Treatment Of C. Difficile Infection Research Articles

The vanRCd Mutation 343A>G, Resulting in a Thr115Ala Substitution, Is Associated with an Elevated Minimum Inhibitory Concentration (MIC) of Vancomycin in Clostridioides difficile Clinical Isolates from Florida.

Clostridioides difficile, the primary cause of nosocomial antibiotic-associated diarrhea, has a complex relationship with antibiotics. While the use of broad-spectrum antibiotics disrupts the gut microbiota and increases the risk of C. difficile infection (CDI), antibiotics are also the primary treatment for CDI. However, only a few antibiotics, including vancomycin, fidaxomicin, and rifaximin, are effective against CDI, and resistance to these antibiotics has emerged recently. In this study, we report the identification of two RT027 C. difficile clinical isolates (TGH35 and TGH64) obtained from symptomatic CDI-diagnosed patients in Tampa, Florida in 2016. These two strains showed an elevated minimum inhibitory concentration (MIC) of vancomycin (MIC = 4 μg/mL, compared to the EUCAST breakpoint of 2 μg/mL) and contained a vanRCd 343A>G mutation resulting in a Thr115Ala substitution in the VanRCd response regulator. This mutation was absent in the vancomycin-sensitive control epidemic strain RT027/R20291. TGH64 was also resistant to rifaximin (MIC ≥ 128 μg/mL) and carried the previously reported Arg505Lys and Ile548Met mutations in RpoB. Furthermore, we report on the antimicrobial resistance (AMR) and genomic characterization of additional C. difficile isolates, including RT106/TGH120, RT017/TGH33, and RT017/TGH51, obtained from the same patient sample cohort representing the highly prevalent and regionally distributed C. difficile ribotypes worldwide. Considering that the VanRCd Thr115Ala mutation was also independently reported in seven C. difficile clinical isolates from Texas and Israel in 2019, we recommend epidemiological surveillance to better understand the impact of this mutation on vancomycin resistance. IMPORTANCE The perpetually evolving antimicrobial resistance (AMR) of C. difficile is an important contributor to its epidemiology and is a grave concern to global public health. This exacerbates the challenge of treating the infections caused by this multidrug-resistant causative organism of potentially life-threatening diarrhea. Further, the novel resistance-determining factors can be transferred between different strains and species of bacteria and cause the spread of AMR in clinical, environmental, and community settings. In this study, we have identified a mutation (vanRCd 343A>G) that causes a Thr115Ala substitution and is linked to an increased MIC of vancomycin in clinical isolates of C. difficile obtained from Florida in 2016. Understanding the mechanisms of AMR, especially those of newly evolving strains, is essential to effectively guide antibiotic stewardship policies to combat antibiotic resistance as well as to discover novel therapeutic targets.

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.

Clostridioides difficile, a New "Superbug".

Clostridioides difficile is a Gram-positive, spore-forming, anaerobic bacterium. The clinical features of C. difficile infections (CDIs) can vary, ranging from the asymptomatic carriage and mild self-limiting diarrhoea to severe and sometimes fatal pseudomembranous colitis. C. difficile infections (CDIs) are associated with disruption of the gut microbiota caused by antimicrobial agents. The infections are predominantly hospital-acquired, but in the last decades, the CDI patterns have changed. Their prevalence increased, and the proportion of community-acquired CDIs has also increased. This can be associated with the appearance of hypervirulent epidemic isolates of ribotype 027. The COVID-19 pandemic and the associated antibiotic overuse could additionally change the patterns of infections. Treatment of CDIs is a challenge, with only three appropriate antibiotics for use. The wide distribution of C. difficile spores in hospital environments, chronic persistence in some individuals, especially children, and the recent detection of C. difficile in domestic pets can furthermore worsen the situation. "Superbugs" are microorganisms that are both highly virulent and resistant to antibiotics. The aim of this review article is to characterise C. difficile as a new member of the "superbug" family. Due to its worldwide spread, the lack of many treatment options and the high rates of both recurrence and mortality, C. difficile has emerged as a major concern for the healthcare system.

Clinical outcomes for Clostridioides difficile associated diarrhea in inflammatory bowel disease patients versus non-IBD population: A retrospective cohort study.

Patients with inflammatory bowel disease (IBD) have a higher incidence of Clostridioides difficile infection (CDI). Previous studies have demonstrated negative clinical outcomes in IBD patients with CDI compared to patients without CDI. The clinical presentation of CDI is indistinguishable from IBD exacerbation, thus posing a frequent clinical dilemma on the role of Clostridioides infection in the testing, diagnosis, and treatment of these patients. To compare clinical outcomes of CDI in patients with IBD to those without IBD. Retrospective cohort of adult patients admitted to Rabin Medical Center Israel between the years 2014 and 2020 with a concurrent diagnosis of IBD and CDI. Matching 1:2 was performed between the IBD patients and the non-IBD population with respect to age and sex. Sixty-seven patients with IBD and 134 patients without IBD were included in the study. The groups' median age was 40.6 (interquartile range [IQR] of 29.8-68.9), with 45.8% male and 54.2% female. The non-IBD group had a higher Charlson score with 2 (IQR 0; 5) versus 0 (IQR 0; 4) in the IBD group (P value <.01). Patients with IBD had more exposure to systemic antibiotics, 71.1% versus 26.3% (P value <.01). In a multivariable analysis we found no difference in 90-day mortality and rate of relapse between the 2 study groups with an odds ratio of 1.709 (95% confidence interval 0.321-9.905) and odds ratio of 0.209 (95% confidence interval 0.055-1.513) respectively. In our cohort patients with IBD who present with diarrhea and concomitant CDI have similar rates of relapse and mortality compared with patients without IBD.

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.

Real-World Budget Impact of Fidaxomicin versus Vancomycin or Metronidazole for In-Hospital Treatment of Clostridioides difficile Infection

Fidaxomicin, a macrocyclic antibiotic, selectively kills Clostridioides difficile and reduces C. difficile infection (CDI) recurrence compared with vancomycin, but some studies and guidelines report fidaxomicin as being less cost-effective. The aim of this study was to compare the cost-effectiveness and budget impact of fidaxomicin versus vancomycin or metronidazole for treating CDI in a real-world UK setting. Data were retrospectively collected from medical records of 86 patients with CDI treated with vancomycin or metronidazole at a single UK hospital between April 2011 and March 2012, and prospectively from 62 patients with CDI treated with fidaxomicin between August 2012 and July 2013. CDI cases were matched by age, financial year, and healthcare resource use to control cases. CDI recurrence rates were lower with fidaxomicin (6.5%) than vancomycin/metronidazole (19.8%). An estimated 12 additional recurrent CDIs were prevented with fidaxomicin treatment. Patients with CDI had significantly higher healthcare costs than those without CDI, with a mean excess spend of GBP 10,748 and GBP 17,451 per patient in the fidaxomicin (p = 0.015) and vancomycin/metronidazole cohorts (p < 0.001), respectively. A second CDI was associated with mean excess costs of GBP 8373 and GBP 20,249 per patient in the fidaxomicin and vancomycin/metronidazole cohorts, respectively. Despite higher fidaxomicin drug costs, overall cost savings were estimated at GBP 140,292 (GBP 2125 per CDI). In this real-world study, first-line CDI treatment with fidaxomicin reduced healthcare costs versus vancomycin/metronidazole, consistent with previous studies.

Microbial ecology between Clostridioides difficile and gut microbiota.

Clostridioides difficile colonizes a polymicrobial environment in the intestine and is a causative agent for antibiotic-associated diarrhea (AAD) and pseudomembranous colitis (PMC). The most important virulence factors of C. difficile are bacterial toxins, and three toxins (toxin A, toxin B, and binary toxin) are produced by toxigenic strains. Other virulence factors include spores, flagella, capsules, biofilms, hydrolytic enzymes and adhesins. C. difficile infection (CDI) is specifically diagnosed by anaerobic culture and toxin detection by either nucleic acid amplification test (NAAT) or enzyme-linked immunosorbent assay (ELISA). For treatment of CDI, metronidazole, vancomycin and fidaxomicin are used based on the severity of CDI. Mutual interaction between C. difficile and gut microbiota is associated with pathogenesis of CDI, and decreased microbial diversity with altered gut microbiome was detected in CDI patients. Restoration of certain gut microbiota is considered to be potentially effective for the prevention and treatment of CDI, and an ideal goal for CDI patients is restoration of the gut microbiota to a healthy state. Fecal microbiota transplantation (FMT) is a highly successful method of microbiome restoration and has been reported to be effective for the prevention of recurrent CDI. In addition, approaches to restoring the gut microbiota by using probioitcs and live biotherapeutic products (LBPs) are currently being studied to examine the effect on CDI. Further microbial ecological research on C. difficile and gut microbiota could lead to a better understanding of the pathogenesis and treatment of CDI.

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 &amp;gt; 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.

730. A Phase 3, Randomized, Double-Blind Study to Evaluate the Efficacy and Safety of Ridinilazole Compared with Vancomycin for the Treatment of Clostridioides difficile Infection

Abstract Background Vancomycin (VAN) therapy for C. difficile infection (CDI) is effective with &amp;gt; 80% clinical response (CR) but is associated with 20–30% recurrence rate (rCDI). Secondary bile acids (2° BAs) inhibit C. difficile germination and help prevent rCDI. VAN depletes the gut microbiome decreasing the conversion of primary bile acids to 2° BAs. Ridinilazole (RDZ) is a highly selective anti-CDI, DNA-binding antibiotic in development for the treatment of CDI and prevention of rCDI. Methods A global, double-blinded, randomized Phase 3 trial assessed a 10-day treatment with RDZ 200 mg BID vs VAN 125 mg QID for CDI. The primary endpoint was sustained clinical response (SCR) defined as CR and no rCDI through 30 days post-end of treatment (EOT). Other endpoints included rCDI, microbiome diversity and composition, and microbiome-derived 2° BAs concentration. rCDI was defined as a new episode of diarrhea with confirmed positive free toxin test (FTT), requiring additional CDI therapy. All participants were monitored for treatment emergent adverse events (TEAE). Results Of the 759 patients (pts) enrolled, 745 were included in the mITT population (RDZ n=370, VAN n=375). RDZ achieved a numerically higher SCR rate than VAN (73.0% vs 70.7%) p=0.4672. RDZ resulted in a significant reduction in rCDI rate (8.1% vs 17.3%, p=0.0002) (Fig 1). In a pre-specified subpopulation, this was most notable in pts not receiving other antibiotics (rCDI 6.7% in RDZ vs 16.5% in VAN, p=0.0005). Microbiome alpha diversity was higher for RDZ vs VAN at EOT and EOT+30d (p&amp;lt; 0.0001 and p≤ 0.0007 respectively, Fig 2) as were relative abundance (p&amp;lt; 0.0001 and p=0.0203 respectively), and concentrations of 2° BAs (Fig 3). Higher microbiome diversity and concentrations of 2° BAs at EOT were associated with both lower rCDI and higher SCR rates. RDZ was well tolerated (pts with ≥ 1 TEAE: RDZ 36.4% vs VAN 35.5%, treatment discontinuation due to TEAE: RDZ 0.8% vs. VAN 2.9%). Conclusion RDZ was effective for sustained clinical response and safe for the treatment of patients with CDI. This was most notable in pts not receiving antibiotics. Compared to VAN, RDZ patients had faster recovery of fecal 2° BA, consistent with the preservation of microbiome diversity, resulting in a significantly lower rate of rCDI. Disclosures Pablo C. Okhuysen, MD, AstraZeneca: Stocks/Bonds|Beam Therapeutics: Stocks/Bonds|Biontech: Stocks/Bonds|Deinove: Grant/Research Support|Ferring: Advisor/Consultant|Glaxo Smith Kleine: Stocks/Bonds|Johnson and Johnson: Stocks/Bonds|Melinta: Grant/Research Support|Merck Sharp &amp; Dohme Corp: Grant/Research Support|Moderna: Stocks/Bonds|Napo Pharmaceuticals: Advisor/Consultant|Napo Pharmaceuticals: Grant/Research Support|Novavax: Stocks/Bonds|Pfizer: Stocks/Bonds|Summit: Advisor/Consultant|Summit: Grant/Research Support Kevin W. Garey, PharmD, MS, Acurx: Grant/Research Support|cidara: Advisor/Consultant|cidara: Grant/Research Support|Paratek: Grant/Research Support|Seres Health: Grant/Research Support|Summit: Grant/Research Support Thomas J. Louie, MD, adiso therapeutics: Advisor/Consultant|adiso therapeutics: Grant/Research Support|crestone: Advisor/Consultant|crestone: Grant/Research Support|Finch: Advisor/Consultant|Finch: Grant/Research Support|Seres Therapeutics: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Seres Therapeutics: Honoraria|summit plc: Grant/Research Support|vedanta biosciences: Advisor/Consultant|vedanta biosciences: Grant/Research Support Jianling LI, MS, Abbott: Stocks/Bonds|Abbvie: Stocks/Bonds|ALX Oncology: Stocks/Bonds|BioNTech: Stocks/Bonds|Bluebird Bio: Stocks/Bonds|Cytokinetics: Stocks/Bonds|I-Mab: Stocks/Bonds|Johnson &amp; Johnson: Stocks/Bonds|Moderna: Stocks/Bonds|TG Therapeutics: Stocks/Bonds Esther Duperchy, PhD, Summit Plc: Employee Jose G. Montoya, MD, Summit: Honoraria|Summit: Stocks/Bonds Lori Styles, MD, Abbvie: Stocks/Bonds|Summit Therapeutics: employee|Summit Therapeutics: Stocks/Bonds Fong Clow, Sc. D, Summit Therapeutics: Employee Danelle James, MD, Summit Therapeutics: Employee.

406. Vancomycin Activity against Clostridioides difficile Over Three Decades in Chicago

Abstract Background In 2017, the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiologist of America (SHEA) updated the C. difficile (CD) treatment guidelines recommending vancomycin as the preferred therapy for C. difficile infections (CDI). We assessed the in vitro vancomycin minimum inhibitory concentration (MIC) against CD across three decades to determine if the vancomycin MIC had increased since these guidelines were published. Methods We performed antimicrobial agar dilution susceptibility testing on 89 clinically relevant CD isolates collected within Chicagoland area. These isolates were selected from 3 separate timeframes: 2005 – 2007, 2013 – 2015, and 2021. Isolates were selected based on the prevalence of restriction endonuclease analysis (REA) strain types within each time cohort. Treatment response to vancomycin was reviewed for patients from the 2021 cohort if CD isolates had a vancomycin MIC of ≥ 16 μg/ml. Results The in vitro vancomycin geometric mean MIC against all 89 CD isolates was 2.53 μg/ml with a MIC50 of 2 μg/ml and MIC90 of 4 μg/ml. Comparing the 3 timeframes, the geometric mean vancomycin MICs from 2005-2007, 2013-2015, and 2021 were 2.35, 2.27, and 2.91, respectively (p=0.11). Comparison of the isolates collected from 2005 – 2015 to 2021, the in vitro vancomycin geometric mean MICs were 2.31 and 2.91, respectively (p = 0.037). REA group BI was the most common strain group to have an increased in vitro vancomycin MIC within the 2021 cohort as 4 of the 5 isolates tested had a MIC of 16 μg/ml. All 4 of the patients infected with these strains with an elevated vancomycin MICs were treated vancomycin. All 4 patients had a resolution of symptoms on vancomycin and 2 suffered from a recurrent infection within ≤4 weeks of completing vancomycin. Conclusion The vancomycin MIC against CD has trended upwards slightly over the past 20 years. The most notable change occurred between 2015 and 2021. We hypothesize that this increase is due to increased use of oral vancomycin for the treatment of CDI. However, these data indicate that most isolates still have a MIC of ≤4 μg/ml and an elevated MIC does not appear to impact clinical outcomes. Further study is required to determine if this upward trend in vancomycin MIC continues and if this could have any potential clinical implications. Disclosures Stuart Johnson, M.D., Ferring Pharmaceuticals: Membership on Ferring Publication Steering Committee|Ferring Pharmaceuticals: Employee|Summit Plc: Advisor/Consultant.

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 &amp;gt; 65, sex, ethnicity, severity, and inpatient status (p &amp;gt; 0.05). There were no differences in comorbidities (kidney disease, cardiovascular disease, diabetes, malignancy, or pulmonary disease, p &amp;gt; 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.

Application of recombinant antibodies for treatment of Clostridioides difficile infection: Current status and future perspective.

Clostridioides difficile (C. difficile), known as the major cause of antibiotic-associated diarrhea, is regarded as one of the most common healthcare-associated bacterial infections worldwide. Due to the emergence of hypervirulent strains, development of new therapeutic methods for C. difficile infection (CDI) has become crucially important. In this context, antibodies have been introduced as valuable tools in the research and clinical environments, as far as the effectiveness of antibody therapy for CDI was reported in several clinical investigations. Hence, production of high-performance antibodies for treatment of CDI would be precious. Traditional approaches of antibody generation are based on hybridoma technology. Today, application of in vitro technologies for generating recombinant antibodies, like phage display, is considered as an appropriate alternative to hybridoma technology. These techniques can circumvent the limitations of the immune system and they can be exploited for production of antibodies against different types of biomolecules in particular active toxins. Additionally, DNA encoding antibodies is directly accessible in in vitro technologies, which enables the application of antibody engineering in order to increase their sensitivity and specificity. Here, we review the application of antibodies for CDI treatment with an emphasis on recombinant fragment antibodies. Also, this review highlights the current and future prospects of the aforementioned approaches for antibody-mediated therapy of CDI.

Which is the Preferred Regimen for Non-Severe Clostridioides difficile Infection in Korea, Vancomycin or Metronidazole?

The emergence of hypervirulent Clostridioides difficile strains has decreased the efficacy of metronidazole in the treatment of C. difficile infection (CDI). Therefore, revised guidelines no longer recommend the use of metronidazole as a first-line regimen for CDI and restrict its use for non-severe CDI, only when vancomycin and fidaxomicin are unavailable. In Korea, an epidemic caused by a hypervirulent C. difficile strain or the emergence of metronidazole resistant C. difficile strains have not been reported. This review article aims to compare the treatment outcomes and adverse effects of vancomycin and metronidazole and discuss the validity of the guidelines of various agencies, which restrict the use of metronidazole, for Korean patients. There are no substantial adverse effects of metronidazole, and its clinical outcomes against non-severe CDI are similar to those of vancomycin. Based on these findings, we recommend that the use of metronidazole for the treatment of non-severe CDI is still an appropriate option in Korea.

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)

38. Impact of Antimicrobial Stewardship Interventions on Adherence to Clostridioides difficile Treatment Guidelines

Abstract Background Facility-specific treatment guidelines are a priority intervention recommended in the CDC Core Elements of Hospital Antimicrobial Stewardship Programs (ASPs). Our ASP sought to improve adherence to the facility C. difficile infection (CDI) treatment guideline by implementing prospective audit and feedback of CDI cases, changing fidaxomicin from being restricted to Infectious Diseases consult use, to only requiring prospective audit and feedback, and allowing fidaxomicin and oral vancomycin orders only through the order set. This study reviews the impact of these interventions. Methods This single-center retrospective quasi-experimental study evaluated inpatient CDI lab events 3 months pre-intervention (10/1/2019-12/31/2019) and post-intervention (10/14/2020-1/14/2021). Patient and treatment data was evaluated via chart review. The primary outcome was adherence to CDI treatment guideline. ASP intervention types were categorized. Statistical analyses were performed using Chi-squared or Fischer’s exact, where appropriate. Results Baseline characteristics were well matched between the 58 and 70 patients pre and post intervention respectively (Table 1). ASP interventions resulting from the prospective audit and feedback are described in Table 2 and overall acceptance rates were high (88%). Guideline adherence improved significantly from 71% pre to 90% post-intervention (p=0.005). Reasons for non-adherence included vancomycin dose incorrect for the severity of illness (9 pre vs 2 post), inappropriate duration (4 pre vs 0 post), use of combination therapy in non-fulminant disease (5 pre vs 3 post), and not using fidaxomicin for recurrent disease (3 pre vs 2 post). Clinical outcomes pre and post intervention were not different in this small sample size: colectomy 1 (2%) vs 1 (1%) p=1, 60 day all- cause mortality 15 (26%) vs 14 (20%) p=0.43, and CDI recurrence at day 60 9/43 (21%) vs 5/56 (9%) p=0.131. Conclusion A bundle of ASP interventions including prospective audit and feedback of CDI cases improved adherence to facility-specific CDI treatment guidelines. Disclosures Tamara Krekel, PharmD, BCPS, BCIDP, Merck (Speaker’s Bureau) Erik R. Dubberke, MD, MSPH, Ferring (Grant/Research Support)Merck (Consultant)Pfizer (Consultant, Grant/Research Support)Seres (Consultant)Summit (Consultant)

Impact of Clostridioides difficile Therapy on Nosocomial Acquisition of Vancomycin-Resistant Enterococci.

Vancomycin is frequently used for the treatment of C. difficile infections (CDI). There are concerns that this might increase the risk of selecting vancomycin resistant enterococci (VRE). Here, we evaluated whether there is an increased risk of VRE acquisition following vancomycin for CDI specific treatment. Patients with CDI, metronidazole, or oral vancomycin treatment and without preexisting VRE were monitored for VRE acquisition. VRE isolates from patients with acquired and preexisting colonization were collected and subjected to whole genome sequencing. In total, 281 patients (median age 56 years, 54% of the male sex) presented with toxin positive C. difficile. Of them, 170 patients met the inclusion criteria, comprising 37 patients treated with metronidazole and 133 treated with oral vancomycin. In total, 14 patients meeting the inclusion criteria acquired VRE (vancomycin: n = 11; metronidazole: n = 3). Statistical analysis revealed no significant differences between both VRE acquisition rates. Genetic comparison of detected VRE isolates resulted in eight clusters of closely related genotypes comprising acquired and preexisting strains. Our results suggest that vancomycin and metronidazole likewise increase the risk of VRE acquisition. Genetic comparison indicates that VRE acquisition is a result of both antibiotic selection and pathogen transmission.

A new phenothiazine derivate is active against Clostridioides difficile and shows low cytotoxicity.

The rapid evolution of antibiotic resistance in Clostridioides difficile and the consequent effects on prevention and treatment of C. difficile infections (CDIs) are matters of concern for public health. Thioridazine, a compound belonging to the phenothiazine group, has previous shown antimicrobial activity against C. difficile. The purpose of this present study was to investigate the potential of a novel phenothiazine derivative, JBC 1847, as an oral antimicrobial for treatment of intestinal pathogens and CDIs. The minimal inhibition concentration and the minimum bactericidal concentration of JBC 1847 against C. difficile ATCC 43255 were determined 4 μg/mL and high tolerance after oral administration in mice was observed (up to 100 mg/kg bodyweight). Pharmacokinetic modeling was conducted in silico using GastroPlusTM, predicting low (< 10%) systemic uptake after oral exposure and corresponding low Cmax in plasma. Impact on the intestinal bacterial composition after four days of treatment was determined by 16s rRNA MiSeq sequencing and revealed only minor impact on the microbiota in non-clinically affected mice, and there was no difference between colony-forming unit (CFU)/gram fecal material between JBC 1847 and placebo treated mice. The cytotoxicity of the compound was assessed in Caco-2 cell-line assays, in which indication of toxicity was not observed in concentrations up to seven times the minimal bactericidal concentration. In conclusion, the novel phenothiazine derivative demonstrated high antimicrobial activity against C. difficile, had low predicted gastrointestinal absorption, low intestinal (in vitro) cytotoxicity, and only induced minor changes of the healthy microbiota, altogether supporting that JBC 1847 could represent a novel antimicrobial candidate. The clinical importance hereof calls for future experimental studies in CDI models.

Antimicrobial resistance in Clostridioides difficile.

Antimicrobial resistance (AMR) in Clostridioides difficile remains a significant threat to global healthcare systems, not just for the treatment of C. difficile infection (CDI), but as a reservoir of AMR genes that could be potentially transferred to other pathogens. The mechanisms of resistance for several antimicrobials such as metronidazole and MLSB-class agents are only beginning to be elucidated, and increasingly, there is evidence that previously unconsidered mechanisms such as plasmid-mediated resistance may play an important role in AMR in this bacterium. In this review, the genetics of AMR in C. difficile will be described, along with a discussion of the factors contributing to the difficulty in clearly determining the true burden of AMR in C. difficile and how it affects the treatment of CDI.

Recent advances in Clostridioides difficile infection epidemiology, diagnosis and treatment in children.

The US Centers for Disease Control and Prevention (CDC) classified Clostridioides difficile as an 'urgent' public health threat that requires 'urgent and aggressive action'. This call to action has led to new discoveries that have advanced C. difficile infection (CDI) epidemiology, diagnosis and treatment, albeit predominantly in adults. In 2017, the Infectious Diseases Society of America and Society for Healthcare Epidemiology of America published clinical practice guidelines for both adults and children. At that time, recommendations in children were generally limited to relatively low-quality evidence. Since publication of this guidance, there have been many advancements in the understanding of CDI in children. These include better understanding of healthcare settings as uncommon sources of C. difficile acquisition in children; risk factors for recurrent and community-associated CDI; performance of diagnostic tests in children and strategies for optimizing their use; and a more rigorous evidence base for CDI treatment in children, including the first-ever randomized controlled trial of CDI treatment in children and the largest study of fecal microbiota transplantation in children. This review highlights the most recent salient advancements in paediatric CDI knowledge and practice that supplement published clinical guidance provided prior to these advancements.

Antimicrobial resistance surveillance of Clostridioides difficile in Australia, 2015–18

Clostridioides difficile was listed as an urgent antimicrobial resistance (AMR) threat in a report by the CDC in 2019. AMR drives the evolution of C. difficile and facilitates its emergence and spread. The C. difficile Antimicrobial Resistance Surveillance (CDARS) study is nationwide longitudinal surveillance of C. difficile infection (CDI) in Australia. To determine the antimicrobial susceptibility of C. difficile isolated in Australia between 2015 and 2018. A total of 1091 strains of C. difficile were collected over a 3 year period by a network of 10 diagnostic microbiology laboratories in five Australian states. These strains were tested for their susceptibility to nine antimicrobials using the CLSI agar incorporation method. All strains were susceptible to metronidazole, fidaxomicin, rifaximin and amoxicillin/clavulanate and low numbers of resistant strains were observed for meropenem (0.1%; 1/1091), moxifloxacin (3.5%; 38/1091) and vancomycin (5.7%; 62/1091). Resistance to clindamycin was common (85.2%; 929/1091), followed by resistance to ceftriaxone (18.8%; 205/1091). The in vitro activity of fidaxomicin [geometric mean MIC (GM) = 0.101 mg/L] was superior to that of vancomycin (1.700 mg/L) and metronidazole (0.229 mg/L). The prevalence of MDR C. difficile, as defined by resistance to ≥3 antimicrobial classes, was low (1.7%; 19/1091). The majority of C. difficile isolated in Australia did not show reduced susceptibility to antimicrobials recommended for treatment of CDI (vancomycin, metronidazole and fidaxomicin). Resistance to carbapenems and fluoroquinolones was low and MDR was uncommon; however, clindamycin resistance was frequent. One fluoroquinolone-resistant ribotype 027 strain was detected.