Khanna, Sahil

Abstract Background Clostridioides difficile infection (CDI) incidence estimates vary between geographic regions; few studies have evaluated the impact of CDI test order frequency on estimated CDI incidence. We evaluated this impact in a sample of hospitals at two CDC Emerging Infections Program (EIP) sites. Methods Daily surveillance was conducted for diarrhea among inpatients at 5 acute care hospitals (2,379 beds) in EIP sites in NY (2 hospitals) and GA (3 hospitals) during two 10-workday periods in 2020 and 2021. Diarrhea onset, test orders, and specimen collection status were ascertained. Stools were tested by PCR/NAAT initially or after negative EIA toxin. Differences in diarrhea incidence, testing frequency, and CDI positivity across site, care locations and hospitals were compared using Wilcoxon rank sum test. Correlates of CDI testing and positivity were assessed using modified Poisson regression. Estimates of incidence using EIP methodology at 5 hospitals was compared between sites using Mantel-Hanzel summary rate ratio. Results Surveillance of 38,365 patient-days (PD) identified 860 diarrhea cases from 107 patient-care locations mapped to 26 unique NHSN defined location-types. Incidence of diarrhea was 22.4/1000 PD (medians 25.8 NY, 16.2 GA, P< 0.01); with similar proportions of diarrhea being hospital-onset (66%) and CDI positive (17%) by site. Overall, 35% were tested for CDI (21% NY, 49% GA, P< 0.01). Percent tested varied by NHSN location type (Figure). Regression models identified location-type (oncology, critical care), laxatives use, chemotherapy, and residing in EIP catchment area predictive of testing (Figure). Adjusting for these factors, NY was 49% less likely than GA to test (aRR 0.51, 95% CI 0.40-0.63). Simulation of EIP methods estimated NY had a 38% lower incidence of CDI than GA (summary rate ratio 0.62, 95% CI, 0.54-0.71). Figure Incidence of Diarrheal Episodes (A) and Proportions Tested (B) among Hospitalized Patients, 2021 (solid, ward; open, critical care; grey, oncology), and adjusted relative risk (solid circles) with 95% confidence intervals (whisker) of independent predictors of testing for CDI (C). Conclusion After adjusting for patient characteristics (e.g., location-type, laxative use), the likelihood of testing still differed between NY and GA sites; the magnitude of the differences in testing was similar to that observed in estimated CDI incidence. Testing practices likely influence surveillance data and is a consideration when comparing data across regions. Disclosures Scott Fridkin, MD, Pfizer: Grant/Research Support christopher J. Myers, MS, Infectious diseases, Pfizer: Grant/Research Support Udodirim N. Onwubiko, MBBS MPH, Pfizer: Grant/Research Support William C. Dube, MPH, Pfizer: Grant/Research Support Sahil Khanna, MBBS, MS, Pfizer: Grant/Research Support Joann M. Zamparo, MPH, Pfizer: Employee|Pfizer: Stocks/Bonds Frederick J. Angulo, DVM PhD, Pfizer Vaccines: Employee|Pfizer Vaccines: Stocks/Bonds Ghinwa Dumyati, MD, Pfizer: Grant/Research Support.

Background: Clostridioides difficile infection (CDI) is associated with poor outcomes in patients with inflammatory bowel diseases (IBD). Objectives: We conducted a nationally representative cohort study to evaluate the impact of recurrent CDI (rCDI)-related hospitalization on longitudinal unplanned healthcare utilization in patients with IBD. Design: This was a retrospective cohort study that utilized the 2017 Nationwide Readmissions Database (NRD). Methods: We identified 13,446 patients with IBD, hospitalized at least twice from January to June 2017 and followed through December 2017; of these, 1,148 had CDI-related hospitalizations. We compared the annual burden of hospitalization and IBD-related surgery in IBD patients with rCDI-related admission versus single CDI-related admission (primary reference), and those with one or more CDI-related admission versus no CDI-related admission (secondary reference). Results: There were no significant differences in risk and burden of unplanned healthcare utilization (time spent in-hospital, 27 days versus 27 days, p = 0.62), 6-month readmission (63% versus 64.3%, p = 0.8) or IBD-related surgery in patients with recurrent (two or more) CDI-related hospitalizations versus single CDI-related admission. However, patients with ⩾1 CDI-related admission versus no CDI admissions experienced higher rate of 6-month readmission (61.1% versus 55.7%, p<.001), total days spent in the hospital per year (median: 26 days versus 21 days, p<.001), total cost across all hospitalizations per year ($212,524 versus $184,384, p < 0.01), and inpatient mortality (3.28% versus 1.81%, p = 0.01), without an increase in risk of IBD-related surgery (6.7% versus 6.4%, p = 0.79). Conclusion: While patients with IBD hospitalized for CDI have poor longitudinal inpatient outcomes, recurrent admissions for CDI may not increase risk of adverse outcomes compared to one-time admission.

The species composition of the human gut microbiota is related to overall health, and a healthy gut microbiome is crucial in maintaining colonization resistance against pathogens. Disruption of gut microbiome composition and functionality reduces colonization resistance and has been associated with several gastrointestinal and non-gastrointestinal diseases. One prime example is Clostridioides difficile infection (CDI) and subsequent recurrent infections that occur after the development of systemic antibiotic-related dysbiosis. Standard-of-care antibiotics used for both acute and recurrent infections do not address dysbiosis and often worsen the condition. Moreover, monoclonal antibodies, recommended in conjunction with standard-of-care antibiotics for the prevention of recurrent CDI in patients at high risk of recurrence, reduce recurrences but do not address the underlying dysbiosis. Fecal microbiota transplantation (FMT) is an evolving therapeutic strategy in which microbes are harvested from healthy donor stool and transplanted into the gut of a recipient to restore the gut microbiome. Although effective in the prevention of recurrent CDI, some existing challenges include screening and the standardization of stool acquisition and processing. Recent safety alerts by the US Food and Drug Administration raised concern about the possibility of transmission of multidrug-resistant organisms or severe acute respiratory syndrome coronavirus 2 via FMT. Increased knowledge that microbes are beneficial in restoring the gut microbiome has led to the clinical development of several newer biotherapeutic formulations that are more regulated than FMT, which may allow for improved restoration of the gut microbiome and prevention of CDI recurrence. This review focuses on mechanisms by which gut microbiome restoration could influence colonization resistance against the pathogen C. difficile. Plain language summary The Role of the Gut Microbiome in Clostridioides difficile Infection Introduction: A rich and diverse gut microbiome is key to immune system regulation and colonization resistance against pathogens. A disruption in the gut microbiome composition can make the gut more vulnerable to diseases such as Clostridioides difficile infection (CDI), caused by the bacterium C. difficile. CDI management presents a therapeutic dilemma, as it is usually treated with antibiotics that can treat the infection but also can damage the microbiome. Treatment of CDI using antibiotics can further reduce microbial diversity and deplete beneficial bacteria from the gut leading to a condition called dysbiosis. Antibiotic treatment can be followed by therapies that restore the gut microbiota, boost colonization resistance, and prevent the development of antimicrobial resistance. It is important to evaluate treatment options to determine their safety and effectiveness. Methods: The researchers provided an overview of the mechanisms that the gut microbiome uses to prevent colonization of the gut by pathogens. They subsequently reviewed the efficacy and shortcomings of the following treatments for CDI: - Antibiotics - Monoclonal antibodies - Fecal microbiota transplantation (FMT) Results: Commensal intestinal bacteria prevent colonization of the gut by pathogens using mechanisms such as: - Competition for key nutrients - Production of inhibitory bile acids - Short-chain fatty acid production - Lowering the luminal pH - Production of bacteriocins Antibiotic therapy is recommended as a standard treatment for CDI. However, patients are vulnerable to recurrent CDI after discontinuation of the therapy. Monoclonal antibodies that inactivate C. difficile toxins may be recommended along with antibiotics to prevent recurrent CDI. However, this approach does not restore the microbiome. FMT is one method of microbial restoration, where stool is harvested from a healthy donor and transplanted into a patient’s colon. Although FMT has shown some efficacy in the treatment of recurrent CDI, the procedure is not standardized. Safety concerns have been raised about the possibility of transmission of multidrug-resistant pathogens via FMT. Conclusion: Treatment methods that can efficiently restore the diversity of the gut microbiome are crucial in preventing recurrence of CDI.

Clostridioides difficile infection (CDI) is classified as an urgent health threat by the Centers for Disease Control and Prevention (CDC), and affects nearly 500,000 Americans annually. Approximately 20–25% of patients with a primary infection experience a recurrence, and the risk of recurrence increases with subsequent episodes to greater than 40%. The leading risk factor for CDI is broad-spectrum antibiotics, which leads to a loss of microbial diversity and impaired colonization resistance. Current FDA-approved CDI treatment strategies target toxin or toxin-producing bacteria, but do not address microbiome disruption, which is key to the pathogenesis of recurrent CDI. Fecal microbiota transplantation (FMT) reduces the risk of recurrent CDI through the restoration of microbial diversity. However, FDA safety alerts describing hospitalizations and deaths related to pathogen transmission have raised safety concerns with the use of unregulated and unstandardized donor-derived products. SER-109 is an investigational oral microbiome therapeutic composed of purified spore-forming Firmicutes. SER-109 was superior to a placebo in reducing CDI recurrence at Week 8 (12% vs. 40%, respectively; p < 0.001) in adults with a history of recurrent CDI with a favorable observed safety profile. Here, we discuss the role of the microbiome in CDI pathogenesis and the clinical development of SER-109, including its rigorous manufacturing process, which mitigates the risk of pathogen transmission. Additionally, we discuss compositional and functional changes in the gastrointestinal microbiome in patients with recurrent CDI following treatment with SER-109 that are critical to a sustained clinical response.

Background: Prolonged symptoms after COVID-19 are an important concern due to the large numbers affected by the pandemic. Objectives: To ascertain the frequency of gastrointestinal (GI) manifestations as part of long GI COVID. Design: A systematic review and meta-analysis of studies reporting GI manifestations in long COVID was performed. Data Sources and Methods: Electronic databases (Medline, Scopus, Embase, Cochrane Central Register of Controlled Trials, and Web of Science) were searched till 21 December 2021 to identify studies reporting frequency of GI symptoms in long COVID. We included studies reporting overall GI manifestations or individual GI symptoms as part of long COVID. We excluded pediatric studies and those not providing relevant information. We calculated the pooled frequency of various symptoms in all patients with COVID-19 and also in those with long COVID using the inverse variance approach. All analysis was done using R version 4.1.1 using packages ‘meta’ and ‘metafor’. Results: A total of 50 studies were included. The frequencies of GI symptoms were 0.12 [95% confidence interval (CI), 0.06–0.22, I 2 = 99%] and 0.22 (95% CI, 0.10–0.41, I 2 = 97%) in patients with COVID-19 and those with long COVID, respectively. The frequencies of abdominal pain, nausea/vomiting, loss of appetite, and loss of taste were 0.14 (95% CI, 0.04–0.38, I 2 = 96%), 0.06 (95% CI, 0.03–0.11, I 2 = 98%), 0.20 (95% CI, 0.08–0.43, I 2 = 98%), and 0.17 (95% CI, 0.10–0.27, I 2 = 95%), respectively, after COVID-19. The frequencies of diarrhea, dyspepsia, and irritable bowel syndrome were 0.10 (95% CI, 0.04–0.23, I 2 = 98%), 0.20 (95% CI, 0.06–0.50, I 2 = 97%), and 0.17 (95% CI, 0.06–0.37, I 2 = 96%), respectively. Conclusion: GI symptoms in patients were seen in 12% after COVID-19 and 22% as part of long COVID. Loss of appetite, dyspepsia, irritable bowel syndrome, loss of taste, and abdominal pain were the five most common GI symptoms of long COVID. Significant heterogeneity and small number of studies for some of the analyses are limitations of the systematic review.

INTRODUCTION: Outcomes and safety of budesonide maintenance therapy in microscopic colitis (MC) are not well known. METHODS: Adult residents of Olmsted County, Minnesota, diagnosed with MC (2002–2019) and treated with budesonide were identified using the Rochester Epidemiology Project. Response was assessed at 12 ± 4 weeks after initiation of therapy and defined as complete (resolution of diarrhea), partial (≥50% improvement in the number of bowel movements), nonresponse (<50% improvement), and intolerance (discontinued because of side effects). For safety outcomes, cases (budesonide maintenance) and MC controls (no budesonide therapy) were matched by sex and age at diagnosis (±2 years). RESULTS: A total of 450 patients were identified, of whom 162 (36.0%) were treated with budesonide for induction of clinical remission (median age 67 [23–91] years and 126 women [77.8%] ). Clinical outcomes for induction were as follows: 130 (80.2%) complete response, 22 (13.6%) partial response, 8 (4.9%) no response, and 2 (1.2%) intolerance. After induction, 96 (63.2%) had recurrence after discontinuation, of whom 27 (28.1%) required further budesonide induction treatment without maintenance, 56 (58.3%) required long-term budesonide maintenance, and 13 (13.5%) were treated with other therapies. Of those receiving budesonide maintenance, all responded (55 [98.2%] complete and 1 [1.8%] partial). No patient stopped maintenance from adverse events. The median duration of follow-up was 5.6 years (0.3–18.9). There was no significant difference between cases and controls in the incidence of osteopenia/osteoporosis, diabetes mellitus, hypertension, glaucoma, or cataracts. DISCUSSION: The long-term use of budesonide in MC seems to be effective and generally well tolerated with limited adverse effects.

Clostridioides difficile infection (CDI) is a complex disease that by virtue of both its initial virulence and proclivity toward recurrent episodes causes a high morbidity, mortality, and financial burden. This burden is felt by patients and their families as well as the U.S. healthcare system. Recurrent CDI episodes can occur in 25–65% of patients, with a cycle of multiple recurrences in a single patient contributing to the complexity of care. Patients with or suspected of having CDI will receive treatment and their care will be managed across multiple healthcare settings and will include many different levels of healthcare workers. The understanding of this infection is essential for all who are involved in the care of these patients. A well-structured and implemented Transition of Care process can ease the burden on the healthcare system, patients, and their families; reduce the cost of care; and improve patient outcomes. We review the development of Transitions of Care processes, resource guides, and their relevance to improving the management of CDI.