Association between epidemiologic case definition categories and adverse clinical outcome in patients with Clostridiodes difficile infection in San Francisco County, California: a five-year retrospective cohort study.

BACKGROUND: Understanding the predictors of adverse clinical outcomes following incident Clostridiodes difficile infection (CDI) can help clinicians identify which patients are at risk of complications and help prioritize the provision of their care. In this study, we assessed the associations between epidemiologic case definition categories and adverse clinical outcomes in patients with CDI in San Francisco County, California. METHODS: We conducted a retrospective cohort study using CDI surveillance data (n = 3274) from the California Emerging Infections Program for the time period 2016 to 2020. After independent associations were established, two multivariable logistic and log-binomial regression models were constructed for the final statistical analysis. RESULT: The mean cumulative incidence of CDI cases was 78.8 cases per 100,000 population. The overall recurrence rate and the 30-day all-cause mortality rate were 11.1% and 4.5%, respectively. After adjusting for potential confounders, compared to the community associated CDI cases, healthcare facility onset (AOR = 3.1; 95% CI [1.3-7]) and community-onset-healthcare facility associated (AOR = 2.4; 95% CI [1.4-4.3]) CDI cases were found to have higher odds of all-cause 30-day mortality. Community onset-healthcare facility-associated CDI case definition category was found to be significantly associated with an increased risk of recurrence of CDI (ARR = 1.7; 95% CI [1.2-2.4]). CONCLUSION: Although the incidence of community-associated CDI cases has been rising, the odds of all-cause 30-day mortality and the risk of recurrent CDI associated with these infections are lower than healthcare facility onset and community-onset healthcare facility-associated CDI cases.

Clinical Decision Support Systems to Reduce Unnecessary Clostridioides difficile Testing Across Multiple Hospitals.

BACKGROUND: Inappropriate Clostridioides difficile testing has adverse consequences for patients, hospitals, and public health. Computerized clinical decision support (CCDS) systems in the electronic health record (EHR) may reduce C. difficile test ordering; however, effectiveness of different approaches, ease of use, and best fit into healthcare providers' (HCP) workflow are not well understood. METHODS: Nine academic and 6 community hospitals in the United States participated in this 2-year cohort study. CCDS (hard stop or soft stop) triggered when a duplicate C. difficile test order was attempted or if laxatives were recently received. The primary outcome was the difference in testing rates pre- and post-CCDS interventions, using incidence rate ratios (IRRs) and mixed-effect Poisson regression models. We performed qualitative evaluation (contextual inquiry, interviews, focus groups) based on a human factors model. We identified themes using a codebook with primary nodes and subnodes. RESULTS: In 9 hospitals implementing hard-stop CCDS and 4 hospitals implementing soft-stop CCDS, C. difficile testing incidence rate (IR) reduction was 33% (95% confidence interval [CI]: 30%-36%) and 23% (95% CI: 21%-25%), respectively. Two hospitals implemented a non-EHR-based human intervention with IR reduction of 21% (95% CI: 15%-28%). HCPs reported generally favorable experiences and highlighted time efficiencies such as inclusion of the patient's most recent laxative administration on the CCDS. Organizational factors, including hierarchical cultures and communication between HCPs caring for the same patient, impact CCDS acceptance and integration. CONCLUSIONS: CCDS systems reduced unnecessary C. difficile testing and were perceived positively by HCPs when integrated into their workflow and when displaying relevant patient-specific information needed for decision making.

Germination of Spores of the Orders Bacillales and Clostridiales.

Dormant Bacillales and Clostridiales spores begin to grow when small molecules (germinants) trigger germination, potentially leading to food spoilage or disease. Germination-specific proteins sense germinants, transport small molecules, and hydrolyze specific bonds in cortex peptidoglycan and specific proteins. Major events in germination include (a) germinant sensing; (b) commitment to germinate; (c) release of spores' depot of dipicolinic acid (DPA); (d) hydrolysis of spores' peptidoglycan cortex; and (e) spore core swelling and water uptake, cell wall peptidoglycan remodeling, and restoration of core protein and inner spore membrane lipid mobility. Germination is similar between Bacillales and Clostridiales, but some species differ in how germinants are sensed and how cortex hydrolysis and DPA release are triggered. Despite detailed knowledge of the proteins and signal transduction pathways involved in germination, precisely what some germination proteins do and how they do it remain unclear.

Comparison of polysaccharide glycoconjugates as candidate vaccines to combat Clostridiodes (Clostridium) difficile.

Two known Clostridiodes (Clostridium) difficile surface antigens, a lipoteichoic acid (LTA) and a polysaccharide (PS-II) were isolated and purified in order to prepare glycoconjugate vaccines to the carrier protein human serum albumin utilising a reductive amination strategy. Mice and rabbits were immunized with a prime and two boost strategy and the resulting sera were examined for their ability to recognise the purified homologous antigens and subsequently killed whole cells of C. difficile strains and other Clostridia species. Immunisation derived antisera from rabbits and mice, recognised all strains of C. difficile vegetative cells examined, with generally similar titers from animals that received the LTA or the PS-II conjugates. Sera raised to the LTA conjugates were able to recognise other Clostridia species C. butyricum, C. bifermentans and C. subterminale whereas sera raised to the PS-II conjugates were not. These LTA and PS-II sera recognised live cells in an immunofluorescence assay and were also able to recognise the spore form of the bacterium. This study has confirmed that the LTA and PS-II polysaccharides are both highly conserved surface polymers of C. difficile that are easily accessible to the immune system and as such may have potential as vaccine antigens or as targets for therapeutics to combat C. difficile infection.

Systematic review on the definition and predictors of severe Clostridiodes difficile infection.

Clostridiodes difficile infection (CDI) is one of the most common hospital-acquired infections with high mortality rates. Optimal management of CDI depends on early recognition of severity. However, currently, there is no acceptable standard of prediction. We reviewed severe CDI predictors in published literature and its definition according to clinical guidelines. We systematically reviewed studies describing clinical predictors for severe CDI in medical databases (Cochrane, EMBASE, Global Health Library, and MEDLINE/PubMed). They were independently evaluated by two reviewers. Six hundred thirty-three titles and abstracts were screened, and 31 studies were included. We excluded studies that were restricted to a specific patient population. There were 16 articles that examined mortality in CDI, as compared with 15 articles investigating non-mortality outcomes of CDI. The commonest risk factors identified were comorbidities, white blood cell count, serum albumin level, age, serum creatinine level and intensive care unit admission. Generally, the studies had small patient populations, were retrospective in nature, and mostly from Western centers. The commonest severe CDI criteria in clinical guidelines were raised white blood cell count, followed by low serum albumin and raised serum creatinine levels. There was no commonly agreed upon definition of severe CDI severity in the literature. Current clinical guidelines' definitions for severe CDI are heterogeneous. Hence, there is a need for prospective multi-center studies using standardized protocol for biospecimen investigation collection and shared data on outcomes of patients in order to devise a universally accepted definition for severe CDI.

Microbiota or placebo after antimicrobial therapy for recurrent Clostridioides difficile at home: A clinical trial with novel home-based enrollment.

INTRODUCTION: Clostridiodes difficile infection is the leading cause of infectious diarrhea in the United States, with substantial morbidity and mortality. Recurrent infection is especially challenging, with each recurrence increasing the likelihood of a successive recurrence, leading to cycles of prolonged symptoms, frequent antimicrobial use, and decreased quality of life. Fecal microbiota transplantation to prevent recurrent infection is a promising intervention with a large effect size in observational studies, but with conflicting results from randomized controlled trials. We are conducting a Veterans Affairs-wide randomized controlled trial utilizing centralized case identification, with enrollment and fecal microbiota transplant administration occurring at the participant's home. This type of trial design significantly improves trial efficiency, greatly decreases trial cost, increases consistency of trial administration, and most importantly makes nationwide clinical trials in less-common diseases possible. METHODS: This is a randomized comparison of capsule-delivered fecal microbiota transplant for the prevention of recurrent Clostridiodes difficile infection, administered after successful initial treatment of recurrent C. difficile infection with standard therapy. The primary endpoint is the incidence of recurrent C. difficile infection or death. Cases are identified by searching the Veterans Affairs Corporate Data Warehouse, with central study coordinators then reaching out to potential participants. Individuals meeting inclusion criteria and interested in participation are scheduled for in-home consent, randomization, and capsule administration, followed by telephone follow-up for 6 months. To mitigate risks of COVID-19, enrollment via video visits has been implemented. RESULTS: A total of 102 participants have been enrolled through January 2021. Centralized case identification and in-home enrollment has facilitated enrollment from 34 unique states, with 38% being from rural or highly rural areas. DISCUSSION: Centralized case identification and in-home enrollment is a feasible and innovative method of conducting randomized controlled trials in the Veterans Affairs system, improving access to clinical research for populations who may have difficulty engaging with the traditional model of clinical trials where enrollment is based at large hospitals in major metropolitan areas.

Laxative Use Does Not Preclude Diagnosis or Reduce Disease Severity in Clostridiodes difficile Infection.

BACKGROUND: To optimize utility of laboratory testing for Clostridiodes difficile infection (CDI), the 2017 Infectious Diseases Society of America-Society for Healthcare Epidemiology of America (IDSA-SHEA) clinical practice guidelines recommend excluding patients from stool testing for C. difficile if they have received laxatives within the preceding 48 hours. Sparse data support this recommendation. METHODS: Patients with new-onset diarrhea (≥3 bowel movements in any 24-hour period in the 48 hours before stool collection) and a positive stool C. difficile nucleic acid amplification test were enrolled. Laxative use within 48 hours before stool testing, severity of illness (defined by 4 distinct scoring methods), and clinical outcomes were recorded. RESULTS: 209 patients with CDI were studied, 65 of whom had received laxatives. There were no significant differences in the proportion of patients meeting severe CDI criteria by 4 severity scoring methods in patients receiving versus not receiving laxatives (66.2% vs 56.3%, respectively; P = .224) by IDSA-SHEA, the primary scoring system. Similar rates of serious outcomes attributable to CDI, including death, intensive care unit admission, and colectomy, were observed in the laxative and no laxative groups. CONCLUSIONS: Our study found similar rates of severe CDI and serious CDI-attributable clinical outcomes in CDI-diagnosed patients who did or did not receive laxatives. Precluding recent laxative users from CDI testing, as proposed by the IDSA-SHEA guideline, carries a potential for harm due to delayed diagnosis and treatment.

Clostridioides difficile in COVID-19 Patients, Detroit, Michigan, USA, March-April 2020.

We describe 9 patients at a medical center in Detroit, Michigan, USA, with severe acute respiratory syndrome coronavirus 2 and Clostridioides difficile. Both infections can manifest as digestive symptoms and merit screening when assessing patients with diarrhea during the coronavirus disease pandemic. These co-infections also highlight the continued importance of antimicrobial stewardship.

A multicenter study to define the epidemiology and outcomes of Clostridioides difficile infection in pediatric hematopoietic cell and solid organ transplant recipients.

Hematopoietic cell transplant (HCT) and solid organ transplant (SOT) recipients are at increased risk for Clostridioides difficile infection (CDI). We conducted a multicenter retrospective study to describe the incidence of CDI in children transplanted between January 2010 and June 2013. Nested case-control substudies, matched 1:1 by transplant type, institution, patient age, and time of year (quartile) of transplant, identified CDI risk factors. Cohorts included 1496 HCT and 1090 SOT recipients. Among HCT recipients, 355 CDI episodes were diagnosed in 265 recipients (18.2%). Nested case-control study identified prior history of CDI (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.5-4.7), proton pump inhibitors (PPIs; OR 2.1, 95% CI 1.3-3.4), and exposure to third- (OR 2.4, 95% CI 1.4-4.2) or fourth-generation (OR 2.1, 95% CI 1.2-3.7) cephalosporins as risk factors. Notably, fluoroquinolone exposure appeared protective (OR 0.6, 95% CI 0.3-0.9). Ninety-two episodes of CDI were diagnosed among 79 SOT recipients (7.3%), and exposure to PPIs (OR 2.4, 95% CI 1.1-5.4) and third-generation cephalosporin therapy (OR 3.9, 95% CI 1.4-10.5) were identified as risk factors. Strategies to decrease PPI use and changes in the class of prophylactic antibiotics may impact CDI incidence and warrant further study.

The Association Between the Frequency of Interruptions in Antibiotic Exposure and the Risk of Health Care-Associated Clostridiodes difficile Infection.

BACKGROUND: Although antibiotic use is an established risk factor for health care-associated Clostridiodes difficile infection, estimates of the association between infection and antibiotic use vary, depending upon how antibiotic exposure is measured. OBJECTIVES: The purpose of this study was to explore the association between the frequency of interruptions in antibiotic exposure and the risk of health care-associated C difficile infection. METHODS: A retrospective chart review cohort study was conducted of all inpatients between 2011and 2016 from a single academic health center who received at least 1 dose of a systemic antibacterial for a cumulative duration of >3 days and ≤30 days. The measures of antibiotic exposure examined were duration-cumulative total calendar days of antibiotics therapy-and continuity-the frequency of interruptions in antibiotic exposure that was defined as the number of antibiotic treatment courses. RESULTS: A total of 52,445/227,967 (23%) patients received antibacterial therapy for >3 days and ≤30 days during their hospitalization. Of these, 1161 out of 52,445 (2.21%) were patients with health care-associated C difficile infection. An adjusted multivariable logistic regression analysis revealed that the risk of C difficile increased with longer cumulative days (odds ratio = 2.7; comparison of >12 days to ≤5 days) and fewer interruptions of antibiotic treatment (odds ratio = 0.78; comparison of >3 discrete antibiotic treatment courses to 1 course or continuous antibiotic treatment course; all P values < 0.05). CONCLUSIONS: For patients who received the same number of cumulative days of therapy, the patients who had more frequently interrupted courses of antibiotic therapy were less likely to experience health care-associated C difficile infection. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

Risk for Clostridiodes difficile Infection among Older Adults with Cancer.

To assess whether risk for Clostridiodes difficile infection (CDI) is higher among older adults with cancer, we conducted a retrospective cohort study with a nested case-control analysis using population-based Surveillance, Epidemiology, and End Results-Medicare linked data for 2011. Among 93,566 Medicare beneficiaries, incident CDI and odds for acquiring CDI were higher among patients with than without cancer. Specifically, risk was significantly higher for those who had liquid tumors and higher for those who had recently diagnosed solid tumors and distant metastasis. These findings were independent of prior healthcare-associated exposure. This population-based assessment can be used to identify targets for prevention of CDI.

Clostridioides difficile ribotypes isolated from domestic environment and from patients in Bangladesh.

Clostridioides difficile infection (CDI) is an emerging but often understudied infectious disease in developing countries. This study was aimed to isolate and characterize C. difficile from shoe sole swabs and diarrheal patient's stool samples in Bangladesh. We collected 94 shoe sole swabs samples from urban communities in Dhaka and 208 diarrheal stool samples from hospitalized patients over a period of 4 months. Samples were incubated anaerobically for C. difficile growth, confirmed toxigenic, and PCR-ribotyped. Eleven of 94 (11.7%) shoe sole swabs and 4 of 208 (1.9%) stool samples were culture positive of which 9 shoe sole isolates were toxigenic. Six PCR ribotypes from the 9 toxigenic isolates were identified with ribotype F014-020 being the most common (n = 4; 44%). The recently identified ribotype 106 strain was also identified. To the best of our knowledge, this is the first report of C. difficile culture, isolation and characterization from environmental sources in Bangladesh.

Clostridioides difficile Infection in Kidney Transplant Recipients.

Clostridioides difficile (C. difficile) is a bacterial organism that typically infects the colon, which has had its homeostasis of healthy gut microbiota disrupted by antibiotics or other interventions. Patients with kidney transplantation are a group that are susceptible to C. difficile infection (CDI) and have poorer outcomes with CDI given that they conventionally require long-term immunosuppression to minimize their risk of graft rejection, weakening their responses to infection. Recognizing the risk factors and complex pathophysiological processes that exist between immunosuppression, dysbiosis, and CDI is important when making crucial clinical decisions surrounding the management of this vulnerable patient cohort. Despite the clinical importance of this topic, there are few studies that have evaluated CDI in the context of kidney transplant recipients and other solid organ transplant populations. The current recommendations on CDI management in kidney transplant and solid organ transplant recipients are mostly extrapolated from data relating to CDI management in the general population. We provide a narrative review that discusses the available evidence examining CDI in solid organ transplant recipients, with a particular focus on the kidney transplant recipient, from the epidemiology of CDI, clinical features and implications of CDI, potential risk factors of CDI, and, ultimately, prevention and management strategies for CDI, with the aim of providing areas for future research development in this topic area.

Clostridioides difficile infection in inflammatory bowel disease: a clinical review.

INTRODUCTION: Strong clinical data demonstrate that inflammatory bowel disease (IBD) is an independent risk factor for Clostridiodes difficile infection (CDI) and suggest a globally increased prevalence and severity of C. difficile coinfection in IBD patients (CDI-IBD). In addition to elderly individuals, children are also at higher risk of CDI-IBD. Rapid diagnosis is essential since the clinical manifestations of active IBD and CDI-IBD are indistinguishable. Antibiotics have been well established in the treatment of CDI-IBD, but they do not prevent recurrence. AREAS COVERED: Herein, the authors focus on reviewing recent research advances on the new therapies of CDI-IBD. The novel therapies include gut microbiota restoration therapies (such as prebiotics, probiotics and FMT), immunotherapy (such as vaccines and monoclonal antibodies) and diet strategies (such as groningen anti-inflammatory diet and mediterranean diet). Future extensive prospective and placebo-controlled studies are required to evaluate their efficacy and long-term safety. EXPERT OPINION: Available studies show that the prevalence of CDI-IBD is not optimistic. Currently, potential treatment options for CDI-IBD include a number of probiotics and novel antibiotics. This review updates the knowledge on the management of CDI in IBD patients, which is timely and important for GI doctors and scientists.

Bezlotoxumab for Prevention of Recurrent Clostridioides difficile Infection With a Focus on Immunocompromised Patients.

Objectives: Approximately 25% of patients with Clostridioides difficile infection (CDI) will experience recurrence, which is greater in immunocompromised patients. We report experience with an institutional guideline targeting high-risk immunocompromised patients. Methods: This was a retrospective cohort of consecutive patients with CDI who met institutional criteria for bezlotoxumab due to high risk for recurrent CDI between June 1, 2017, and November 30, 2018. The primary endpoint of recurrent CDI within 12 weeks was compared between patients who received the standard of care (SoC) plus or minus bezlotoxumab. Results: Twenty-three patients received bezlotoxumab infusion plus SoC and were compared to 30 SoC patients. 84% of patients were immunocompromised and 54.7% were transplant recipients. The primary endpoint occurred in 13% of bezlotoxumab patients compared to 23.3% of SoC patients. No serious adverse effects were identified. Conclusion: Bezlotoxumab was associated with a meaningful reduction in recurrent CDI in this cohort largely comprising immunocompromised and transplant patients. Larger studies are warranted to evaluate bezlotoxumab in this population.

Epidemiological and microbiome associations of Clostridioides difficile carriage in infancy and early childhood.

There has been an increase in the prevalence of Clostridioides difficile (C. diff) causing significant economic impact on the health care system. Although toxigenic C. diff carriage is recognized in infancy, there is limited data regarding its longitudinal trends, associated epidemiolocal risk factors and intestinal microbiome characteristics. The objectives of our longitudinal cohort study were to investigate temporal changes in the prevalence of toxigenic C.diff colonization in children up to 2 years, associated epidemiological and intestinal microbiome characteristics. Pregnant mothers were enrolled prenatally, and serial stool samples were collected from their children for 2 years. 2608 serial stool samples were collected from 817 children. 411/817 (50%) were males, and 738/817 (90%) were born full term. Toxigenic C.diff was detected in 7/569 (1%) of meconium samples, 116/624 (19%) of 2 m (month), 221/606 (37%) of 6 m, 227/574 (40%) of 12 m and 18/235 (8%) of 24 m samples. Infants receiving any breast milk at 6 m were less likely to be carriers at 2 m, 6 m and 12 m than those not receiving it. (p = 0.002 at 2 m, p < 0.0001 at 6 m, p = 0.022 at 12 m). There were no robust differences in the underlying alpha or beta diversity between those with and without toxigenic C. diff carriage at any timepoint, although small differences in the relative abundance of certain taxa were found. In this largest longitudinal cohort study to date, a high prevalence of toxigenic C. diff carrier state was noted. Toxigenic C. diff carrier state in children is most likely a transient component of the dynamic infant microbiome.

A Predictive Model to Identify Complicated Clostridiodes difficile Infection.

Background: Clostridioides difficile infection (CDI) is a leading cause of health care-associated infection and may result in organ dysfunction, colectomy, and death. Published risk scores to predict severe complications from CDI demonstrate poor performance upon external validation. We hypothesized that building and validating a model using geographically and temporally distinct cohorts would more accurately predict risk for complications from CDI. Methods: We conducted a multicenter retrospective cohort study of adults diagnosed with CDI. After randomly partitioning the data into training and validation sets, we developed and compared 3 machine learning algorithms (lasso regression, random forest, stacked ensemble) with 10-fold cross-validation to predict disease-related complications (intensive care unit admission, colectomy, or death attributable to CDI) within 30 days of diagnosis. Model performance was assessed using the area under the receiver operating curve (AUC). Results: A total of 3646 patients with CDI were included, of whom 217 (6%) had complications. All 3 models performed well (AUC, 0.88-0.89). Variables of importance were similar across models, including albumin, bicarbonate, change in creatinine, non-CDI-related intensive care unit admission, and concomitant non-CDI antibiotics. Sensitivity analyses indicated that model performance was robust even when varying derivation cohort inclusion and CDI testing approach. However, race was an important modifier, with models showing worse performance in non-White patients. Conclusions: Using a large heterogeneous population of patients, we developed and validated a prediction model that estimates risk for complications from CDI with good accuracy. Future studies should aim to reduce the disparity in model accuracy between White and non-White patients and to improve performance overall.