S., L. S., and F. C. are employees of Summit, Inc, and own Summit stock options. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Clostridioides difficile ( C. difficile ) is one of the leading causes of healthcare-associated infections worldwide. The increasing incidence of strains resistant to currently available therapies highlights the need for alternative treatment options with a novel mode of action. Oxazolidinones that are connected to a quinolone moiety with a pyrrolidine linker, such as compound 1 , are reported to exhibit potent broadspectrum antibacterial activity. In an effort to optimize this class of compounds for the treatment of C. difficile infection (CDI), we have identified cadazolid ( 9 ), a first-in-class quinoxolidinone antibiotic, which is a potent inhibitor of C. difficile protein synthesis. In order to achieve narrow-spectrum coverage of clinically most relevant strains without affecting the gut microbiota, an emphasis was placed on abolishing activity against commensals of the intestinal microbiome while retaining good coverage of pathogenic C. difficile , including hypervirulent and epidemic strains.

Objectives: To assess the effectiveness of shortened regimens of vancomycin or fidaxomicin in the treatment of Clostridioides difficile infection (CDI)., Methods: Adult patients with CDI hospitalized from January 2022 to May 2023 were included in this observational study. In patients with CDI treated with vancomycin or fidaxomicin, antibiotic treatment was discontinued after either 5 or 7 days of vancomycin or 5 days of fidaxomicin if there was a clinical response and improvement in laboratory parameters. The control cohort was treated with the standard 10 day regimen of either vancomycin or fidaxomicin. The follow-up was 60 days. Causative C. difficile strains were characterized by ribotyping and toxin gene detection when available., Results: Twenty-five patients (median age 76 years) received shortened treatment with vancomycin (n = 21), or fidaxomicin (n = 4). Five cases fulfilled the criteria for severe CDI. Twenty-three patients completed follow-up; two died from causes other than CDI, and two developed recurrent CDI (8.0%). Ribotypes (RTs) 001 and 014 were the most prevalent with 20% each. In two C. difficile isolates, binary toxin genes were detected (RTs 078 and 023). In the control group of 22 patients recurrent CDI developed in 5 patients (22.7%). No statistically significant differences were found between the groups., Conclusions: Shortened treatment regimens for CDI with vancomycin and fidaxomicin were shown to be effective in our cohort of patients compared with 10 days of treatment. The recurrence rate was lower in the study group. A larger, prospective, double-blind, randomized, multicentre study is needed to support our findings., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Objectives: To determine the frequencies and clonal distributions of putative genetic determinants of resistance to antimicrobials applied for treatment of Clostridioides difficile infection (CDI), as documented in the genomic record., Methods: We scanned 26 557 C. difficile genome sequences publicly available from the EnteroBase platform for plasmids, point mutations and gene truncations previously reported to reduce susceptibility to vancomycin, fidaxomicin or metronidazole, respectively. We measured the antimicrobial susceptibility of 143 selected C. difficile isolates., Results: The frequency of mutations causing reduced susceptibility to vancomycin and metronidazole, respectively, increased strongly after 2000, peaking at up to 52% of all sequenced C. difficile genomes. However, both mutations declined sharply more recently, reflecting major changes in CDI epidemiology. We detected mutations associated with fidaxomicin resistance in several major genotypes, but found no evidence of international spread of resistant clones. The pCD-METRO plasmid, conferring metronidazole resistance, was detected in a single previously unreported C. difficile isolate, recovered from a hospital patient in Germany in 2008. The pX18-498 plasmid, putatively associated with decreased vancomycin susceptibility, was confined to related, recent isolates from the USA. Phenotype measurements confirmed that most of those genetic features were useful predictors of antibiotic susceptibility, even though ranges of MICs typically overlapped among isolates with and without specific mutations., Conclusions: Genomic data suggested that resistance to therapeutic antimicrobial drugs is rare in C. difficile. Public antimicrobial resistance marker databases were not equipped to detect most of the genetic determinants relevant to antibiotic therapy of CDI., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy.)

Clostridioides difficile infection (CDI) is associated with substantial morbidity and mortality. This study described outcomes associated with mandatory infectious diseases (ID) consultation in hospitalized patients with CDI. ID consultation was associated with increased appropriate concomitant antibiotic use, however longer courses of concomitant antibiotics were administered.

Clostridium paraputrificum bacteremia is very rare, and its clinical importance is poorly understood. An 86-year-old man was receiving lascufloxacin therapy for acute pharyngolaryngitis before presenting to our emergency department with a recurrent fever. Two sets of blood cultures on admission revealed C. paraputrificum. A stool culture showed a reduced presence of intestinal commensal bacteria. After admission, the patient's fever resolved without antibiotics. Colonoscopy revealed a rectal tumor. Rectal tumor and microbial substitutions caused by antibiotics may have led to bacteremia. When treating C. paraputrificum bacteremia, physicians should be mindful of coexisting gastrointestinal disorders and a history of antibiotic administration.

Infections caused by Gram-negative pathogens are increasingly prevalent and are typically treated with broad-spectrum antibiotics, resulting in disruption of the gut microbiome and susceptibility to secondary infections 1-3 . There is a critical need for antibiotics that are selective both for Gram-negative bacteria over Gram-positive bacteria, as well as for pathogenic bacteria over commensal bacteria. Here we report the design and discovery of lolamicin, a Gram-negative-specific antibiotic targeting the lipoprotein transport system. Lolamicin has activity against a panel of more than 130 multidrug-resistant clinical isolates, shows efficacy in multiple mouse models of acute pneumonia and septicaemia infection, and spares the gut microbiome in mice, preventing secondary infection with Clostridioides difficile. The selective killing of pathogenic Gram-negative bacteria by lolamicin is a consequence of low sequence homology for the target in pathogenic bacteria versus commensals; this doubly selective strategy can be a blueprint for the development of other microbiome-sparing antibiotics., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: There is a paucity of data guiding treatment duration of oral vancomycin for Clostridiodes difficile infection (CDI) in patients requiring concomitant systemic antibiotics., Objectives: To evaluate prescribing practices of vancomycin for CDI in patients that required concurrent systemic antibiotics and to determine whether a prolonged duration of vancomycin (>14 days), compared to a standard duration (10-14 days), decreased CDI recurrence., Methods: In this retrospective cohort study, we evaluated adult hospitalized patients with an initial episode of CDI who were treated with vancomycin and who received overlapping systemic antibiotics for >72 hours. Outcomes of interest included CDI recurrence and isolation of vancomycin-resistant Enterococcus (VRE)., Results: Among the 218 patients included, 36% received a standard duration and 64% received a prolonged duration of treatment for a median of 13 days (11-14) and 20 days (16-26), respectively. Patients who received a prolonged duration had a longer median duration of systemic antibiotic overlap with vancomycin (11 vs 8 days; P < .001) and significantly more carbapenem use and infectious disease consultation. Recurrence at 8 weeks (12% standard duration vs 8% prolonged duration; P = .367), recurrence at 6 months (15% standard duration vs 10% prolonged duration; P = .240), and VRE isolation (3% standard duration vs 9% prolonged duration; P = .083) were not significantly different between groups. Discontinuation of vancomycin prior to completion of antibiotics was an independent predictor of 8-week recurrence on multivariable logistic regression (OR, 4.8; 95% CI, 1.3-18.1)., Conclusions: Oral vancomycin prescribing relative to the systemic antibiotic end date may affect CDI recurrence to a greater extent than total vancomycin duration alone. Further studies are needed to confirm these findings.

Background: Clostridioides difficile is the most common cause of healthcare-associated infection, and severe cases can result in significant complications. While anti-microbial therapy is central to infection management, adjunctive therapies may be utilised as preventative strategies., Aim: This article aims to review updates in the epidemiology, diagnosis, and management, including treatment and prevention, of C. difficile infections., Methods: A narrative review was performed to evaluate the current literature between 1986 and 2023., Results: The incidence of C. difficile infection remains significantly high in both hospital and community settings, though with an overall decline in recent years and similar surveillance estimates globally. Vancomycin and fidaxomicin remain the first line antibiotics for treatment of non-severe C. difficile infection, though due to lower recurrence rates, infectious disease society guidelines now favour use of fidaxomicin. Faecal microbiota transplantation should still be considered to prevent recurrent C. difficile infection. However, in the past year the field has had a significant advancement with the approval of the first two live biotherapeutic products-faecal microbiota spores-live brpk, an oral capsule preparation, and faecal microbiota live-jslm-both indicated for the prevention of recurrent C. difficile infection, with additional therapies on the horizon., Conclusion: Although the prevalence of C. difficile infection remains high, there have been significant advances in the development of novel therapeutics and preventative measures following changes in recent practice guidelines, and will continue to evolve in the future., (© 2024 John Wiley & Sons Ltd.)

Purpose: Urinary tract infection (UTI) is the second most common indication for antibiotic therapy among inpatients in the United States. Ceftriaxone, a third-generation cephalosporin, is habitually chosen to treat inpatient UTIs due to familiarity, cost, and perceived safety. However, third-generation cephalosporins increase the risk of health care facility-onset Clostridioides difficile infection (HOCDI) more than any other antibiotic group, while no statistical risk exists for first-generation cephalosporins. Recent evidence comparing Enterobacterales susceptibility for first- and third-generation cephalosporins in urinary specimens in the United States is limited. This analysis assessed the comparative activity of cefazolin and ceftriaxone for Enterobacterales urinary isolates and incidence of HOCDI to determine the usefulness of cefazolin as an empirical agent to manage inpatient UTI and limit ceftriaxone collateral damage., Methods: This was a retrospective single-center observational study. Microbiologic susceptibility data were analyzed for Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis urinary specimens taken from adult inpatients admitted from January 1, 2022, to December 31, 2022. Primary outcome was incidence of E coli, K pneumoniae, and P mirabilis susceptibility to cefazolin in uncomplicated UTI (MIC <16 µg/mL). Secondary outcomes include susceptibility for complicated UTI and HOCDI risk associated with cefazolin and ceftriaxone., Findings: A total of 1150 urine samples were identified as E coli, K pneumoniae, and P mirabilis in 2022. Susceptibility to cefazolin was observed in 1064 (92.5%) of 1150 isolates using the MIC breakpoint for uncomplicated UTI and to ceftriaxone in 1115 (97.0%) of 1150 isolates (P < 0.001). From 2016 to 2022, either cefazolin or ceftriaxone was administered in 26,462 inpatient admissions, with HOCDI diagnoses occurring in 89 admissions. HOCDI developed in 78 admissions (0.40%) with ceftriaxone exposure, and 11 cases (0.15%) developed in cefazolin-exposed admissions (adjusted odds ratio, 2.44; 95% CI, 1.25-4.76; P < 0.001)., Implications: Cefazolin exhibits high susceptibility for uropathogens commonly implicated in cases of uncomplicated UTI, the most common UTI diagnosis among inpatients. Although ceftriaxone shows a higher susceptibility rate against these common uropathogens, it more than doubles the risk for HOCDI compared with cefazolin. For institutions evaluating opportunities to reduce ceftriaxone use to limit associated collateral damage such as HOCDI, use of cefazolin for uncomplicated UTI may be evaluated by using local susceptibility data., Competing Interests: Declaration of competing interest None declared., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The emerging antibiotic resistance has been named by the World Health Organization (WHO) as one of the top 10 threats to public health. Notably, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecalis (VREF) are designated as serious threats, whereas Clostridioides difficile (C. difficile) is recognized as one of the most urgent threats to human health and unmet medical need. Herein, they report the design and application of novel biodegradable polymers - the lipidated antimicrobial guanidinylate polycarbonates. These polymers showed potent antimicrobial activity against a panel of bacteria with fast-killing kinetics and low resistance development tendency, mainly due to their bacterial membrane disruption mechanism. More importantly, the optimal polymer showed excellent antibacterial activity against C. difficile infection (CDI) in vivo via oral administration. In addition, compared with vancomycin, the polymer demonstrated a much-prolonged therapeutic effect and virtually diminished recurrence rate of CDI. The convenient synthesis, easy scale-up, low cost, as well as biodegradability of this class of polycarbonates, together with their in vitro broad-spectrum antimicrobial activity and orally in vivo efficacy against CDI, suggest the great potential of lipidated guandinylate polycarbonates as a new class of antibacterial biomaterials to treat CDI and combat emerging antibiotic resistance., (© 2024 Wiley‐VCH GmbH.)

Clostridioides difficile , a Gram-positive anaerobic bacterium, is the leading cause of hospital-acquired antibiotic-associated diarrhea worldwide. The severity of C. difficile infection (CDI) varies, ranging from mild diarrhea to life-threatening conditions such as pseudomembranous colitis and toxic megacolon. Central to the pathogenesis of the infection are toxins produced by C. difficile , with toxin A (TcdA) and toxin B (TcdB) as the main virulence factors. Additionally, some strains produce a third toxin known as C. difficile transferase (CDT). Toxins damage the colonic epithelium, initiating a cascade of cellular events that lead to inflammation, fluid secretion, and further tissue damage within the colon. Mechanistically, the toxins bind to cell surface receptors, internalize, and then inactivate GTPase proteins, disrupting the organization of the cytoskeleton and affecting various Rho-dependent cellular processes. This results in a loss of epithelial barrier functions and the induction of cell death. The third toxin, CDT, however, functions as a binary actin-ADP-ribosylating toxin, causing actin depolymerization and inducing the formation of microtubule-based protrusions. In this review, we summarize our current understanding of the interaction between C. difficile toxins and host cells, elucidating the functional consequences of their actions. Furthermore, we will outline how this knowledge forms the basis for developing innovative, toxin-based strategies for treating and preventing CDI.

Aim: Our antimicrobial guidelines (AGs) were changed in 2021 to recommend once-daily ceftriaxone in place of three-times-daily cefuroxime as preferred cephalosporin. This analysis sought to assess the effects of this on incidence of Clostridioides difficile infection (CDI), third-generation cephalosporin-resistant Enterobacterales (3GCR-E) and resource utilisation., Method: Before and after analysis of 30-day CDI and 3GCR-E incidence following receipt of cefuroxime/ceftriaxone pre- and post-AG change. Total nursing time and waste production relating to cefuroxime/ceftriaxone delivery were calculated pre- and post-change., Results: CDI incidence was 0.6% pre- and 1.0% post-change (adjusted odds ratio [aOR] 1.44, p=0.07) and 3GCR-E incidence 3.5% and 3.1% (aOR 0.90, p=0.33). Mean per-quarter estimated nursing administration time decreased from 2,065 to 1,163 hours (902 nurse-hour reduction) and antibiotic-related waste generation from 1,131kg to 748kg (383kg reduction). Overall days of therapy per-quarter of cefuroxime/ceftriaxone were unchanged between periods., Conclusion: This simplification of our AG from a three-times-daily to a once-daily antibiotic resulted in considerable savings for our hospital (roughly 1.7 full-time equivalent nurses and over a tonne of waste yearly), with no significant increases in CDI or 3GCR-E. The impact of dosing schedules on non-antibiotic-spectrum factors, such as nursing time and resource usage, is worthy of consideration when designing AGs., Competing Interests: The authors have no conflicts of interest to declare. This work was supported by internal departmental funds., (© PMA.)

Background: Active surveillance pharmacovigilance is an emerging approach to identify medications with unanticipated effects. We previously developed a framework called pharmacopeia-wide association studies (PharmWAS) that limits false positive medication associations through high-dimensional confounding adjustment and set enrichment. We aimed to assess the transportability and generalizability of the PharmWAS framework by using medical claims data to reproduce known medication associations with Clostridioides difficile infection (CDI) or gastrointestinal bleeding (GIB)., Methods: We conducted case-control studies using Optum's de-identified Clinformatics Data Mart Database of individuals enrolled in large commercial and Medicare Advantage health plans in the United States. Individuals with CDI (from 2010 to 2015) or GIB (from 2010 to 2021) were matched to controls by age and sex. We identified all medications utilized prior to diagnosis and analysed the association of each with CDI or GIB using conditional logistic regression adjusted for risk factors for the outcome and a high-dimensional propensity score., Findings: For the CDI study, we identified 55,137 cases, 220,543 controls, and 290 medications to analyse. Antibiotics with Gram-negative spectrum, including ciprofloxacin (aOR 2.83), ceftriaxone (aOR 2.65), and levofloxacin (aOR 1.60), were strongly associated. For the GIB study, we identified 450,315 cases, 1,801,260 controls, and 354 medications to analyse. Antiplatelets, anticoagulants, and non-steroidal anti-inflammatory drugs, including ticagrelor (aOR 2.81), naproxen (aOR 1.87), and rivaroxaban (aOR 1.31), were strongly associated., Interpretation: These studies demonstrate the generalizability and transportability of the PharmWAS pharmacovigilance framework. With additional validation, PharmWAS could complement traditional passive surveillance systems to identify medications that unexpectedly provoke or prevent high-impact conditions., Funding: U.S. National Institute of Diabetes and Digestive and Kidney Diseases., Competing Interests: Declaration of interests RKV and WFG are employees of the Department of Veterans Affairs in the United States. This research does not necessarily represent the views of Department of Veterans Affairs or the United States Government. ARB, RF: No relevant disclosures. SDR: Co-Investigator on NIH grant R01-HS027985 from the National Institutes of Health (the funder of this research). RES: Research support from Exact Sciences, Immunovia, and Freenome not related to this research. JDL: Consulted for AbbVie, Merck, Scipher Medicine, Eli Lilly. Served on advisory board for Amgen, Arena Pharmaceuticals, Galapagos, Gilead, Janssen Pharmaceuticals, Pfizer, Protagonist Therapeutics, and Sanofi. He has had research funding from Nestle Health Science, Takeda, Janssen Pharmaceuticals, and AbbVie. He has performed legal work on behalf of generic manufacturers of ranitidine, including L. Perrigo Company, Glenmark Pharmaceuticals Inc., Amneal Pharmaceuticals LLC, Aurobindo Pharma USA, Inc., Dr. Reddy’s Laboratories, Inc., Novitium Pharma, Ranbaxy Inc. and Sun Pharmaceutical Industries, Inc., Strides Pharma, Inc., and Wockhardt USA LLC. He owns stock in Dark Canyon Labs. He has received honoraria from Nestle Health Science, and Celgene., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Vancomycin (VAN) and metronidazole (MTR) remain the current drugs of choice for the treatment of non-severe Clostridioides difficile infection (CDI); however, while their co-administration has appeared in clinical treatment, the efficacy varies greatly and the mechanism is unknown. In this study, a CDI mouse model was constructed to evaluate the therapeutic effects of VAN and MTR alone or in combination. For a perspective on the intestinal ecology, 16S rRNA amplicon sequencing and non-targeted metabolomics techniques were used to investigate changes in the fecal microbiota and metabolome of mice under the co-administration treatment. As a result, the survival rate of mice under co-administration was not dramatically different compared to that of single antibiotics, and the former caused intestinal tissue hyperplasia and edema. Co-administration also significantly enhanced the activity of amino acid metabolic pathways represented by phenylalanine, arginine, proline, and histidine, decreased the level of deoxycholic acid (DCA), and downregulated the abundance of beneficial microbes, such as Bifidobacterium and Akkermansia . VAN plays a dominant role in microbiota regulation in co-administration. In addition, co-administration reduced or increased the relative abundance of antibiotic-sensitive bacteria, including beneficial and harmful microbes, without a difference. Taken together, there are some risks associated with the co-administration of VAN and MTR, and this combination mode should be used with caution in CDI treatment.

Purpose: The clinical significance of negative toxin enzyme immunoassays (EIA) for Clostridioides difficile infections (CDIs) is unclear. Our study aimed to investigate the significance of toxin EIA-negative in the diagnosis and prognosis of CDI., Methods: All stool specimens submitted for C. difficile toxin EIA testing were cultured to isolate C. difficile. In-house PCR for tcdA, tcdB, cdtA, and cdtB genes were performed using C. difficile isolates. Stool specimens were tested with C. difficile toxins A and B using EIA kit (RIDASCREEN Clostridium difficile toxin A/B, R-Biopharm AG, Darmstadt, Germany). Characteristics and subsequent CDI episodes of toxin EIA-negative and -positive patients were compared., Results: Among 190 C. difficile PCR-positive patients, 83 (43.7%) were toxin EIA-negative. Multivariate analysis revealed independent associations toxin EIA-negative results and shorter hospital stays (OR = 0.98, 95% CI 0.96-0.99, p = 0.013) and less high-risk antibiotic exposure in the preceding month (OR = 0.38, 95% CI 0.16-0.94, p = 0.035). Toxin EIA-negative patients displayed a significantly lower white blood cell count rate (11.0 vs. 35.4%, p < 0.001). Among the 54 patients who were toxin EIA-negative and did not receive CDI treatment, three (5.6%) were diagnosed with CDI after 7-21 days without complication., Conclusion: Our study demonstrates that toxin EIA-negative patients had milder laboratory findings and no complications, despite not receiving treatment. Prolonged hospitalisation and exposure to high-risk antibiotics could potentially serve as markers for the development of toxin EIA-positive CDI., (© 2024. The Author(s).)

Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

Background: Current models for predicting Clostridioides difficile infection (CDI) recurrence rates have a limited capacity to account for important risk factors. This study developed a clinical prediction rule for CDI recurrence., Methods: This retrospective cohort study evaluated 209 patients with CDI at a university hospital in Japan. Logistic regression and receiver operating characteristic curve analyses were performed to identify potential predictors (age, sex, underlying diseases, antibiotic use, acid suppressants, immunosuppressants, CDI history) of CDI recurrence., Results: Forty-five patients developed recurrent CDI. Univariate analyses identified several significant recurrence predictors (enteral feeding, inflammatory bowel diseases [IBD], community-onset CDI, severe CDI). Enteral feeding (odds ratio: 3.87, 95% confidence interval: 1.75-8.56) and IBD (odds ratio: 7.08, 95% confidence interval: 1.28-39.06) were significant factors in the multivariate analysis. The CHIEF predictive scoring system was developed using 5 relevant variables (carbapenem use, hematologic malignancy, IBD, enteral feeding, fluoroquinolone use); the area under the receiver operating characteristic curve for the CHIEF score was 0.70., Discussion: The CHIEF score incorporates useful, clinically available factors and could help identify patients at risk of recurrent CDI., Conclusions: These findings contribute to the understanding of risk factors associated with CDI recurrence and provide support for the development of prevention strategies., (Copyright © 2023. Published by Elsevier Inc.)

Background: The clinical burden of Clostridioides difficile infections (CDIs) remains substantial globally. This study aimed to investigate the ribotypes (RTs) and antimicrobial susceptibility of C. difficile isolates collected in Taiwan., Methods: C. difficile isolates were prospectively collected from four medical centers in Taiwan from 2019 to 2021. In a reference laboratory, in vitro susceptibility to clindamycin, moxifloxacin, metronidazole, vancomycin, fidaxomicin, and rifaximin were tested, and ribotyping was conducted to determine their genetic diversity., Results: A total of 568 C. difficile isolates were included. Metronidazole resistance was not observed, and the susceptibility rate of vancomycin was 99.5 %. Clindamycin showed poor activity against these isolates, with a resistance rate of 74.8 %. Fidaxomicin exhibited potent activity and 97.4 % of isolates were inhibited at 0.25 μg/mL. Rifaximin MIC 90 increased from 0.015 μg/mL in 2019 to 0.03 μg/mL in 2020 and 2021. Of 40 RTs identified, two predominant RTs were RT 078/126 (78, 14 %) and 014/020 (76, 13 %). RT 017, traditional harboring truncated tcdA, accounted for 3 % (20 isolates) and there was no isolate belonging to RT 027. The proportions of RT 078 increased from 11.2 % in 2019 to 17.1 % in 2021, and the predominance of RT 078/126 was more evident in central Taiwan., Conclusions: Vancomycin, fidaxomicin, and metronidazole remain in vitro effective against clinical C. difficile isolates in Taiwan. The reservoirs and genetic relatedness of two major RTs with zoonotic potentials, RT 078/126 and 014/020, warrant further investigations., (Copyright © 2023. Published by Elsevier B.V.)