Clostridiodes Difficile Infection Research Articles

Live biotherapeutic products: a capstone for prevention of recurrent Clostridiodes difficile infection

Clostridiodes difficile infection (CDI) continues to be one of the leading causes of healthcare-acquired diarrhea and infections, and recurrence is the biggest challenge in its management. As technology and research have led to a better understanding of the pathophysiology of C. difficile, we have come to appreciate the role that the gastrointestinal microbiota plays in infection onset and the prevention of recurrence. The gut microbiota is disrupted in those with CDI, which allows further propagation of the infection leading to recurrence, if the microbiota deficiency is unable to regrow itself. While antimicrobial therapy is necessary for treatment of any CDI, these therapeutics do not address the underlying disturbance of microbiota. Microbial remodulation therapies have been developed supplementing the microbiota deficiency that exists after the standard of care antimicrobial resulting in a reduction of recurrence. Fecal microbiota transplantation (FMT) was the initial attempt for this type of therapeutic and proved to be safe and effective, however never achieved FDA approval. In light of this, live biotherapeutic products (LBPs) were developed by pharmaceutical companies through a more standardized and regulated process. These products are safe and efficacious in reducing CDI recurrence when given after a standard of care antimicrobial, eventually leading to FDA approval of two products that can now be used widely in clinical practice.

The impact of the COVID-19 pandemic on longitudinal trends of surgical mortality and inpatient quality of care in Ontario, Canada.

Previous studies have shown the COVID-19 pandemic was associated with reductions in volume across a spectrum of non-SARS-CoV-2 hospitalizations. In the present study, we examine the impact of the pandemic on patient safety and quality of care. This is a retrospective population-based study of discharge abstracts. We applied a set of nationally validated indicators for measuring the quality of inpatient care to hospitalizations in Ontario, Canada between January 2010 and December 2022. We measured 90-day mortality after selected types of higher risk admissions (such as cancer surgery and cardiovascular emergency) and the rate of patient harm events (such as delirium, pressure injuries and hospital-acquired infections) occurring during the hospital stay. A total 13,876,377 hospitalization episodes were captured. Compared with the pre-pandemic period, and independent of SARS-CoV-2 infection, the pandemic period was associated with higher rates of mortality after bladder cancer resection (adjusted risk ratio [aRR] 1.20 (1.07-1.34)) and open repair for abdominal aortic aneurysm (aRR 1.45 (1.06-1.99)). The pandemic was also associated with higher rates of delirium (adjusted odds ratio [aOR] 1.04 (1.02-1.06)), venous thromboembolism (aOR 1.10 (1.06-1.13)), pressure injuries (aOR 1.28 (1.24-1.33)), aspiration pneumonitis (aOR 1.15 (1.12-1.18)), urinary tract infections (aOR 1.02 (1.01-1.04)), Clostridiodes difficile infection (aOR 1.05 (1.02-1.09)), pneumothorax (aOR 1.08 (1.03-1.13)), and use of restraints (aOR 1.12 (1.10-1.14)), but was associated with lower rates of viral gastroenteritis (aOR 0.22 (0.18-0.28)). During the pandemic, SARS-CoV-2-positive admissions were associated with a higher likelihood of various harm events. The COVID-19 pandemic was associated with higher rates of patient harm for a wide range of non-SARS-CoV-2 inpatient populations. Understanding which quality measures are improving or deteriorating can help health systems prioritize quality improvement initiatives. No patient or public contribution.

Assessing the Impact of Comorbid Hypercalcemia on Inpatient Outcomes of Patients With Diffuse Large B-cell Lymphoma During Admission for Chemotherapy.

Introduction Diffuse large B-cell lymphoma (DLBCL) may be complicated by hypercalcemia at various stages of treatment. The impact of hypercalcemia on chemotherapy admission outcomes in DLBCL is not well described. Methods In a retrospective analysis, using the National Inpatient Sample database (2018 - 2020), patients with DLBCL admitted for chemotherapy were dichotomized based on the presence of hypercalcemia. Our primary outcome was all-cause mortality. Secondary outcomes included length of stay (LOS), total charge, rate of acute kidney injury (AKI), tumor lysis syndrome (TLS), hyperkalemia, metabolic acidosis, acute encephalopathy, septic shock, Clostridiodes difficile infection, acute respiratory failure, and venous thromboembolic events (VTE). Results We identified 78,955 patients, among whom 1,375 (1.74%) had hypercalcemia. Hypercalcemia was associated with higher odds of all-cause mortality (aOR:3.05, p-value:0.020), TLS (aOR:8.81, p-value<0.001), acute metabolic encephalopathy (aOR:4.89, p-value<0.001), AKI (aOR:5.29, p-value<0.001), hyperkalemia (aOR:2.84, p-value:0.002), metabolic acidosis (aOR:3.94, p-value<0.001) and respiratory failure (aOR:2.29, p-value:0.007) and increased LOS by 1 day andtotal charge by 12, 501 USD. Conclusions In patients with DLBCL admitted for inpatient chemotherapy, those with hypercalcemia compared to a cohort without had higher odds of; all-cause mortality, TLS, AKI, acute encephalopathy, acute metabolic acidosis, hyperkalemia, and acute respiratory failure as well as higher LOS and total charge.

Impact of oral vancomycin treatment duration on rate of Clostridioides difficile recurrence in patients requiring concurrent systemic antibiotics.

There is a paucity of data guiding treatment duration of oral vancomycin for Clostridiodes difficile infection (CDI) in patients requiring concomitant systemic antibiotics. 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. 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). 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). 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.

388. Evaluating Rates of Co- and Secondary Infections in Pediatric Patients with COVID-19 Infections in Relation to Antibiotic Prescribing: An Observational Study

Abstract Background All ages have been greatly impacted by the Coronavirus disease 2019 (COVID-19) pandemic. While many patients with COVID-19 are prescribed antibiotics, there is often little microbiologic evidence for concurrent or secondary bacterial infection. Such prescribing practices may lead to increased antimicrobial resistance. The purpose of this study is to evaluate the number of microbiologically confirmed bacterial co- and secondary infections in pediatric patients with COVID-19 and characterize associated antimicrobial use at a large academic medical center. Methods An observational, retrospective review of pediatric patients ≤ 18 years admitted to Children’s Medical Center Dallas campus with COVID-19 infections from 5/01/2020 to 9/30/2022 was performed. Basic demographic, epidemiologic, laboratory, and microbiologic data was obtained upon admission and each new antibiotic course. Cultures and microbiologic data were reviewed for relevance. Antibiotic use was characterized based on drug selection, indication, and spectrum. Results Using the International Classification of diseases, tenth revision (ICD-10) code for COVID-19 pneumonia (U07.1) identified 229 patients, of which 164 met inclusion criteria. Within the included patient population, a total of 22 microbiologically-proven infections were found. Both co- and secondary infections were rare (8/164 (5%) and 8/164 (5%), respectively) and consisted of various organisms from differing sites (9 pulmonary, 9 bloodstream, 4 urinary tract, 1 Clostridiodes difficile infection). The most frequently identified organism was Staphylococcus aureus, followed by Escherichia coli and Pseudomonas aeruginosa. 102/164 (63%) children received antibiotics ≤ 48 hours of admission. There were 43 additional instances where antibiotics were started &amp;gt; 48 hours after admission. Conclusion Both co- and secondary bacterial infections are rare in pediatric patients with COVID-19 pneumonia, but many hospitalized patients are given antibiotics. Antibiotics were continued in the absence of microbiologic data potentially increasing antimicrobial resistance. There is clearly a role for antimicrobial stewardship in pediatric patients with COVID-19 pneumonia. Disclosures All Authors: No reported disclosures

Fecal Microbiota Transplantation: Information for the Pediatrician.

Fecal microbiota transplantation (FMT) involves the delivery of an entire microbial community from a healthy donor to a recipient with the intention of ameliorating or curing a specific disease. Current evidence strongly supports a role for FMT in the treatment of Clostridiodes difficile infection, with cure rates of approximately 80% to 90%. This success has led to increasing attention for FMT as a potential therapeutic intervention for other conditions associated with disturbances of the intestinal microbiome, including inflammatory bowel diseases, autism spectrum disorder, and obesity. This clinical report endorses the joint society statement by the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, and the European Society for Pediatric Gastroenterology, Hepatology and Nutrition and is meant to provide the general pediatrician with a broad overview to enable appropriate guidance to families seeking FMT as treatment of a child's condition.

S1741 Impact of an Electronic Smart Order-Set on Clostridiodes Difficile Infection Testing in a Community Healthcare System in South Florida

S1741 Impact of an Electronic Smart Order-Set on Clostridiodes Difficile Infection Testing in a Community Healthcare System in South Florida

PCR-based versus conventional stool tests in children with diarrhea who underwent solid organ transplantation or hematopoietic stem cell transplantation.

Infectious diarrhea is a common problem among post-transplant recipients. Compared to conventional tests, polymerase chain reaction (PCR)-based stool tests have been shown to improve diagnostic yield but the aforementioned data in children remain limited. Our aims were to assess the detection rate of PCR-based tests in post-transplant children and compare with the conventional tests; and to investigate how these stool tests help in managing these children. We enrolled children aged 1 to 19 years who underwent solid organ transplantation or hematopoietic stem cell transplantation that remained on immunosuppressive agents and developed diarrhea ≥ 24 hours between January 2015 and February 2023. Besides stool tests, data on demographics, clinical characteristics and management were collected. We analyzed 68 patients and 92 episodes of diarrhea with PCR-based tests. PCR-based tests provided a detection rate of 41.8% versus 16.5% for the conventional tests. While conventional tests may detect a higher proportion of Clostridiodes difficile infection, PCR-based tests showed greater yields in detecting Salmonella spp. and viruses especially norovirus. PCR-based tests had an impact in management among 22/38 (58%) diarrheal episodes especially with Campylobacter jejuni and C difficile; and among 16 episodes that positive PCR-based tests had a minimal impact, the most common reason was due to the need for continuation of antimicrobial agents for concomitant site-specific infection (69%). Among transplanted children presenting with diarrhea, PCR-based tests provide a higher yield when compared with the conventional tests. The PCR-based stool tests may also further guide clinicians for providing proper antimicrobial agents.

A profile of the live biotherapeutic product RBX2660 and its role in preventing recurrent Clostridioides difficile infection

ABSTRACT Introduction Clostridiodes difficile infection (CDI) is a life-threatening illness that has been labelled as an urgent threat by the Centers for Disease prevention (CDC). Areas Covered RBX2660, a live biotherapeutic product offers a very promising treatment option for patients with recurrent Clostridiodes difficile infection(rCDI). RBX2660 restores the healthy gut microbiome and shows clinically meaningful benefits for patients suffering from rCDI. Safety, efficacy, and tolerability of RBX2660 have been thoroughly assessed . Expert Opinion An FDA-approved, standardized, and accessible microbiota restoration product like RBX2660 would provide a new option for patients in need of treatment for rCDI by breaking the cycle of disease recurrence.

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

BackgroundUnderstanding 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.MethodsWe 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.ResultThe 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]).ConclusionAlthough 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.

Antimicrobial Stewardship Techniques for Critically Ill Patients with Pneumonia

Pneumonia is common in the intensive care unit (ICU), infecting 27% of all critically ill patients. Given the high prevalence of this disease state in the ICU, optimizing antimicrobial therapy while minimizing toxicities is of utmost importance. Inappropriate antimicrobial use can increase the risk of antimicrobial resistance, Clostridiodes difficile infection, allergic reaction, and other complications from antimicrobial use (e.g., QTc prolongation, thrombocytopenia). This review article aims to discuss methods to optimize antimicrobial treatment in patients with pneumonia, including the following: procalcitonin use, utilization of methicillin-resistant Staphylococcus aureus nares testing to determine need for vancomycin therapy, utilization of the Biofire® FilmArray® pneumonia polymerase chain reaction (PCR), and microbiology reporting techniques.

A systematic review of real-world healthcare resource use and costs of Clostridioides difficile infections.

To conduct a systematic review of published real-world evidence describing the cost and healthcare resource use for Clostridiodes difficile infection (CDI) in the United States. A systematic literature review was conducted searching for terms for CDI and healthcare costs. Titles of articles and abstracts were reviewed to identify those that met study criteria. Studies were evaluated to examine overall design and comparison groups in terms of healthcare resource use and cost for CDI. In total, 28 articles met the inclusion criteria. Moreover, 20 studies evaluated primary CDI or did not specify, and 8 studies1-8 evaluated both primary CDI and recurrent (rCDI). Data from Medicare were used in 6 studies. Nearly all studies used a comparison group, either controls without CDI (N = 20) or comparison between primary CDI and rCDI (N = 7). Two studies examined costs of rCDI by the number of recurrences. Overall, the burden of CDI is significant, with higher aggregate costs for patients with rCDI. Compared with non-CDI controls, hospital length of stay increased in patients with both primary and rCDI compared to patients without CDI. Patients with primary CDI cost healthcare systems $24,000 more than patients without CDI. Additionally, 2 studies that evaluated the impact of recurrence among those patients with an index case of CDI demonstrated significantly higher direct all-cause medical costs among those with rCDI compared to those without. CDI, and particularly rCDI, is a costly condition with hospitalizations being the main cost driver.

S606 High Rates of Clostridioides difficile Colonization Among Patients Undergoing Gastrointestinal Endoscopy

Introduction: Endoscopy is an essential part of medical care for both diagnostic and therapeutic indications. Gastro-intestinal endoscopy (GIE) can also provide a window into individuals’ microbiome. Clostridiodes difficile infection (CD) is a common healthcare associated infection (HAI) that causes significant morbidity and mortality. The aim of our study is to evaluate the presence of CD in patients undergoing GIE for cancer screening or other indications. Methods: A prospective non-randomized study was performed between December 2021 and April 2022 at GIE suite at an academic medical center. The study included 115 individuals who underwent GIE for screening and other medical reasons (110 outpatients and 5 inpatients). Electronic health records were reviewed for procedure-related information as well previous infection or colonized with CD and resistant bacteria within the past 2 years. A water sample was obtained from the GIE used immediately after use and after processing and high-level disinfection. An environmental culture was used for CD detection. Results: The study had 74 (64%) females and 41 (36%) males with mean age of 57 with a standard deviation of 13 years. The procedures were done by 12 physicians with an average time for the procedure of 37 with a standard deviation of 20 minutes. Only 1 patient was diagnosed with CD previously. However, environmental CD culture was positive in 28 (24%) patients. Post disinfection samples were all negative for CD. The majority of the patients had no multidrug resistant organisms 3 (2.6%). Colonoscopies were predominantly performed for colon cancer screening 104 patients (90%). Conclusion: Colonoscopic examination revealed high prevalence of within the community. Endoscope processing was effective in eliminating CD from the GIE. Hospital associated CD infection could be originating from a community source. Colonized hospitalized patients are at high risk for developing CD disease especially after antibiotic use.

A retrospective cohort study of the effect of rapid versus delayed-result procalcitonin testing on antibiotic use at a community hospital.

Procalcitonin is a serum biomarker used to distinguish bacterial infection from viral or noninfectious syndromes. Primary literature shows mixed data on use of procalcitonin for de-escalation of antimicrobials. Delays in test results of send-out procalcitonin assays may result in prolonged antimicrobial durations. It is unknown whether availability of rapid-result assays may shorten time to antibiotic de-escalation. This retrospective, cohort study compared antibiotic durations of treatment between groups with rapid-result versus delayed send-out, procalcitonin test modality. This study was exempt from Ethics Committee Approval, as determined by the Institutional Review Board at the study site. Adult hospitalized patients were included if they had at least one procalcitonin test performed during the study period. The primary outcome compared mean duration of antimicrobial therapy between groups receiving a rapid-result procalcitonin test and a send-out test. Secondary outcomes included incidence of Clostridiodes difficile infection, mention of procalcitonin testing in the electronic medical record in reference to antimicrobial therapy decision making, and presence of comorbidities which affect procalcitonin levels independent of infection. A total of 350 lab results were analyzed. The duration of antimicrobial treatment between groups was not statistically different with the median duration of treatment in the send-out group being 2.95days compared to 3.35 in the rapid result group, p = 0.856. Patient comorbidities with potential to lead to a noninfectious elevation or falsely high level of procalcitonin were common. Use of a rapid-result procalcitonin assay does not reduce hospital antimicrobial therapy duration as compared with send-out testing.

Impact of Clostridioides Difficle Infection and its Therapy on Nutritional Status.

Clostridiodes difficile infection (CDI) is a leading nosocomial cause of increased morbidity and mortality in hospitalized patients and the presentation can vary from asymptomatic infection to severe fulminant colitis and sepsis. It can significantly impact nutritional status in hospitalized patients and lead to longer length of stay with increased morbidity and mortality. An interplay of various intrinsic and extrinsic factors such as systemic inflammation, diarrheal losses, and impact of isolation influence the nutritional status of patients with CDI. While diarrheal losses can lead to dehydration and electrolyte disturbances, isolation can further hamper adequate nutritional support and make early signs of malnutrition overlooked. Similar detrimental impacts on nutritional status can also be observed in other bacterial and viral colonic infections. While prompt diagnosis and early treatment is crucial to prevent mortality, emphasis on nutritional rehabilitation can help reduce morbidity and promote recovery in CDI. Initiation of early feeding in critically sick patients with close monitoring for early signs of malnutrition promotes favorable outcomes.

Clinical and Economic Outcomes After Implementation of a Fidaxomicin Treatment Optimization and Access Pathway at a US Hospital System.

This study aimed to evaluate the clinical and economic outcomes of implementing a Clostridiodes difficile infection (CDI) Treatment Optimization and Access Pathway (treatment pathway) directing first-line use of fidaxomicin for CDI. This was a retrospective, quasi-experimental study of adult patients with CDI using Electronic Health Record data from a single center. The primary intervention was implementation of a treatment pathway directing first-line use of fidaxomicin for patients with first/second CDI episode and at high risk of recurrence. The primary clinical outcome was CDI recurrence within 30days of completing therapy in patients achieving clinical cure. Secondary clinical outcomes included clinical cure and sustained response evaluated at 90days after completion of CDI treatment. Economic outcomes included costs associated with hospital stay at index admission and 30- and 90-day readmission. Differences between the pre- and post-implementation cohorts were assessed for baseline characteristics, CDI treatment utilization, clinical outcomes, and economic outcomes. The budget impact was calculated for the pre- vs. post-implementation cohorts, each normalized to 100 patients. Post- vs. pre-implementation, 30-day recurrence (6.4% vs. 18.0%., p = 0.001), 90-day recurrence (14.9% vs. 27.1%, p = 0.009), and 30-day (4.6% vs. 12.7%, p = 0.007) and 90-day CDI-related readmissions (8.5% vs. 18.9%, p = 0.007) were lower. The clinical cure (94.1% vs. 84.4%, p = 0.002) and 90-day sustained response rates were higher (73.3% vs. 55.9%, p < 0.001). Median total costs were also lower in the post- vs. pre-implementation cohorts at index admission ($11,934.64 vs. $14,523.27, p = 0.048), and 30-day ($7685.82 vs. $12,424.44, p = 0.102) and 90-day CDI-related readmission episodes ($8246.69 vs. $12,729.57, p = 0.042). The budget impact analyses of 100 patients post- vs. pre-implementation found saving of $222,895 overall and $9432 per CDI-readmission avoided. Implementation of the CDI treatment pathway was associated with better clinical outcomes and hospital cost savings. The findings help validate real-world value of fidaxomicin for CDI disease management.

Next-Generation Probiotic Therapy to Protect the Intestines From Injury.

Probiotics are live microorganisms that, when administered in adequate amounts, provide health benefits to the host. Some strains of the probiotic Lactobacillus reuteri (L. reuteri) have both antimicrobial and anti-inflammatory properties that may be exploited for the treatment and prevention of different gastrointestinal diseases, including necrotizing enterocolitis (NEC) and Clostridioides difficile (C. difficile) infection. Our laboratory has developed a new delivery system for L. reuteri in which the probiotic is incubated with biocompatible, semipermeable, porous dextranomer microspheres (DM) that can be loaded with beneficial and diffusible cargo. L. reuteri can be induced to form a biofilm by incubating the bacteria on the surface of these microspheres, which enhances the efficacy of the probiotic. Loading the DM with sucrose or maltose induces L. reuteri to produce more biofilm, further increasing the efficacy of the probiotic. Using a rat model of NEC, L. reuteri administered in its biofilm state significantly increases animal survival, reduces the incidence of NEC, preserves gut barrier function, and decreases intestinal inflammation. In a murine model of Clostridiodes difficile infection, L. reuteri administered in its biofilm state decreases colitis when administered either before or after C. difficile induction, demonstrating both prophylactic and therapeutic efficacy. There are currently no FDA-approved probiotic preparations for human use. An FDA-approved phase I clinical trial of L. reuteri in its biofilm state in healthy adults is currently underway. The results of this trial will be used to support a phase 1 clinical trial in neonates, with the goal of utilizing L. reuteri in its biofilm state to prevent NEC in premature neonates in the future.

EE429 A Systematic Review of Healthcare Resource Use and Costs of the Treatment of Clostridioides Difficile Infections

Clostridiodes difficile infection (CDI) is the most common healthcare-associated infection in the US. Resource use and costs to manage CDI are not fully appreciated by healthcare professionals and payers across the range of US healthcare entities, including Medicare, commercial managed care organizations, hospitals, and long-term care facilities. A systematic review of the real-world evidence of CDI cost and healthcare resource use in the US was conducted.

Cost-Effective Treatment of Clostridiodes difficile Infection.

Cost-Effective Treatment of Clostridiodes difficile Infection.

The impact of diagnostic stewardship interventions on Clostridiodes difficile test ordering practices and results

Clostridiodes difficile infection (CDI) is a leading cause of healthcare associated infection and is associated with increased morbidity and mortality. Diagnostic stewardship is critical in optimizing testing accuracy for CDI. Multiple algorithms have been used for testing combining toxin A/B, glutamate dehydrogenase antigen and nucleic acid amplification test (NAAT) to enhance sensitivity. This study evaluated the effectiveness of two interventions on the rates and appropriateness of Clostridiodes difficile test orders and hospital-onset (HO) CDI. All Clostridiodes difficile orders and results in the study period (1/2018–2/2021) were included. To evaluate ordering appropriateness, we reviewed the medical charts of a random subsample of 100 orders that were collected from three periods within the study: pre-intervention and following each intervention. The first intervention was a clinical decision support system (CDSS) tool guiding providers to order testing only if CDI clinical criteria were met. The second intervention eliminated automatic NAAT reflex for indeterminate results and required antimicrobial stewardship team approval. A total of 3004 orders were registered during the study period. There was a 33% reduction in the rates of Clostridiodes difficile orders by the end of the study period (p < 0.001). The rates of reportable HO-CDI were significantly reduced by 57.1% (p = 0.003). We also noted a trend of increased appropriateness of testing overtime. In conclusion, combining CDSS intervention with NAAT reflex restriction was an effective tool to reduce inappropriate Clostridiodes difficile orders and decrease the rates of reportable HO-CDI.