C. Difficile Infection Episodes Research Articles

Prevalence of Non-Toxigenic Clostridioides difficile in Diarrhoea Patients and Their Clinical Characteristics.

Non-toxigenic Clostridioides difficile (NTCD) has been shown to decrease the risk of recurrent C. difficile infection (CDI) in patients following metronidazole or vancomycin treatment for CDI. Limited data on the prevalence of NTCD strains in symptomatic patients and their clinical characteristics are available. We conducted this study to investigate the prevalence of NTCD in diarrhoea patients and their clinical characteristics. Between July 2017 and June 2018, unduplicated stool specimens were collected from patients with diarrhoea. The characteristics and episodes of C. difficile infection in patients with NTCD and toxigenic strains were compared. Among the 1182 stool specimens collected, 236 (18.5%) were identified as growing C. difficile, and 19.5% of the identified isolates were found to be NTCD. Multivariate analysis showed that community-onset diarrhoea (OR = 4.13, 95% CI 1.07-15.97; p = 0.040), underlying diabetes (OR = 3.64, 95% CI 1.46-9.25; p = 0.006), previous use of glycopeptides (OR = 4.75, 95% CI 1.37-16.42; p = 0.014), and the lack of use of proton pump inhibitors (PPIs) (OR = 3.57, 95% CI 1.39-9.09; p = 0.009) were independently associated with the NTCD group. Although there was no statistical significance, the number of CDI episodes occurring after 90 days tended to be lower in the NTCD group (2.2%) than in the toxigenic group (11.2%). A considerable portion of the C. difficile strains isolated from patients with diarrhoea showed NTCD. Further, more extensive studies are needed to clearly define the protective effects of NTCD strains in patients with diarrhoea.

Effective Colonization by Nontoxigenic Clostridioides difficile REA Strain M3 (NTCD-M3) Spores following Treatment with Either Fidaxomicin or Vancomycin.

Colonization with nontoxigenic Clostridioides difficile strain M3 (NTCD-M3) has been demonstrated in susceptible hamsters and humans when administered after vancomycin treatment. NTCD-M3 has also been shown to decrease risk of recurrent C. difficile infection (CDI) in patients following vancomycin treatment for CDI. As there are no data for NTCD-M3 colonization after fidaxomicin treatment, we studied the efficacy of NTCD-M3 colonization and determined fecal antibiotic levels in a well-studied hamster model of CDI. Ten of 10 hamsters became colonized with NTCD-M3 after 5 days of treatment with fidaxomicin when NTCD-M3 was administered daily for 7 days after treatment discontinuation. The findings were nearly identical to 10 vancomycin-treated hamsters also given NTCD-M3. High fecal levels of OP-1118, the major fidaxomicin metabolite, and vancomycin were noted during treatment with the respective agents and modest levels noted 3 days after treatment discontinuation at the time when most of the hamsters became colonized. These findings support the ongoing development of NTCD-M3 for the prevention of recurrent CDI. IMPORTANCE NTCD-M3 is a novel live biotherapeutic, that has been shown in a Phase 2 clinical trial to prevent recurrence of C. difficile infection (CDI) when administered shortly after antibiotic treatment of the initial CDI episode. Fidaxomicin was not, however, in widespread use at the time this study was conducted. A large multi-center Phase 3 clinical trial is now currently in the planning stage, and it is anticipated that many patients eligible for this study will be treated with fidaxomicin. Since efficacy in the hamster model of CDI has predicted success in patients with CDI, we studied the ability of NTCD-M3 to colonize hamsters after treatment with either fidaxomicin or vancomycin.

Controversies in the Prevention and Treatment of Clostridioides difficile Infection in Adults: A Narrative Review.

Clostridioides difficile remains a problematic pathogen resulting in significant morbidity and mortality, especially for high-risk groups that include immunocompromised patients. Both the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America (IDSA/SHEA), as well as the American College of Gastroenterology (ACG) and the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) recently provided guideline updates for C. difficile infection (CDI). In this narrative review, the authors reviewed available literature regarding the prevention or treatment of CDI in adults and focused on disagreements between the IDSA/SHEA and ACG guidelines, as well as articles that have been published since the updates. Several options for primary prophylaxis are available, including probiotics and antibiotics (vancomycin, fidaxomicin). The literature supporting fidaxomicin is currently quite limited. While there are more studies evaluating probiotics and vancomycin, the optimal patient populations and regimens for their use have yet to be defined. While the IDSA/SHEA guidelines discourage metronidazole use for mild CDI episodes, evidence exists that it may remain a reasonable option for these patients. Fidaxomicin has an advantage over vancomycin in reducing recurrences, but its use is limited by cost. Despite this, recent studies suggest fidaxomicin's cost-effectiveness as a first-line therapy, though this is highly dependent on institutional contracts and payment structures. Secondary prophylaxis should focus on non-antimicrobial options to lessen the impact on the microbiome. The oral option of fecal microbiota transplantation (FMT), SER109, and the now FDA-approved RBX2660 represent exciting new options to correct dysbiosis. Bezlotoxumab is another attractive option to prevent recurrences. Further head-to-head studies of newer agents will be needed to guide selection of the optimal therapies for CDI primary and secondary prophylaxis.

2002. Clostridioides difficile Infection Recurrence Trends and Characteristics at a Community Medical Center

Abstract Background Updated IDSA C. difficile Infection (CDI) guidelines recommend fidaxomicin as preferred therapy for initial infection as studies demonstrate increased sustained response 4 weeks after the end of therapy compared with vancomycin. Implementation of this is dependent upon available resources and vancomycin is recommended as an acceptable alternative. A course of fidaxomicin costs 30-50 times more than oral vancomycin and presents a pharmacoeconomic challenge. This study evaluated the incidence and characteristics of CDI recurrence in a community medical center to assess feasibility of implementing new CDI treatment recommendations. Methods This multicenter, retrospective study was conducted at Scripps Health from 1/1/2019 - 12/31/2019. Adult patients with an initial CDI diagnosis (EIA antigen/toxin positive) were included. The primary endpoint was clinical cure, defined as no recurrent episodes of CDI one year after treatment. Secondary endpoints evaluated baseline characteristics and treatment between patients experiencing recurrence or no recurrence. Outcomes were assessed using count and proportion for descriptive data and Chi-Square, Fisher’s Exact and Logistic Regression for categorical data. Results A total of 223 patients were included, of which 18.4% (41/223) had recurrence. There was no difference in recurrence based on age > 65, sex, ethnicity, severity, and inpatient status (p > 0.05). There were no differences in comorbidities (kidney disease, cardiovascular disease, diabetes, malignancy, or pulmonary disease, p > 0.05) with the exception of cerebrovascular disease which was significantly higher in patients with recurrence (34.2% vs 13.2%, P = 0.001). Recurrence rates were similar between treatment groups (p = 0.383) which included vancomycin (n = 193, 20%), fidaxomicin (n = 4, 25%), metronidazole (n = 9, 0%), and vancomycin + metronidazole (n = 17, 12%). Conclusion Presence of cerebrovascular disease was the only characteristic associated with a higher incidence of CDI recurrence. The majority of patients were treated with oral vancomycin, and there was no difference in recurrence based on treatment although there were low numbers in non-vancomycin cohorts. Vancomycin is an acceptable alternative for the management of CDI in our population. Disclosures All Authors: No reported disclosures.

383. Assessing the 2021 IDSA Treatment Clostridioides difficile Guidelines in a Small, Community Hospital

Abstract Background Cambridge Health Alliance (CHA) is an academic healthcare system in the greater Boston area that includes two acute care, community hospitals. Oral vancomycin has been the first line treatment option for initial C. difficile infection (CDI). In 2021, IDSA updated its guidelines to recommend fidaxomicin as the preferred treatment for initial episodes. At our institution, fidaxomicin is restricted to infectious diseases approval.The objective of this evaluation was to assess CDI recurrence rate and to identify a target population within our organization who may benefit from fidaxomicin as initial CDI treatment. Methods A retrospective chart review of all inpatients ordered for oral vancomycin or fidaxomicin from January 2021 to February 2022 was conducted to assess treatment success, failure, and 60 day recurrence rate of CDI at two community teaching hospitals. Treatment success was defined as resolution of diarrhea or absence of diarrhea for two consecutive days after completion of therapy. Treatment failure was defined as continuation of symptoms for greater than 6 days after treatment initiation. Risk factors for recurrence evaluated were age > 65 years, immunocompromised status, fulminant infection, and use of vancomycin versus fidaxomicin. Results A total of 47 patients administered oral vancomycin or fidaxomicin for CDI treatment between January 2021 and February 2022 were included in the analysis. Only one patient received fidaxomicin. The median age was 66 years and 55.3% female. Four patients were immunocompromised. Only one immunocompromised patient over 65 years had CDI recurrence. In our population, oral vancomycin had a treatment success rate of 85.1% and a recurrence rate of 2%. The one patient who received fidaxomicin did not have recurrence. Given the low recurrence rate, we were unable to identify significant risk factors associated with CDI recurrence in our population. Conclusion In our population, oral vancomycin had a high treatment success rate, which correlates with current literature. Limitations of our analysis include its retrospective design, small sample size, and inclusion of few immunocompromised patients. Oral vancomycin remains the preferred treatment for an initial CDI episode in our population, as recurrence rate is low. Disclosures All Authors: No reported disclosures.

Fidaxomicin monotherapy versus standard therapy combined with bezlotoxumab for treating patients with Clostridioides difficile infection at high risk of recurrence: a matched cohort study.

Both fidaxomicin and bezlotoxumab (used in combination with an antibiotic against Clostridioides difficile) achieve reductions in recurrence rates of C. difficile infection (CDI). However, the two strategies have never been compared. Data from two retrospective cohorts of 'real-life' use of fidaxomicin and bezlotoxumab in combination with a standard anti-C. difficile antibiotic were used to compare the rates of recurrence of both strategies. Since the two cohorts were not identical, we used a propensity score analysis. Three hundred and two patients were included: 244 in the fidaxomicin cohort and 78 in the bezlotoxumab cohort. A history of renal failure or immunosuppression was more frequent in patients receiving bezlotoxumab (39.7% and 66.7% versus 26.6% and 38.9%; P = 0.03 and P < 0.001, respectively), but the severity and number of previous CDI episodes were similar in both cohorts. We observed that 19.3% of the patients in the fidaxomicin cohort experienced recurrence, compared with 14.1% in the bezlotoxumab cohort (OR 1.45; 95% CI 0.71-2.96; P = 0.29) but the difference remained non-significant after propensity score matching using previously defined variables (OR 1.24; 95% CI 0.50-3.07; P = 0.64). Moreover, the multivariate analysis did not show differences depending on the drug used. We observed that fidaxomicin and bezlotoxumab are prescribed in similar clinical scenarios, although those treated with bezlotoxumab have greater comorbidity. The proportion of recurrences was numerically lower in those treated with bezlotoxumab, although the propensity analysis did not find significant differences between the two drugs.

16. Attributable Mortality, Healthcare Costs and Out-of-Pocket Costs of Clostridioides difficile Infection in US Medicare Advantage Enrollees

BackgroundUS attributable CDI mortality and cost data are primarily from Medicare fee-for-service populations. Little is known about Medicare Advantage Enrollees (MAEs), who comprise about 39% of the Medicare population.MethodsUsing 2017‒2019 Optum’s de-identified Clinformatics® Data Mart database, this retrospective cohort study identified first C difficile infection (CDI) episodes occurring in 2018 among eligible MAEs ≥66 y of age who were continuously enrolled for 12 mo before CDI diagnosis (baseline period). CDI was defined via ICD10 diagnosis codes or evidence of toxin testing with CDI antibiotic treatment. To assess all-cause mortality and CDI-associated healthcare and patient out-of-pocket (OOP) costs, CDI+ cases were matched 1:1 to CDI– controls using propensity scores (PS) and were followed through the earliest of death, disenrollment or end of the 12 mo followup. Additionally, outcome analyses were stratified by infection acquisition and hospitalization status.ResultsAmong 3,450,354 eligible MAEs, 15,195 (0.4%) had a CDI episode in 2018. Using PS generated from >60 variables collected in the baseline period, 14,928 CDI+ cases were matched to CDI– controls.Over 12 mo of follow-up, the difference in 1-y attributable mortality was 7.9% in the CDI+ (26.3%) vs CDI– (18.4%) cohort (Figure 1). CDI-attributable mortality was higher among hospitalized CDI+ cases (18.4% for healthcare associated [HA]; 13.1% for community associated [CA]) vs nonhospitalized CDI+ cases (HA, 4.5%; CA, 1.0%). Similarly, healthcare costs were higher for CDI+ vs CDI– patients, with excess mean total cost of &13,363 at the 2-mo follow-up (Figure 2). Total excess mean healthcare costs were greater among hospitalized CDI+ patients (HA, &28,139; CA, &28,136) than for nonhospitalized CDI+ patients (HA, &5741; CA, &2503). CDI-associated excess mean OOP cost was &409 for CDI+ cases at the 2 mo followup. Total excess mean OOP cost was highest in CA hospitalized CDI+ cases, followed by HA hospitalized CDI+ cases, HA nonhospitalized CDI+ cases and finally CA nonhospitalized CDI+ cases (&964, &574, &231 and &197, respectively). ConclusionCDI is associated with major mortality and total healthcare and OOP costs. Preventing CDI in the elderly may improve outcomes and reduce costs for healthcare systems and patients. Disclosures Holly Yu, MSPH, Pfizer Inc (Employee, Shareholder) Jennifer L Nguyen, ScD, MPH, Pfizer Inc. (Employee) Tamuno Alfred, PhD, Pfizer Inc. (Employee) Jingying Zhou, MA, MEd, Pfizer Inc (Employee, Shareholder) Margaret A. Olsen, PhD, MPH, Pfizer (Consultant, Research Grant or Support)

746. Clinical and Microbiological Characteristics of Clostridioides difficile Infection After a Change in Diagnostic Testing Algorithm

Abstract Background There is a lack of consensus on the most appropriate testing for C. difficile infection (CDI). The objective of this study was to determine the clinical and microbiological characteristics of CDI following a switch from stool PCR testing only to PCR reflexed to toxin testing. Figure 1. PCR Cycle Threshold Values Methods We reviewed the characteristics and outcomes of 50 consecutive patients who tested positive for CD by PCR (Xpert CD, Cepheid) between October 2019 and January 2020 at the Hines VA Hospital. Cases were defined by results of reflex toxin testing (Cdiff quick check complete, Alere/TechLab) after a positive PCR result. Baseline characteristics, symptoms, initial laboratory data, and treatments were compared as well as patient outcomes, including hospital readmission due to CDI at 30 days, and recurrent CDI (rCDI) at 30 and 90 days. The cycle threshold for the stool PCR result was recorded. Stools were cultured anaerobically for CD, and restriction endonuclease analysis (REA) strain typing was performed on the recovered CD isolates. Results Toxin testing was positive in 19/50 (38%) cases. Compared to stool toxin-negative cases, toxin-positive cases were older (95% vs. 71% were age ≥ 65, p = 0.06), more likely to have a history of CDI (37% vs. 23%, p = 0.34), and have ≥ 1 CDI episodes within 6 months (37% vs. 19%, p = 0.26). Treatment for CDI was more common in patients who had a positive toxin text. (95% vs 61%, p= 0.009). Among the 38 patients that received treatment, 33 received vancomycin (87%) and 8 patients (21%) had rCDI at 30 days. Of the 8 patients with rCDI, 2 were re-admitted to the hospital for CDI. The average PCR cycle threshold was lower in the toxin-positive stools compared to toxin-negative stools (24.46 and 29.96, p&amp;lt; 0.001; Fig. 1) The endemic REA group Y was the most common CD strain recovered (30%) and the previously epidemic and virulent REA group BI strain was recovered in 11% of the cases. Conclusion CDI cases diagnosed by positive stool PCR and positive toxin tests had more typical risk factors for CDI, a lower PCR cycle threshold and were more likely to have been treated for CDI. Outcomes were similar in this setting where infection with the virulent BI strain was uncommon. Disclosures Stuart Johnson, MD, Acurx Pharmaceuticals (Advisor or Review Panel member)Bio-K+ (Advisor or Review Panel member)Ferring Pharmaceutical (Advisor or Review Panel member)

#37: Clinical Characterization of the Cases Relating to the Outbreak of Clostridioides difficile, in a Third-level Hospital in Mexico City: Diagnosis, Treatment, and Relay

Abstract Background Clostridioides difficile is an important cause of healthcare-associated infections. The epidemiology of C. difficile infection (CDI) in children has changed over the past few decades. There is now a higher incidence in hospitalized children, and there has been an emergence of community-onset infection. Neonates and young infants have high rates of colonization but rarely have symptoms. The well-known risk factor for CDI in children age 2 years or older is antibiotic use. Inflammatory bowel disease and cancer are associated with increased incidence and severity of CDI. Vancomycin or fidaxomicin is recommended for an initial episode of CDI. In environments where access to Vancomycin or Fidaxomycin is limited, it is suggested to use metronidazole for an initial episode of nonsevere CDI only. Methods A series of cases were carried out, in a study period from March to May 2018, total cases 8; the age group, sex, basic diagnosis, clinical findings, diagnostic method, and outcome in hospitalized patients in the Pediatric division of the “CMN 20 de Noviembre, ISSSTE” were described, where there is a total of 377 Sensitive beds, and 53 beds in the pediatric area of which 30 are not sensitive. Results We analyzed 8 cases of diarrhea with identification of C. difficile, in a period of 3 months, where there was a total of 148 admissions to the division of Pediatrics (100%) and presented a prevalence of 0.05% of the total income. Of those 8 cases reported, 37.5% were women and 62.5% men; The age fluctuated between 6 months and 18 years. All children had associated comorbidities. The frequency and type of comorbidities were Cancer 87.5% (Leukemias and Solid Tumors) and Neurological 12.5% ​​(Arterial Malformation and Neurological Sequelae). The main symptom that occurred was mucous diarrhea in 100% of patients, abdominal pain in 25% and evacuation with blood in 12.5% ​​of cases. All had a history of prior treatment with 100% broad-spectrum antibiotics, in a period of less than one month. All were treated with metronidazole (100%) and all presented clinical improvement, without complications; Similarly, all were diagnosed by PCR for toxin B (100%). The attributable risk of presenting Clostridioides disease in patients with Leukemia is 0.11. Conclusions Patients with Leukemia were the most affected during the C. difficile outbreak, of which 11 out of 100 of these patients are at risk of presenting C. difficile disease. The most important thing in these cases is prevention. Therefore, specific prevention measures were implemented to reduce the possibility of future outbreaks, such as handwashing with chlorexidine, contact isolation, handwashing every time there is contact with the patient, use of gloves when performing procedures, insulation of bedding in plastic bags and training of health personnel.

Outcomes associated with recent guideline recommendations removing metronidazole for treatment of non-severe Clostridioides difficile infection: a retrospective, observational, nationwide cohort study

ObjectivesThe 2017 Society for Healthcare Epidemiology of America (SHEA) and Infectious Diseases Society of America (IDSA) Clinical Practice Guidelines for Clostridioides difficile (C. difficile) infection (CDI) removed metronidazole as a preferred option for initial episodes of non-severe CDI. This study aimed to determine if the shift away from metronidazole improved clinical outcomes of initial episodes of non-severe CDI. MethodsThe study was a retrospective, observational, nationwide cohort study using a Veterans Health Administration national clinical administrative database. Adult patients treated for non-severe CDI before and after the February 2018 publication of the 2017 IDSA/SHEA C. difficile Clinical Practice Guidelines were included. The primary outcome was the composite of treatment failure or probable recurrence. ResultsA total of 3608 patients were included, with 1809 in the pre-guideline cohort (mean [SD] age, 65.5 [14.2] years; 1602 [88.6%] male) and 1799 in the post-guideline cohort (mean [SD] age, 64 [14.6] years; 1584 [88%] male). Overall composite of treatment failure or probable recurrence was similar between both cohorts (318 of 1809 [17.6%] pre-guideline cohort vs. 317 of 1799 [17.6%] post-guideline cohort [P = 0.97]). ConclusionThe shift away from metronidazole as a preferred option in initial non-severe Clostridioides difficile infection did not improve the composite of treatment failure or recurrence.

729. Real World Efficacy of Bezlotoxumab for Prevention of Clostridioides Difficile Recurrence in Immunosuppressed Patients

BackgroundBezlotoxumab has been shown to prevent recurrent episodes of C. difficile infection (CDI) in high risk patients. Current studies define therapeutic efficacy within the first 12 weeks when the risk of recurrence is greatest. However, the risk of recurrent CDI can occur beyond the 12-week window in the immunosuppressed population. Given that bezlotoxumab has detectable serum levels for up to 24 weeks after infusion, the primary endpoint is to determine overall efficacy in immunosuppressed patients with recurrent CDI at 4 weeks, 12 weeks, and 24 weeks after initial infusion. Secondary endpoints consist of risk factors for recurrent CDI, treatment of CDI, and antibiotics usage before and after bezlotoxumab.MethodsThis analysis included immunosuppressed patients at high risk for CDI recurrence who received bezlotoxumab from February 2017 to December 2019. Patients were excluded if they were not immunosuppressed, had no follow-up appointments, and/or without a C. difficile positive test. High risk antibiotics included fluoroquinolones, beta lactamase inhibitors, third generation cephalosporins, or carbapenems.ResultsTwenty-seven bezlotoxumab doses were given to 26 patients. Baseline characteristics for CDIs prior to bezlotoxumab is reported in Table 1. The overall CDI recurrence rate at all intervals after bezolotoxumab was 4 (15%), one recurrent CDIs occurred at < 4 weeks, two recurrent CDIs occurred at 5-12 weeks, and one recurrent CDI at 13-24 weeks. High risk antibiotics were given in 2/4 (50%) of CDIs recurrences and 22/75 (29%) in the non-recurrence group. Of the four CDI recurrences, all were mild to moderate in disease severity given no evidence of colitis was seen on CT scan and a median Zar score of 1 (range 0-1) due to age > 60 years.Table 1: Baseline Characteristics ConclusionIn immunosuppressed patients with CDI, bezlotoxumab is effective at reducing CDI episodes up to 24 weeks. Additionally, this highly antibiotic exposed population continued to receive benefit up to 24 weeks after bezlotoxumab.Disclosures All Authors: No reported disclosures

792. Evaluation of Persistent Diarrhea and Recurrence Following Fecal Microbiota Transplantation for Recurrent Clostridioides difficile Infection

BackgroundPatients treated for C. difficile infection (CDI) have high rates of recurrence. Fecal microbiota transplantation (FMT) is an effective therapy for patients with recurrent CDI. While highly successful, there are limited data to help clinicians predict which patients are more likely to have adverse outcomes following FMT. Here we aim to identify factors that are associated with recurrent CDI or persistent diarrhea following FMT for treatment of recurrent CDI.MethodsAt a large academic medical center, we conducted a retrospective cohort study of patients receiving their first FMT for recurrent CDI using product from a commercial stool bank. Patients were included if follow-up data on post-FMT outcomes were available. Through manual chart review, we collected information on patient demographics, comorbid disease burden, prior CDI, and antibiotic use prior to FMT. Outcomes included recurrent CDI and persistent diarrhea not from CDI, both within 90 days of FMT. Unadjusted and adjusted analyses via logistic regression were used to model the outcomes.ResultsThis study included 81 subjects, of which 72 (89%) experienced no recurrence following FMT. In the multivariable model, the odds of recurrence decreased as BMI rose and with each 1-log increase in the duration of antibiotic therapy for CDI prior to FMT (Table). Among the 72 subjects not diagnosed with recurrent CDI following FMT, 26 (36%) experienced persistent diarrhea for which further work-up or therapy was recommended. History of irritable bowel syndrome (IBS) was the only predictor independently associated with persistent diarrhea while adjusting for age and number of prior CDI episodes (Table). IBS was also the most common etiology identified by the subjects’ clinical teams for persistent diarrhea following FMT.Table. Multivariable models of adverse outcomes following FMT for CDI ConclusionWe found FMT for CDI at our center to be effective in curing CDI without subsequent recurrence, at a level similar to what is seen from randomized controlled trials. Higher BMI and longer duration of antibiotic therapy for CDI prior to FMT may be protective against recurrence. Still, a significant proportion of patients experienced persistent non-C. difficile related diarrhea, and patients with a history of IBS were more likely to have persistent diarrhea after FMT.DisclosuresKrishna Rao, MD, MS, Bio-K+ International, Inc. (Consultant)Merck and Co., Inc. (Research Grant or Support)Roche Molecular Systems, Inc. (Consultant)

Navigating changes in Clostridioides difficile prevention and treatment.

Clostridioides difficile (C. difficile, previously known as Clostridium difficile) infections are a major health care concern. The Centers for Disease Control and Prevention (CDC) estimates that C. difficile causes almost half a million illnesses in the United States yearly, and approximately 1 in 5 patients with a C. difficile infection (CDI) will experience 1 or more recurrent infections. The incidence of infection has risen dramatically in recent years, and infection severity has increased due to the emergence of hypervirulent strains. There have been noteworthy advances in the development of CDI prevention and treatment, including a growth in the understanding of the role a patient's gut microbiome plays. The 2017 Infectious Diseases Society of America (IDSA) guidelines made a significant change in treatment recommendations for first time CDI episodes by recommending the use of oral vancomycin or fidaxomicin in place of metronidazole as a first-line treatment. The guidelines also included detailed recommendations on the use of fecal microbiota transplant (FMT) in those patients who experience 3 or more recurrent CDI episodes. A number of novel therapies for the treatment of CDI are in various stages of development. Treatments currently in phase 3 trials include the antibiotic ridinilazole, the microbiome products SER-109 and RBX2660, and a vaccine. All of these agents have shown promise in phase 1 and 2 trials. Additionally, several other antibiotic and microbiome candidates are currently in phase 1 or phase 2 trials. A qualitative review and evaluation of the literature on the cost-effectiveness of treatments for CDI in the U.S. setting was conducted, and the summary provided herein. Due to the higher cost of newer agents, cost-effectiveness evaluations will continue to be critical in clinical decision making for CDI. This paper reviews the updated CDI guidelines for prevention and treatment, the role of the microbiome in new and recurrent infections, pipeline medications, and comparative effectiveness research (CER) data on these treatments. DISCLOSURES: Durham and Le have nothing to disclose. Cassano reports consulting fees from Baxter Healthcare. Peer reviewers Drs. Ami Gopalan and Mark Rubin and Ms. Kathleen Jarvis have nothing to disclose. Planners Dr. Christine L. Cooper and Ms. Susan Yarbrough have nothing to disclose.

Development and verification of an enzyme-linked immunosorbent assay for the quantification of toxoid A and toxoid B from Clostridioides difficile

Clostridioides difficile (C. difficile) is the most common cause of nosocomial antibiotic associated diarrhoea. The incidence of C. difficile infection (CDI) has been rising worldwide over the last 20 years with consequent rises in morbidity, mortality and healthcare costs, although the incidence has fallen in the UK over the last few years. Confirmation of diagnosis and early intervention are critical to the management of CDI. The standard treatment for CDI is the administration of antibiotics. However, vaccination has been recognized as the most cost-effective treatment for the prevention and possible long-term protection against CDI episode. There are several promising vaccine candidates in various stages of development. Many of these vaccines have displayed good efficacy for CDI under laboratory conditions or in clinical trials. With the emergence of vaccines against C. difficile, here we describe the development and verification of an Enzyme Linked Immunosorbent Assay (ELISA) that can be used for the quality control testing of candidate vaccines against C. difficile through the measurement of vaccine antigen content. Verification of the assay was performed by assessment of specificity, sensitivity, intermediate precision and relative accuracy. The ELISAs were specific for the toxoids being detected and the detection limit of the assay for toxoid A was 4.88 ng/mL and 3.91 ng/mL for toxoid B. The geometric coefficients of variation for intermediate precision did not exceed 25% and relative accuracy was within 77–130%. We therefore conclude that the ELISA described here is sufficiently sensitive, specific, precise and accurate for use for the quality control testing of candidate C. difficile vaccines.

S0650 Fecal Microbiota Transplantation Decolonizes C. difficile in Patients With Inflammatory Bowel Disease and Concomitant C. difficile Infection

INTRODUCTION: Patients with inflammatory bowel disease (IBD) are at increased risk for C. difficile infection (CDI) and associated morbidity and mortality. Persistent C. difficile colonization occurs even after standard-of-care CDI antibiotics, and may contribute to the increased risk of recurrent CDI. Additionally, C. difficile colonization has public health consequences as patients may spread C. difficile and may lead to contact isolation and high-cost cleaning procedures in a healthcare setting. Fecal microbiota transplantation (FMT) is a promising therapy for recurrent CDI, however its efficacy among IBD patients is limited and the rate of decolonization is unknown. Accordingly, we assessed the safety, efficacy and C. difficile decolonization rate in in IBD patients with recurrent CDI following FMT. METHODS: This open-label, prospective single-arm multicenter cohort study enrolled patients from 4 tertiary care centers. Patients with IBD and 2 or more episodes of CDI received a single colonoscopic FMT from a universal stool bank. CDI testing (GDH/Toxin EIA and PCR) was performed pre-FMT, and at 1, 8, and 12 weeks post-FMT. The primary outcome was FMT failure through week 8 (defined as diarrhea and Toxin EIA positive for C. difficile). The secondary outcome assessed was C. difficile decolonization post-FMT (defined as negative PCR testing) at week 12. RESULTS: 50 participants were enrolled with a mean age of 43.3 years (range 21–91) and primarily female (n = 28, 56%), 14 of which had Crohn's disease (CD) (mean HBI = 6.4) and 36 had ulcerative colitis (UC) (mean Partial Mayo Score = 4.5). One patient did not receive FMT after enrollment. There were no treatment-related serious adverse events. Among the treated patients, 8% (4/49) participants experienced a confirmed FMT failure and received a second FMT. Two additional patients received a repeat FMT based on investigator discretion. In terms of C. difficile decolonization, 88.9% (40/45 eligible participants) experienced decolonization at week 12 follow-up period. CONCLUSION: To our knowledge, this is the largest prospective trial to assess the safety, efficacy and C. difficile decolonization rate of FMT in patients with IBD-CDI. This data suggests FMT is a safe and promising therapy for preventing CDI recurrence and achieving C. difficile decolonization which may have public health and economic implications. Future randomized controlled trials are needed.

Faecal Microbiota Transplantation is Effective for the Initial Treatment of Clostridium difficile Infection: A Retrospective Clinical Review.

IntroductionClostridium difficile (C. difficile) infection (CDI) is commonly recognised as a nosocomial infection but is increasingly identified in patients in the community. Antimicrobial exposure which compromises gut microbiota is the main risk factor for CDI, although antibiotics remain the main treatment for this infection. Faecal microbiota transplantation (FMT) is also an effective treatment for CDI. FMT involves the transfer of microbiota from a healthy donor to an unwell patient. Currently FMT is mostly used after repeated antibiotic treatments fail to cure CDI. This study investigated the effect of FMT as first-line treatment for CDI to avoid repeated antibiotic damage of the microbiome.MethodsThis retrospective, single-centre study included 59 patients between 2012 and 2017 whose first episode of CDI was treated with FMT. The patients’ symptoms and presence of C. difficile in stool samples both at the baseline and post treatment were documented.ResultsFifty-four patients completed a final stool test 4–8 weeks post treatment in which 98% of patients were negative for C. difficile. There were no adverse effects. There was a significant reduction in abdominal pain, diarrhoea, bloating and blood in the stool at 4–8 weeks post treatment. Data from 24 patients who completed an extended 6 months follow-up showed significant reduction in abdominal pain, diarrhoea and blood in the stool.ConclusionThis study demonstrates the safety and efficacy of FMT as first-line treatment for patients’ initial episode of CDI. Future randomised studies are required to confirm FMT as the initial treatment for CDI.

Healthcare associated Clostridioides difficile infection in adult surgical and medical patients hospitalized in tertiary hospital in Belgrade, Serbia: a seven years prospective cohort study

ABSTRACT Introduction: Clostridioides difficile (C. difficile) infection (CDI) is one of the most common healthcare-associated (HA) infections in contemporary medicine. The risk factors (RFs) for HA CDI in medical and surgical patients are poorly investigated in countries with a limited resource healthcare system. Therefore, the aim of the study was to investigate differences in patients’ characteristics, factors related to healthcare and outcomes associated with HA CDI in surgical and medical patients in tertiary healthcare centre in Serbia. Materials and Methods: A prospective cohort study was conducted including adult patients diagnosed with initial episode of HA CDI, first recurrence of disease, readmission to hospital, while deaths within 30 days of CDI diagnosis and in-hospital mortality were also recorded. Patients hospitalized for any non-surgical illness, who developed initial HA CDI were assigned to medical group, whereas those who developed initial HA CDI after surgical procedures were in surgical group. The data on patients’ characteristics and factors related to healthcare were collected, too. Results: During 7-year period, from 553 patients undergoing in-hospital treatment and diagnosed with CDI, 268 (48.5%) and 285 (51.5%) were surgical and medical patients, respectively. Age ≥ 65 years, use of proton pump inhibitors, chemotherapy and fluoroquinolones were positively associated with being in medical group, whereas admission to intensive care unit and use of second- and third-generation cephalosporins were positively associated with being in surgical group. Conclusions: Based on obtained results, including significant differences in 30-day mortality and in-hospital mortality, it can be concluded that medical patient were more endangered with HA CDI than surgical ones.

Antimicrobial susceptibility and molecular characterisation using whole-genome sequencing of Clostridioides difficile collected in 82 hospitals in Japan between 2014 and 2016.

We studied the antimicrobial susceptibility and the molecular characteristics using draft whole-genome sequencing of Clostridioides (Clostridium) difficile strains before and after treatment in adults with C. difficile infection (CDI) enrolled in a Phase III, randomised, nationwide study of fidaxomicin versus vancomycin in Japan (NCT02179658). C. difficile strains were cultured from stool samples collected before and after standard treatment with either fidaxomicin or vancomycin. Overall, 285 C. difficile strains were recovered, with 188 derived from CDI cases at baseline (87 patients received fidaxomicin and 101 received vancomycin). No strains isolated from episodes of CDI at baseline were shown to have reduced susceptibilities to fidaxomicin (MIC ≥1 mg/L), or resistance to vancomycin and metronidazole. Thirty-three sequence types (STs) were identified, the most common being ST17 (n=61; 32.4%), ST8 (n=26; 13.8%) and ST2 (n=21; 11.2%). Core-genome single nucleotide polymorphism analysis showed that outbreaks of C. difficile were unlikely to have occurred at each hospital. The predominant toxin gene profile was tcdA+tcdB+cdtA/cdtB- (n=149; 79.3%). Six of 87 patients who received fidaxomicin harboured C. difficile isolates with reduced fidaxomicin susceptibilities conferred by previously described mutations, Val1143Leu/Gly/Asp in RpoB or Arg89Gly in RpoC or putative mutations, Gln1149Pro in RpoB or Arg326Cys in RpoC. Allelic exchange studies of these putative mutations were not performed. Prior to fidaxomicin use, we found no C. difficile strains with reduced fidaxomicin susceptibilities causing CDI in Japan; however, mutant strains with reduced fidaxomicin susceptibilities were detected after fidaxomicin treatment.

210 Clostridioides (Clostridium) difficile PCR Amplification Cycle Threshold: More Than Just a Number?

INTRODUCTION: The optimal diagnostic approach for C. difficile infection (CDI) is controversial. Infectious Disease Society of America currently recommends a high sensitivity test such as a nucleic acid amplification test (NAAT) PCR, followed by a stool toxin enzyme immunoassay to confirm clinical suspicion of CDI. C. difficile PCR cycle threshold (Ct) is the number of cycles required for a signal to exceed background fluorescence with low numbers reflecting a larger C. difficile nucleic acid burden. Recent reports correlate Ct in symptomatic patients with disease severity and mortality. Data regarding the predictive value of PCR Ct in recurrence of CDI is preliminary. We aim to determine the association between Ct and recurrence of CDI. METHODS: This was an IRB approved, single-center retrospective chart review cohort of 76 randomly chosen patients ≥18 y.o., with completely unformed stools that were C.difficile NAAT positive. 10 patients were excluded due to lack of Ct values. Recurrence defined as any positive test for C. difficile within 3 months after treatment for CDI. Severe CDI defined as WBC &gt;15,000 or creatinine ≥1.5 md/dL and fulminant disease as refractory hypotension, ileus or megacolon. Poor clinical outcome defined as severe or fulminant CDI, or death within 30 days of diagnosis. A t-test or Mann Whitney U test was performed on populations with or without a normal distribution, respectively. A scatterplot was generated with Ct values for patients with initial vs recurrent episodes of CDI. RESULTS: Of 66 patients, mean Ct values of 8 patients with recurrent CDI (12.1%) and 58 without recurrence were 25.71 and 26.15 respectively (P = 0.79). Recurrence rates after the initial episode of CDI (n = 4), 1st recurrence (n = 1), and 2nd/subsequent recurrence (n = 3) were 9.1%, 12.5% and 21.2%, respectively. Mean Ct values trended lower for patients with poor outcomes (25.40 vs 26.42, P = 0.37). CONCLUSION: In our single center study, Ct values did not associate with a recurrence of CDI. Our findings suggest that Ct cannot be used to predict which patients will be at risk for recurrent CDI. The trend of lower Ct values associating with worse outcomes is worth a prospective study. Interestingly, there was no association with Ct values and common risk factors for CDI such as prior antibiotic use, suggesting that Ct values may not clarify current controversies in testing for CDI.

Ribotype variability of Clostridioides difficile strains in patients with hospital-acquired C. difficile infections, community-acquired C. difficile infections, and colonization with toxigenic and non-toxigenic strains of C. difficile

There have been few available data that presented a direct comparison between polymerase chain reaction ribotype (RT) distribution of Clostridioides difficile strains from C. difficile infection (CDI) and colonization. To understand the epidemiology of CDI in a hospital setting, we compared RTs of C. difficile strains from hospital-acquired CDI (HA-CDI) and toxigenic colonization and from community-acquired CDI (CA-CDI) and non-toxigenic colonization using the stool samples submitted for C. difficile cultures at an institution during 2009, 2012, and 2014. Overall, 721 C. difficile strains were identified from 607 patients. Among them, 450 (62.4%) were HA-CDI, 20 (2.8%) were CA-CDI, 126 (17.5%) were toxigenic colonization, and 125 (17.3%) were non-toxigenic colonization. RT018, RT017, RT002, RT015, and RT001 isolates were the most prevalent RTs in HA-CDI, and they comprised 74.9% of the total HA-CDI isolates but accounted for 60.4% of isolates from toxigenic colonization. In total, 32 strain compromising 18 RTs from HA-CDI (7.1%) were not seen among the toxigenic colonization group, and 3 RTs with 5 strains from toxigenic colonization were not seen among the HA-CDI group. The distribution of RTs was the most diverse in CA-CDI and the least diverse in HA-CDI. Although 5 RT strains, which were prevalent in HA-CDI, comprised 40% of CA-CDI, 5 isolates (25%) revealed unknown RTs, which were uncommon in HA-CDI or toxigenic colonization. In 12 patients with both episodes of CDI and toxigenic colonization, 8 had 2 isolates with different RTs and 4 had isolates with identical RTs. In conclusion, although RT017 and RT018 were the most common in HA-CDI and toxigenic colonization, C. difficile strains from toxigenic colonization were more diverse than those from HA-CDI.