Heterogeneity in practices to reduce the risk of transmission of Clostridioides difficile in healthcare settings: a survey of ESCMID Study Group for Clostridioides difficile (ESGCD) members.

Clostridioides difficile is a leading cause of healthcare-associated infections. The main objective was to assess the current landscape of CDI infection prevention and control (IPC) practices. An anonymous survey of IPC practices for CDI was conducted between July 25 and October 31, 2022. Precautions for symptomatic patients were applicable for 75.9% and were discontinued 48 h minimum after the resolution of diarrhea for 40.7% of respondents. Daily cleaning of CDI patients' rooms was reported by 23 (42.6%). There was unexpected heterogeneity in IPC practices regarding the hospital management of CDI.

The Impact of Universal Glove and Gown Use on Clostridioides Difficile Acquisition: A Cluster-Randomized Trial.

BACKGROUND: Clostridioides difficile is the most common cause of healthcare-associated infections in the United States. It is unknown whether universal gown and glove use in intensive care units (ICUs) decreases acquisition of C. difficile. METHODS: This was a secondary analysis of a cluster-randomized trial in 20 medical and surgical ICUs in 20 US hospitals from 4 January 2012 to 4 October 2012. After a baseline period, ICUs were randomized to standard practice for glove and gown use versus the intervention of all healthcare workers being required to wear gloves and gowns for all patient contact and when entering any patient room (contact precautions). The primary outcome was acquisition of toxigenic C. difficile determined by surveillance cultures collected on admission and discharge from the ICU. RESULTS: A total of 21 845 patients had both admission and discharge perianal swabs cultured for toxigenic C. difficile. On admission, 9.43% (2060/21 845) of patients were colonized with toxigenic C. difficile. No significant difference was observed in the rate of toxigenic C. difficile acquisition with universal gown and glove use. Differences in acquisition rates in the study period compared with the baseline period in control ICUs were 1.49 per 100 patient-days versus 1.68 per 100 patient-days in universal gown and glove ICUs (rate difference, -0.28; generalized linear mixed model, P = .091). CONCLUSIONS: Glove and gown use for all patient contact in medical and surgical ICUs did not result in a reduction in the acquisition of C. difficile compared with usual care. CLINICAL TRIALS REGISTRATION: NCT01318213.

In-vitro determination of inhibitory effects of probiotic strains on Clostridioides difficile.

Commercial probiotic strains inhibited C. difficile, and other Clostridium cultures with zones 14.2-78.9 mm. The highest inhibition was observed with commercial culture on C. difficile ATCC 700057. Organic acids were the leading cause of inhibition. Probiotic cultures may be used as a support culture or through fermented foods for treatment.

Systematic Review with Meta-Analysis: Fecal Microbiota Transplantation for Severe or Fulminant Clostridioides difficile.

BACKGROUND: Severe and fulminant Clostridioides difficile infection (CDI) is associated with significant morbidity and mortality. While fecal microbiota transplantation (FMT) has proved to be a highly effective treatment for recurrent CDI, its efficacy in severe or fulminant CDI remains uncertain. AIMS: To perform a systematic review with meta-analysis evaluating clinical outcomes and safety of FMT in severe and fulminant CDI. METHODS: A systemic review with meta-analysis was performed through comprehensive search of Embase, Medline (Ovid), trial registers, and conference abstracts through January 2020. Studies on FMT in severe and fulminant CDI were included. Meta-analysis was done with random effects models given heterogeneity to estimate rates of cure, mortality, and colectomy. Publication bias was assessed using Egger's test. RESULTS: Sixteen studies comprised of one randomized controlled trial, four cohort studies, and eleven case series were analyzed. In total, 676 patients underwent FMT for severe or fulminant CDI. The overall rate of clinical cure after single FMT was 61.3% (95% CI 43.2-78.0%) with 10.9% (95% CI 0.2-30.2%) of patients experiencing major adverse events. The overall pooled colectomy rate after FMT was 8.2% (95% CI 0.1-23.7%) with a pooled all-cause mortality rate after FMT of 15.6% (95% CI 7.8-25.0%). CONCLUSION: Low-quality data support the use of fecal microbiota transplantation in patients with severe and fulminant Clostridioides difficile infection.

Enhanced Clostridioides difficile Infection Prevention With a Pharmacy-Controlled Policy That Adds a 3-Strain Lactobacillus Probiotic Concomitantly to Antibiotic Therapy.

When 70% of antibiotic users took a 3-strain Lactobacillus probiotic preparation the hospital-wide rate of healthcare-associated Clostridioides difficile infection improved significantly. The incidence of C. difficile infection for those taking the probiotic along with multiple antibiotics or a single high-risk antibiotic was decreased by at least half.

RBX7455, a Non-frozen, Orally Administered Investigational Live Biotherapeutic, Is Safe, Effective, and Shifts Patients' Microbiomes in a Phase 1 Study for Recurrent Clostridioides difficile Infections.

BACKGROUND: Recurrent Clostridioides difficile infections (rCDI) are a global public health threat. To reduce rCDI, microbiota-restoring therapies are needed, particularly standardized, easy-to-administer formulations. METHODS: This phase I open-label trial assessed the safety, efficacy in preventing rCDI recurrence, and intestinal microbiome effects of RBX7455, a room temperature-stable, orally administered investigational live biotherapeutic. Adult participants with 1 or more prior episodes of rCDI received: 4 RBX7455 capsules twice daily for 4 days (group 1); 4 RBX7455 capsules twice daily for 2 days (group 2); or 2 RBX7455 capsules twice daily for 2 days (group 3). For all groups, the first dose was administered in clinic, with remaining doses self-administered at home. Adverse events were monitored during and for 6 months after treatment. Treatment success was defined as rCDI prevention through 8 weeks after treatment. Participants' microbiome composition was assessed prior to and for 6 months after treatment. RESULTS: Nine of 10 group 1 patients (90%), 8 of 10 group 2 patients (80%), and 10 of 10 group 3 patients (100%) were recurrence-free at the 8-week endpoint with durability to 6 months. Seventy-five treatment-emergent adverse events were observed in 27 participants with no serious investigational product-related events. Prior to treatment, participants' microbiomes were dissimilar from the RBX7455 composition with decreased Bacteroidia- and Clostridia-class bacteria, whereas after treatment, responders' microbiomes showed increased Bacteroidia and Clostridia. CONCLUSIONS: Three dosing regimens of RBX7455 were safe and effective at preventing rCDI. Responders' microbiomes converged toward the composition of RBX7455. These results support its continued clinical evaluation. CLINICAL TRIALS REGISTRATION: NCT02981316.

SER-109, an Investigational Microbiome Drug to Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial.

BACKGROUND: Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs. METHODS: In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile-positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed. RESULTS: 89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11-2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity. CONCLUSIONS: Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial. CLINICAL TRIALS REGISTRATION: NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4.

A Multicenter Evaluation of Probiotic Use for the Primary Prevention of Clostridioides difficile Infection.

BACKGROUND: Primary prevention of Clostridioides difficile infection (CDI) is a priority for hospitals. Probiotics have the potential to interfere with colonization and CDI. In this study, we evaluated the impact of a computerized clinical decision support (CCDS) tool to prescribe probiotics for primary prevention of CDI among adult hospitalized patients. METHODS: A CCDS tool was implemented into the electronic medical record at 4 hospitals to prompt prescription of a probiotic preparation at the time of antibiotic prescription in high-risk patients in May 2019. Interrupted time series using segmented regression analysis was conducted to evaluate hospital-wide CDI incidence for the year pre- and post-CCDS implementation. In addition, multivariable logistic regression was used to evaluate CDI incidence in patients who qualified for probiotics in the pre- vs post-intervention periods, adjusting for potential confounders. To adjust for potential differences in patients who received probiotics in the post-intervention period, propensity score-matched pairs were developed to evaluate CDI risk by receipt of probiotics. RESULTS: Quarterly CDI incidence increased over time post-intervention relative to baseline trends (slope change, 1.4; 95% confidence interval [CI], .9-1.9). The odds ratio (OR) of CDI was 1.41 in eligible patients post-intervention compared with pre-intervention (adjusted OR, 1.41; 95% CI, 1.11-1.79). Propensity score-matched analysis showed that patients who received probiotics did not have lower rates of CDI compared with those who did not receive probiotics (OR, 1.46; 95% CI, .87-2.45). CONCLUSIONS: Use of probiotics for primary prevention of CDI among adult inpatients receiving antibiotics is not supported.

Risks and Preventive Strategies for Clostridioides difficile Transmission to Household or Community Contacts during Transition in Healthcare Settings.

The burden of Clostridioides difficile infection (CDI) has greatly increased. We evaluated the risks for CDI transmission to community members after hospitalized patients are discharged. We conducted a systematic literature review in MEDLINE/PubMed, EMBASE, CINAHL plus EBSCO, Web of Science, Cochrane Library, and gray literature during January 2000‒February 2019 and identified 4,798 citations were identified. We eliminated 4,554 citations through title and abstract screening; 217 additional citations did not meet full criteria. We reviewed texts for the 27 remaining articles qualitatively for internal/external validity. A few identified studies describing risks to community members lacked accurate risk measurement or preventative strategies. Primary data are needed to assess efficacy of and inform current expertise-driven CDI prevention practices. Raising awareness among providers and researchers, conducting clinical and health services research, linking up integrated monitoring and evaluation processes at hospitals and outpatient settings, and developing and integrating CDI surveillance systems are warranted.

Suggestions for the prevention of Clostridioides difficile spread within outpatient hemodialysis facilities.

Clostridioides difficile infections (CDIs) cause substantial morbidity and mortality. Patients on maintenance hemodialysis are 2 to 2.5 times more likely to develop CDI, with mortality rates 2-fold higher than the general population. Hospitalizations due to CDI among the maintenance hemodialysis population are high, and the frequency of antibiotic exposures and hospitalizations may contribute to CDI risk. In this report, a panel of experts in clinical nephrology, infectious diseases, and infection prevention provide guidance, based on expert opinion and published literature, aimed at preventing the spread of CDI in outpatient hemodialysis facilities.

Efficacy and Safety of Monoclonal Antibodies Against Clostridioides difficile Toxins for Prevention of Recurrent Clostridioides difficile Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: Clostridioides difficile infection is one of the most common health care-associated infections. To reduce the recurrent Clostridioides difficile infection (rCDI), monoclonal antibodies against Clostridioides difficile toxin A (actoxumab) and toxin B (bezlotoxumab) were developed. In the present study, we performed a systematic review and meta-analysis to assess their efficacy and safety. MATERIALS AND METHODS: An electronic database was searched for relevant randomized controlled trials assessing bezlotoxumab and/or actoxumab. Outcomes included rate of rCDI and adverse events including cardiovascular and gastrointestinal events. RESULTS: Four randomized controlled trials comparing antitoxin antibodies (n=1916) versus placebo (n=889) were identified. rCDI was significantly reduced by bezlotoxumab plus actoxumab (risk ratio=0.54, 95% confidence interval=0.41-0.70, P<0.001) and bezlotoxumab monotherapy (risk ratio=0.62, 95% confidence interval=0.51-0.76, P<0.001) compared with placebo. Subgroup analysis showed that bezlotoxumab plus actoxumab was remarkably preventive for patients with the following high-risk features: inpatients, vancomycin treatment, and BI/NAP/027 strain. Regarding safety, there was no difference in cardiovascular and gastrointestinal events as well as all-cause mortality between bezlotoxumab-treated patients and placebo. CONCLUSIONS: The results of our meta-analysis demonstrated the effectiveness and safety of bezlotoxumab for the prevention of rCDI. Bezlotoxumab may be a good therapeutic option for severe C. difficile infection rather than mild cases.

Updates and Challenges in Fecal Microbiota Transplantation for Clostridioides difficile Infection in Children.

ABSTRACT: Fecal microbiota transplantation (FMT) is currently the most effective but loosely regulated therapy, for recurrent Clostridioides difficile infection (rCDI) in pediatrics. Over the last 2 years, there have been mounting challenges in the ability to provide FMT to pediatric patients. Firstly, an Food and Drug Administration (FDA) safety alert in 2019 reported transmission of a multidrug resistant organism from FMT donor to recipient resulting in the death of 1 patient. Secondly, the coronavirus disease 2019 (COVID-19) pandemic induced further safety and regulatory challenges. Biotherapeutics are promising and more readily regulated treatment options for rCDI, which may replace FMT in the near future for adults upon regulatory agency approvals. Such approvals, however, are expected to be significantly delayed for children, raising concerns for limited access to effective treatment for children with rCDI. In this commentary, we discuss the recent challenges and future directions of FMT and microbial therapeutics in children with rCDI.

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

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

A Systematic Review of Fecal Microbiota Transplantation Versus Vancomycin for Treatment of Recurrent Clostridioides difficile Infection.

Clostridioides difficile infection is a major clinical challenge, which may be associated with severe complications. Clostridioides difficile infection may result in repeated episodes of diarrhea, abdominal pain, and dehydration, leading to an increased risk of mortality. Increasingly high rates of recurrent Clostridioides difficile-associated diarrhea, refractory to antibiotic therapy, are difficult to treat. The suboptimal response to antibiotic therapy has led to the need for fecal microbiota transplantation in addition to the more commonly prescribed antibiotic, vancomycin. This systematic review aims to evaluate the effectiveness of fecal microbiota transplantation in the resolution of recurrent Clostridioides difficile infection in adults, compared with an oral vancomycin regimen alone. A systematic literature search was performed, resulting in three randomized control studies. Results from the studies are conflicting, with different variations of study outcomes. In two of the three randomized control trials, fecal microbiota transplantation was statistically significant in effectively resolving Clostridioides difficile infection, but not significant in the third. Although fecal microbiota transplantation results are promising, there are many different variables within the studies, and further research is recommended to explore the effects of these variables within larger sample sizes.

Bezlotoxumab for the Prevention of Recurrent Clostridioides difficile Infection: 12-Month Observational Data From the Randomized Phase III Trial, MODIFY II.

From Monoclonal Antibodies for C. difficile Therapy II, no participants (n = 0/69) with a sustained clinical cure through 12 weeks following bezlotoxumab infusion experienced recurrent Clostridioides difficile infection (rCDI) after 9 months (versus actoxumab + bezlotoxumab, n = 2/65; versus placebo, n = 1/34). Bezlotoxumab's efficacy appears to be due to prevention rather than delayed onset of rCDI. Clinical Trials Registration. NCT01513239.

Investigation of the effect of the adsorbent DAV131A on the propensity of moxifloxacin to induce simulated Clostridioides (Clostridium) difficile infection (CDI) in an in vitro human gut model.

BACKGROUND: Clostridioides difficile infection (CDI) remains a high burden worldwide. DAV131A, a novel adsorbent, reduces residual gut antimicrobial levels, reducing CDI risk in animal models. OBJECTIVES: We used a validated human gut model to investigate the efficacy of DAV131A in preventing moxifloxacin-induced CDI. METHODS: C. difficile (CD) spores were inoculated into two models populated with pooled human faeces. Moxifloxacin was instilled (43 mg/L, once daily, 7 days) alongside DAV131A (5 g in 18 mL PBS, three times daily, 14 days, Model A), or PBS (18 mL, three times daily, 14 days, Model B). Selected gut microbiota populations, CD total counts, spore counts, cytotoxin titre and antimicrobial concentrations (HPLC) were monitored daily. We monitored for reduced susceptibility of CD to moxifloxacin. Growth of CD in faecal filtrate and medium in the presence/absence of DAV131A, or in medium pre-treated with DAV131A, was also investigated. RESULTS: DAV131A instillation reduced active moxifloxacin levels to below the limit of detection (50 ng/mL), and prevented microbiota disruption, excepting Bacteroides fragilis group populations, which declined by ∼3 log10 cfu/mL. DAV131A delayed onset of simulated CDI by ∼2 weeks, but did not prevent CD germination and toxin production. DAV131A prevented emergence of reduced susceptibility of CD to moxifloxacin. In batch culture, DAV131A had minor effects on CD vegetative growth, but significantly reduced toxin/spores (P < 0.005). CONCLUSIONS: DAV131A reduced moxifloxacin-induced microbiota disruption and emergence of antibiotic-resistant CD. Delayed onset of CD germination and toxin production indicates further investigations are warranted to understand the clinical benefits of DAV131A in CDI prevention.