Reducing Recurrence of C. difficile Infection.

Clostridium difficile infection (CDI) is facilitated by alteration of the microbiome following antibiotic administration. Antimicrobial therapy directed against the pathogen can treat CDI. Unfortunately, ∼20% of successfully treated patients will suffer recurrence. Bezlotoxumab, a human monoclonal antibody, binds to C. difficile toxin B (TcdB), reducing recurrence presumably by limiting epithelial damage and facilitating microbiome recovery.

Long-term Safety of Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection.

BACKGROUND: Fecal microbiota transplantation (FMT) is highly effective for treating recurrent Clostridioides difficile infection (CDI), with emerging data on intermediate and long-term safety. METHODS: A prospective survey-based study was conducted (September 2012-June 2018) in patients undergoing FMT for recurrent CDI. Data on demographics and comorbidities were abstracted from medical records. Patients were contacted at 1 week, 1 month, 6 months, 1 year (short-term), and ≥2 years post-FMT (long-term). Symptoms and new medical diagnoses were recorded at each time point. Data were weighted to account for survey nonresponse bias. Multivariate logistic regression models for adverse events were built using age (per 10-year increment), sex, time of survey, and comorbidities. P < .05 was considered statistically significant. RESULTS: Overall, 609 patients underwent FMT; median age was 56 years (range, 18-94), 64.8% were women, 22.8% had inflammatory bowel disease (IBD). At short-term follow-up (n = 609), >60% of patients had diarrhea and 19%-33% had constipation. At 1 year, 9.5% reported additional CDI episodes. On multivariable analysis, patients with IBD, dialysis-dependent kidney disease, and multiple FMTs had higher risk of diarrhea; risk of constipation was higher in women and lower in IBD (all P < .05). For long-term follow-up (n = 447), median time of follow-up was 3.7 years (range, 2.0-6.8). Overall, 73 new diagnoses were reported: 13% gastrointestinal, 10% weight gain, 11.8% new infections (all deemed unrelated to FMT). Median time to infections was 29 months (range, 0-73) post-FMT. CONCLUSION: FMT appears safe with low risk of transmission of infections. Several new diagnoses were reported, which should be explored in future studies.

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

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

[Severe pseudomembranous colitis in patients with previous coronavirus infection]. / Psevdomembranoznyi kolit na fone perenesennoi koronavirusnoi infektsii.

OBJECTIVE: To analyze treatment outcomes in patients with severe pseudomembranous colitis and previous coronavirus infection. MATERIAL AND METHODS: We retrospectively analyzed treatment outcomes, clinical, laboratory and histological data in convalescents of COVID-19 who admitted to the department of coloproctology for moderate-to-severe pseudomembranous colitis confirmed by endoscopic examination between 2020 and 2021. RESULTS: There were 13 patients with moderate pseudomembranous colitis and 6 ones with severe pseudomembranous colitis. Mean period after recovery from coronavirus infection was 19 days. Endoscopy revealed whitish-yellow or gray raised plaques on colonic mucosa in all cases. Four patients with signs of peritonitis underwent emergency surgery. Three patients had perforation of caecum; one patient had perforation of sigmoid colon and widespread peritonitis. Two patients underwent urgent surgery for progressive toxic megacolon and ineffective therapy. Subtotal colectomy and ileostomy were performed in all cases. Histological examination revealed necrosis of not only superficial layer of colon mucosa typical for clostridial colitis, but also the entire thickness of mucosa, as well as submucosal and partially muscular layers in some cases. Mucosal crypt atrophy, fibrinoid effusion in muscular layer, diffuse polymorphonuclear cell infiltration and necrosis of muscular and submucosal nerve plexuses, as well as necrosis of vascular walls with deposition of hyaline-like structures characterize microcirculatory ischemic processes in the colon wall. CONCLUSION: Severe pseudomembranous colitis associated with COVID-19 may not be associated with clostridial infection. Further analysis of possible ischemic etiology and pathogenesis of gastrointestinal lesions in COVID-19 is needed for preventive and therapeutic measures.

Proton-Pump Inhibitor Use and the Risk of Community-Associated Clostridium difficile Infection.

BACKGROUND: Proton-pump inhibitors (PPIs) have been reported to increase the risk of community-associated Clostridium difficile infection (CDI), but the association remains disputed. METHODS: A nationwide cohort study among adults in Denmark, 2010-2013, linking register data on C. difficile testing, filled prescriptions, and patient characteristics. All incident episodes of community-associated CDI (ie, positive culture, molecular assay, or toxin test in individuals without previous hospitalization in the prior 12 weeks and without a positive test for C. difficile in the prior 8 weeks) were identified in the Danish National Microbiological Database. Self-controlled case-series analyses were used to estimate incidence rate ratios (IRRs) for community-associated CDI, comparing periods with and without exposure to PPIs. By design, models took fixed confounders such as chronic disease, genetics, and socioeconomic status into account; further, time-varying confounders, including hospital stay and antibiotic and corticosteroid use were adjusted for. RESULTS: 3583 episodes of community-associated CDI were identified, of which 964 occurred during current use of PPIs, 324 occurred 0-6 months after treatment cessation, 123 occurred 6-12 months after treatment cessation, and 2172 occurred during time periods without use of PPIs. The adjusted IRR was 2.03 (95% confidence interval, 1.74-2.36), comparing use of PPI with nonuse. The increased risk remained elevated in later time periods: 1.54 (1.31-1.80) for 0-6 months, 1.24 (1.00-1.53) for 6-12 months after current use. CONCLUSIONS: Use of PPIs was associated with moderately increased risk of community-associated CDI. The risk remained elevated up to 1 year after PPI treatment had ended.

Cytomegalovirus-associated pseudomembranous colitis in a kidney transplant recipient.

Pseudomembranous colitis (PMC) is classically associated with Clostridium difficile infection. We report a rare case of cytomegalovirus (CMV)-associated PMC in a 52-year-old female patient who had undergone kidney transplantation more than 20 years ago and was on low dose prednisolone and ciclosporin. She presented with an acute history of fever, lethargy, vomiting and diarrhoea on admission. Computed tomography of the abdomen showed extensive colitis, and colonoscopy revealed extensive pseudomembrane formation. Multiple tests for Clostridium difficile and other common microbiological causes of colitis were negative. CMV DNAemia and colonic biopsies confirmed the diagnosis of CMV colitis. The patient responded to prompt CMV treatment, as demonstrated by clinical, endoscopic, and histological response. While CMV is a common pathogen in the solid organ transplant population that is familiar to most transplant physicians, it may present atypically as PMC. Here, we review the literature on CMV-associated PMC and its relevance to solid organ transplant recipients. To our knowledge, this is the first reported case of CMV-associated PMC in a kidney transplant recipient.

Characterization of an Endolysin Targeting Clostridioides difficile That Affects Spore Outgrowth.

Clostridioides difficile is a spore-forming enteric pathogen causing life-threatening diarrhoea and colitis. Microbial disruption caused by antibiotics has been linked with susceptibility to, and transmission and relapse of, C. difficile infection. Therefore, there is an urgent need for novel therapeutics that are effective in preventing C. difficile growth, spore germination, and outgrowth. In recent years bacteriophage-derived endolysins and their derivatives show promise as a novel class of antibacterial agents. In this study, we recombinantly expressed and characterized a cell wall hydrolase (CWH) lysin from C. difficile phage, phiMMP01. The full-length CWH displayed lytic activity against selected C. difficile strains. However, removing the N-terminal cell wall binding domain, creating CWH351-656, resulted in increased and/or an expanded lytic spectrum of activity. C. difficile specificity was retained versus commensal clostridia and other bacterial species. As expected, the putative cell wall binding domain, CWH1-350, was completely inactive. We also observe the effect of CWH351-656 on preventing C. difficile spore outgrowth. Our results suggest that CWH351-656 has therapeutic potential as an antimicrobial agent against C. difficile infection.

The Importance of Therapeutically Targeting the Binary Toxin from Clostridioides difficile.

Novel therapeutics are needed to treat pathologies associated with the Clostridioides difficile binary toxin (CDT), particularly when C. difficile infection (CDI) occurs in the elderly or in hospitalized patients having illnesses, in addition to CDI, such as cancer. While therapies are available to block toxicities associated with the large clostridial toxins (TcdA and TcdB) in this nosocomial disease, nothing is available yet to treat toxicities arising from strains of CDI having the binary toxin. Like other binary toxins, the active CDTa catalytic subunit of CDT is delivered into host cells together with an oligomeric assembly of CDTb subunits via host cell receptor-mediated endocytosis. Once CDT arrives in the host cell's cytoplasm, CDTa catalyzes the ADP-ribosylation of G-actin leading to degradation of the cytoskeleton and rapid cell death. Although a detailed molecular mechanism for CDT entry and host cell toxicity is not yet fully established, structural and functional resemblances to other binary toxins are described. Additionally, unique conformational assemblies of individual CDT components are highlighted herein to refine our mechanistic understanding of this deadly toxin as is needed to develop effective new therapeutic strategies for treating some of the most hypervirulent and lethal strains of CDT-containing strains of CDI.

Unique Clindamycin-Resistant Clostridioides difficile Strain Related to Fluoroquinolone-Resistant Epidemic BI/RT027 Strain.

During a surveillance study of patients in a long-term care facility and the affiliated acute care hospital in the United States, we identified a Clostridioides difficile strain related to the epidemic PCR ribotype (RT) 027 strain associated with hospital outbreaks of severe disease. Fifteen patients were infected with this strain, characterized as restriction endonuclease analysis group DQ and RT591. Like RT027, DQ/RT591 contained genes for toxin B and binary toxin CDT and a tcdC gene of identical sequence. Whole-genome sequencing and multilocus sequence typing showed that DQ/RT591 is a member of the same multilocus sequence typing clade 2 as RT027 but in a separate cluster. DQ/RT591 produced a similar cytopathic effect as RT027 but showed delayed toxin production in vitro. DQ/RT591 was susceptible to moxifloxacin but highly resistant to clindamycin. Continued surveillance is warranted for this clindamycin-resistant strain that is related to the fluoroquinolone-resistant epidemic RT027 strain.

Clostridioides difficile-Associated Antibiotics Alter Human Mucosal Barrier Functions by Microbiome-Independent Mechanisms.

A clinically relevant risk factor for Clostridioides difficile-associated disease (CDAD) is recent antibiotic treatment. Although broad-spectrum antibiotics have been shown to disrupt the structure of the gut microbiota, some antibiotics appear to increase CDAD risk without being highly active against intestinal anaerobes, suggesting direct nonantimicrobial effects. We examined cell biological effects of antibiotic exposure that may be involved in bacterial pathogenesis using an in vitro germfree human colon epithelial culture model. We found a marked loss of mucosal barrier and immune function with exposure to the CDAD-associated antibiotics clindamycin and ciprofloxacin, distinct from the results of pretreatment with an antibiotic unassociated with CDAD, tigecycline, which did not reduce innate immune or mucosal barrier functions. Importantly, pretreatment with CDAD-associated antibiotics sensitized mucosal barriers to C. difficile toxin activity in primary cell-derived enteroid monolayers. These data implicate commensal-independent gut mucosal barrier changes in the increased risk of CDAD with specific antibiotics and warrant further studies in in vivo systems. We anticipate this work to suggest potential avenues of research for host-directed treatment and preventive therapies for CDAD.

Use of carbapenems and glycopeptides increases risk for Clostridioides difficile infections in acute myeloid leukemia patients undergoing intensive induction chemotherapy.

Patients with acute myeloid leukemia (AML) are often exposed to broad-spectrum antibiotics and thus at high risk of Clostridioides difficile infections (CDI). As bacterial infections are a common cause for treatment-related mortality in these patients, we conducted a retrospective study to analyze the incidence of CDI and to evaluate risk factors for CDI in a large uniformly treated AML cohort. A total of 415 AML patients undergoing intensive induction chemotherapy between 2007 and 2019 were included in this retrospective analysis. Patients presenting with diarrhea and positive stool testing for toxin-producing Clostridioides difficile were defined to have CDI. CDI was diagnosed in 37 (8.9%) of 415 AML patients with decreasing CDI rates between 2013 and 2019 versus 2007 to 2012. Days with fever, exposition to carbapenems, and glycopeptides were significantly associated with CDI in AML patients. Clinical endpoints such as length of hospital stay, admission to ICU, response rates, and survival were not adversely affected. We identified febrile episodes and exposition to carbapenems and glycopeptides as risk factors for CDI in AML patients undergoing induction chemotherapy, thereby highlighting the importance of interdisciplinary antibiotic stewardship programs guiding treatment strategies in AML patients with infectious complications to carefully balance risks and benefits of anti-infective agents.

Relationship between faecal metronidazole and lactoferrin concentrations to clinical response of patients with Clostridioides difficile.

OBJECTIVES: We investigated patients with Clostridioides difficile-associated diarrhoea to see if clinical resolution correlated with faecal concentrations of metronidazole or markers of inflammation. METHODS: Faecal metronidazole, lactoferrin and serum CRP were measured daily. These were then compared with clinical progress. RESULTS: Metronidazole concentration correlated with lactoferrin (ρ = 0.17, p = 0.015), CRP (ρ = 0.23, p < 0.001) and number of diarrhoeal stools per day (ρ = 0.29, p < 0.001). Lactoferrin correlated with CRP (ρ = 0.57, p < 0.001) and the number of diarrhoeal stools per day (ρ = 0.52, p < 0.001) as did CRP (ρ = 0.52, p < 0.001). CONCLUSIONS: We found no association between cessation of diarrhoea and metronidazole or lactoferrin concentrations. There was a relationship between metronidazole concentrations and markers of inflammation and stool frequency.

Growing consumption of antibiotics and epidemiology of Clostridioides difficile infections in Poland: A need to develop new solutions.

Clostridioides (formerly Clostridium) difficile infections (CDIs) are becoming more common and more serious. C. difficile is the etiologic agent of antibiotic-associated diarrhea, pseudomembranous enterocolitis, and toxic megacolon while CDIs recur in 7.9% of patients. About 42.9 CDI cases/10,000 patient-days are diagnosed each day in Europe, whereas in Poland 5.6 CDI cases/10,000 patient-days are reported; however, the median for European countries is 2.9 CDI cases/10,000 patient-days. Epidemiology of CDIs has changed in recent years and risk of developing the disease has doubled in the past decade that is largely determined by use of antibiotics. Studies show that rate of antibiotic consumption in the non-hospital sector in Poland is much higher than the European average (27 vs. 21.8 DDD/1,000 patient-days), and this value has increased in recent years. Antibiotic consumption has also increased in the hospital sector, especially in the intensive care units - 1,520 DDD/1,000 patient-days (ranging from 620 to 3,960 DDD/1,000 patient-days) - and was significantly higher than in Germany 1,305 (ranging from 463 to 2,216 DDD/1,000 patient-days) or in Sweden 1,147 (ranging from 605 to 2,134 DDD/1,000 patient-days). The recent rise in CDI incidence has prompted a search for alternative treatments. Great hope is placed in probiotics, bacteriocins, monoclonal antibodies, bacteriophages, and developing new vaccines.

Ceragenin CSA13 Reduces Clostridium difficile Infection in Mice by Modulating the Intestinal Microbiome and Metabolites.

BACKGROUND & AIMS: Clostridium difficile induces intestinal inflammation by releasing toxins A and B. The antimicrobial compound cationic steroid antimicrobial 13 (CSA13) has been developed for treating gastrointestinal infections. The CSA13-Eudragit formulation can be given orally and releases CSA13 in the terminal ileum and colon. We investigated whether this form of CSA13 reduces C difficile infection (CDI) in mice. METHODS: C57BL/6J mice were infected with C difficile on day 0, followed by subcutaneous administration of pure CSA13 or oral administration of CSA13-Eudragit (10 mg/kg/d for 10 days). Some mice were given intraperitoneal vancomycin (50 mg/kg daily) on days 0-4 and relapse was measured after antibiotic withdrawal. The mice were monitored until day 20; colon and fecal samples were collected on day 3 for analysis. Blood samples were collected for flow cytometry analyses. Fecal pellets were collected each day from mice injected with CSA13 and analyzed by high-performance liquid chromatography or 16S sequencing; feces were also homogenized in phosphate-buffered saline and fed to mice with CDI via gavage. RESULTS: CDI of mice caused 60% mortality, significant bodyweight loss, and colonic damage 3 days after infection; these events were prevented by subcutaneous injection of CSA13 or oral administration CSA13-Eudragit. There was reduced relapse of CDI after administration of CSA13 was stopped. Levels of CSA13 in feces from mice given CSA13-Eudragit were significantly higher than those of mice given subcutaneous CSA13. Subcutaneous and oral CSA13 each significantly increased the abundance of Peptostreptococcaceae bacteria and reduced the abundance of C difficile in fecal samples of mice. When feces from mice with CDI and given CSA13 were fed to mice with CDI that had not received CSA13, the recipient mice had significantly increased rates of survival. CSA13 reduced fecal levels of inflammatory metabolites (endocannabinoids) and increased fecal levels of 4 protective metabolites (ie, citrulline, 3-aminoisobutyric acid, retinol, and ursodeoxycholic acid) in mice with CDI. Oral administration of these CSA13-dependent protective metabolites reduced the severity of CDI. CONCLUSIONS: In studies of mice, we found the CSA13-Eudragit formulation to be effective in eradicating CDI by modulating the intestinal microbiota and metabolites.

Clostridioides (Clostridium) difficile infection in hospitalized patients with antibiotic-associated diarrhea: A systematic review and meta-analysis.

Clostridium difficile is the main infectious cause of antibiotic associated diarrhea (AAD). The objective of this study was to determine the frequency of C. difficile AAD in hospitalized patients. We searched MEDLINE (Pubmed), Embase, Web of Science and Cochrane library for subject headings and text words related to C. difficile AAD. Studies that investigated the prevalence or frequency of C. difficile AAD in health care settings were considered eligible. Using a random-effects model, data obtained from the identified studies were combined. Of the 2464 citations identified, twenty studies (5496 patients) met the inclusion criteria of the present study. Pooling all studies, the frequency of C. difficile among AAD patients was 20.0% (95% CI 13.0-28.0). The most frequently used antibiotics in health care settings were the following: Clindamycin, fluoroquinolones and cephalosporins. The current systematic review demonstrated the significant presence of C. difficile among patients with AAD. The limited and rational use of broad spectrum antibiotics and implementation of standard infection control measures are recommended to reduce the risk of C. difficile associated infections in hospitalized patients.

Transmissibility of Clostridium difficile Without Contact Isolation: Results From a Prospective Observational Study With 451 Patients.

Background: Contact precautions are recommended by health authorities in Europe and the United States for patients with Clostridium difficile infection (CDI). Recently, the significance of nosocomial transmission has been challenged by screening on admission studies and whole-genome sequencing, providing evidence for an endogenous source of C. difficile. We discontinued contact precautions for patients with CDI, except for patients infected with hypervirulent ribotypes or with stool incontinence, to determine the rate of transmission. Methods: From January 2004 to December 2013, contacts of each index case with CDI were screened for toxigenic C. difficile by culturing rectal swabs. Transmission was defined as possible if toxigenic C. difficile was detected in contacts, as probable if the identical polymerase chain reaction ribotype was identified in index­contact pairs, and as confirmed if next-generation sequencing (NGS) revealed clonality of strains. Results: Four hundred fifty-one contacts were exposed to 279 index patients nursed in 2-to 4-bed rooms. Toxigenic C. difficile was detected in 6.0% (27/451) after a median contact time of 5 days. Identical ribotypes were identified in 6 index­contact pairs, accounting for probable transmission in 1.3% (6/451). NGS was performed for 4 of 6 pairs with identical strains, and confirmed transmission in 2 contact patients. Conclusions: The rate of transmission of toxigenic, predominantly nonhypervirulent C. difficile, was low and no outbreaks were recorded over a 10-year period after discontinuing contact precautions for patients with CDI who were not severely incontinent and who used dedicated toilets. As contact precautions may lead to lower levels of care, their implementation needs to be balanced against the risk of nosocomial transmission.

Expert Consensus on Metrics to Assess the Impact of Patient-Level Antimicrobial Stewardship Interventions in Acute-Care Settings.

Antimicrobial stewardship programs (ASPs) positively impact patient care, but metrics to assess ASP impact are poorly defined. We used a modified Delphi approach to select relevant metrics for assessing patient-level interventions in acute-care settings for the purposes of internal program decision making. An expert panel rated 90 candidate metrics on a 9-point Likert scale for association with 4 criteria: improved antimicrobial prescribing, improved patient care, utility in targeting stewardship efforts, and feasibility in hospitals with electronic health records. Experts further refined, added, or removed metrics during structured teleconferences and re-rated the retained metrics. Six metrics were rated >6 in all criteria: 2 measures of Clostridium difficile incidence, incidence of drug-resistant pathogens, days of therapy over admissions, days of therapy over patient days, and redundant therapy events. Fourteen metrics rated >6 in all criteria except feasibility were identified as targets for future development.

Oral Vancomycin Followed by Fecal Transplantation Versus Tapering Oral Vancomycin Treatment for Recurrent Clostridium difficile Infection: An Open-Label, Randomized Controlled Trial.

BACKGROUND: Fecal transplantation (FT) is a promising treatment for recurrent Clostridium difficile infection (CDI), but its true effectiveness remains unknown. We compared 14 days of oral vancomycin followed by a single FT by enema with oral vancomycin taper (standard of care) in adult patients experiencing acute recurrence of CDI. METHODS: In a phase 2/3, single-center, open-label trial, participants from Ontario, Canada, experiencing recurrence of CDI were randomly assigned in a 1:1 ratio to 14 days of oral vancomycin treatment followed by a single 500-mL FT by enema, or a 6-week taper of oral vancomycin. Patients with significant immunocompromise, history of fulminant CDI, or irreversible bleeding disorders were excluded. The primary endpoint was CDI recurrence within 120 days. Microbiota analysis was performed on fecal filtrate from donors and stool samples from FT recipients, as available. RESULTS: The study was terminated at the interim analysis after randomizing 30 patients. Nine of 16 (56.2%) patients who received FT and 5 of 12 (41.7%) in the vancomycin taper group experienced recurrence of CDI, corresponding with symptom resolution in 43.8% and 58.3%, respectively. Fecal microbiota analysis of 3 successful FT recipients demonstrated increased diversity. A futility analysis did not support continuing the study. Adverse events were similar in both groups and uncommon. CONCLUSIONS: In patients experiencing an acute episode of recurrent CDI, a single FT by enema was not significantly different from oral vancomycin taper in reducing recurrent CDI. Further research is needed to explore optimal donor selection, FT preparation, route, timing, and number of administrations. CLINICAL TRIALS REGISTRATION: NCT01226992.