CDI Recurrence Research Articles

Host Immune Responses to Clostridioides difficile: Toxins and Beyond.

Clostridioides difficile is often resistant to the actions of antibiotics to treat other bacterial infections and the resulting C. difficile infection (CDI) is among the leading causes of nosocomial infectious diarrhea worldwide. The primary virulence mechanism contributing to CDI is the production of toxins. Treatment failures and recurrence of CDI have urged the medical community to search for novel treatment options. Strains that do not produce toxins, so called non-toxigenic C. difficile, have been known to colonize the colon and protect the host against CDI. In this review, a comprehensive description and comparison of the immune responses to toxigenic C. difficile and non-toxigenic adherence, and colonization factors, here called non-toxin proteins, is provided. This revealed a number of similarities between the host immune responses to toxigenic C. difficile and non-toxin proteins, such as the influx of granulocytes and the type of T-cell response. Differences may reflect genuine variation between the responses to toxigenic or non-toxigenic C. difficile or gaps in the current knowledge with respect to the immune response toward non-toxigenic C. difficile. Toxin-based and non-toxin-based immunization studies have been evaluated to further explore the role of B cells and reveal that plasma cells are important in protection against CDI. Since the success of toxin-based interventions in humans to date is limited, it is vital that future research will focus on the immune responses to non-toxin proteins and in particular non-toxigenic strains.

639. Time to Recurrence of Clostridioides difficile Infection (rCDI) is Rapid Following Completion of Standard of Care Antibiotics: Results from ECOSPOR-III, a Phase 3 Double-Blind, Placebo-Controlled Randomized Trial of SER-109, an Investigational Microbiome Therapeutic

Abstract Background The natural history of CDI recurrence after antibiotics may be helpful to understand the window of opportunity for microbiome repair. ECOSPOR III evaluated the efficacy of SER-109, an investigational microbiome therapeutic, compared to placebo with rates of rCDI as the primary endpoint. SER-109 was superior to placebo in reducing the rate of rCDI following standard-of-care antibiotics at 8 weeks (12.4% vs 39.8%, respectively; P < 0.001). Herein, we describe results from the secondary endpoint, time to recurrence, in this well-characterized study population. Methods A total of 182 C. difficile toxin+ adults with ≥ 3 CDI episodes and symptom resolution on CDI antibiotics were randomly assigned to SER-109 (4 capsules orally x 3 days) or placebo. Recurrence for this analysis was defined as ≥ 3 unformed stools/day for ≥ 48 hours, ± C. difficile stool toxin test, and an investigator decision to treat. Time to CDI recurrence was analyzed using observed data and Kaplan-Meier methods. Data were not imputed for subjects lost to follow-up or discontinued from study. Subjects who did not have a CDI recurrence were censored on the date of study completion, study discontinuation or death. Results Through 24 weeks, 11/89 (12.4%) SER-109 and 36/93 (38.7%) placebo subjects had rCDI (P < 0.001). Of all recurrence events in the study population, 16/47 (34.0%) were observed within 1 week; 30/47 (63.8%) within 2 weeks; and 34/47 (72.3%) within 4 weeks after randomization, highlighting the rapid onset of recurrence. On the other hand, 12/47 (25.5%) recurrences occurred between 4 and 12 weeks, highlighting late onset of recurrence in a subset of patients (Table). Significantly lower rates of recurrence in patients on SER-109 compared to placebo was maintained throughout the 24-week follow-up (Figure). Time of rCDI K-M Plot Conclusion SER-109, an investigational oral microbiome therapeutic, maintained significant efficacy in reducing rCDI vs placebo through 24 weeks. About two-thirds of all recurrences occurred within 14 days of antibiotic completion highlighting the need for rapid repair of the disrupted microbiome. However, the significant number of late recurrences in the placebo arm also highlights that rCDI trials limited to 4 weeks of follow-up after treatment completion may underestimate recurrences. Disclosures Thomas J. Louie, MD, Artugen (Advisor or Review Panel member)Crestone (Consultant, Grant/Research Support)Da Volterra (Advisor or Review Panel member)Finch Therapeutics (Grant/Research Support, Advisor or Review Panel member)MGB Biopharma (Grant/Research Support, Advisor or Review Panel member)Rebiotix (Consultant, Grant/Research Support)Seres Therapeutics (Consultant, Grant/Research Support)Summit PLC (Grant/Research Support)Vedanta (Grant/Research Support, Advisor or Review Panel member) Matthew Sims, MD, PhD, Astra Zeneca (Independent Contractor)Diasorin Molecular (Independent Contractor)Epigenomics Inc (Independent Contractor)Finch (Independent Contractor)Genentech (Independent Contractor)Janssen Pharmaceuticals NV (Independent Contractor)Kinevant Sciences gmBH (Independent Contractor)Leonard-Meron Biosciences (Independent Contractor)Merck and Co (Independent Contractor)OpGen (Independent Contractor)Prenosis (Independent Contractor)Regeneron Pharmaceuticals Inc (Independent Contractor)Seres Therapeutics Inc (Independent Contractor)Shire (Independent Contractor)Summit Therapeutics (Independent Contractor) Richard Nathan, DO, none (Other Financial or Material Support, I am PI on several clinical trials. If you need that information, I would be happy to supply it.) Princy N. Kumar, MD, AMGEN (Other Financial or Material Support, Honoraria)Eli Lilly (Grant/Research Support)Gilead (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria)GSK (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria)Merck & Co., Inc. (Grant/Research Support, Shareholder, Other Financial or Material Support, Honoraria) Elaine E. Wang, MD, Seres Therapeutics (Employee) Elaine E. Wang, MD, Seres Therapeutics (Employee, Shareholder) Robert Stevens, PharmD, Seres Therapeutics (Employee, Shareholder) Kelly Brady, MS, Seres Therapeutics (Employee, Shareholder) Barbara McGovern, MD, Seres Therapeutics (Employee, Shareholder) Lisa von Moltke, MD, Seres Therapeutics (Employee, Shareholder)

19. The Impact of Investigational Purified Microbiome Therapeutic SER-109 on Health-Related Quality of Life (HRQoL) of Patients with Recurrent Clostridioides difficile Infection (rCDI) in ECOSPOR III, a Placebo-Controlled Clinical Trial

BackgroundFollowing standard of care antibiotics, investigational microbiome therapeutic, SER-109, achieved superiority vs placebo (PBO) at 8 weeks in reducing rCDI in patients with ≥3 prior episodes (12.4% vs 39.8%, respectively; p< 0.001). We evaluated the impact of SER-109 vs PBO on HRQoL with general (EQ-5D-5L) and disease-specific (Cdiff32) measures [Garey 2016]. MethodsEQ-5D-5L measures outcomes in 5 domains (mobility, self-care, activities, pain/discomfort, and anxiety/depression) while Cdiff32 measures outcomes in 3 domains (physical, mental, and social) including 5 associated subdomains. Patients completed EQ-5D-5L and Cdiff32 measures at baseline (BL), Wk 8, and at recurrence/early termination. Changes from BL were assessed between SER-109 vs PBO and by clinical outcome (recurrence versus nonrecurrence) in the ITT population and within each treatment arm. The between treatment group comparison analysis controlled for age, gender, prior antibiotics, and number of prior CDI episodes.ResultsMean EQ-5D-5L and Cdiff32 scores were comparable between SER-109 and PBO at BL. EQ-5D-5L did not detect differences at Wk 8 from BL between SER-109 and PBO or by clinical outcome. In contrast, Cdiff32 detected significant improvements at Wk 8 from BL within both SER-109 subjects and PBO subjects (Fig1) and by recurrence status (Fig2). Subjects achieved significant improvement in all domains at Wk 8 from BL regardless of treatment group. When examining recurrence status within treatment arms, all PBO subjects with non-recurrence showed improvement in all health domains, while PBO subjects with recurrence had declines in several subdomains (Fig3B). Similarly, SER-109 subjects with non-recurrence showed improvement in all domains compared to BL. However, overall and mental domain/subdomains scores also improved in SER-109 subjects with recurrence (Fig3A). ConclusionSignificant HRQoL improvements were associated with CDI nonrecurrence, which highlights the negative impact of this debilitating infection. SER-109 was associated with improved overall and mental scores, regardless of clinical outcome. Further investigation is warranted on the impact of SER-109 on mental health even among those with CDI recurrence.Disclosures Elizabeth Hohmann, MD, Seres Therapeutics (Research Grant or Support) Paul Feuerstadt, MD, FACG, Ferring/Rebiotix Pharmaceuticals (Consultant, Scientific Research Study Investigator, Speaker’s Bureau)Finch Pharmaceuticals (Scientific Research Study Investigator)Merck and Co (Speaker’s Bureau)SERES Therapeutics (Consultant, Scientific Research Study Investigator)Takeda Pharmaceuticals (Consultant) Christine Lee, MD, FRCPC, Pfizer (Board Member)Rebiotix-Ferring (Board Member)Rebiotix-Ferring (Grant/Research Support)Seres (Grant/Research Support)Summit (Grant/Research Support) Sissi Pham, PharmD, Seres (Consultant) Pat Ray Reese, PhD, Reese Associates, LLC (Consultant, Independent Contractor) Elaine E. Wang, MD, Seres Therapeutics (Employee) Elaine E. Wang, MD, Seres Therapeutics (Employee, Shareholder) Lisa von Moltke, MD, Seres Therapeutics (Employee, Shareholder) Kevin W. Garey, Pharm.D., M.S., FASHP, Summit Therapeutics (Research Grant or Support)

634. Investigational Microbiome Therapeutic SER-109 Reduces Recurrence of Clostridioides difficile Infection (CDI) Compared to Placebo, Regardless of Risk Factors for Recurrence

Abstract Background Several demographic and clinical characteristics, including age, sex, medication use and presence of comorbid conditions are considered risk factors for recurrent CDI (rCDI). We examined the efficacy of an investigational purified oral microbiome therapeutic, SER-109, versus placebo in an exploratory analysis of subgroups of patients with risk factors for recurrence who enrolled in ECOSPOR III, a double-blind, placebo controlled trial. Forest Plot of Relative Risks for Recurrence at Week 8 for Selected Baseline Characteristics in the ITT population Methods Patients with ≥ 3 CDI episodes were treated with SER-109 or placebo (four capsules daily for three days) following standard treatment of CDI. The primary efficacy objective was to demonstrate superiority of SER-109 versus placebo in reducing rCDI up to 8 weeks after treatment. In this exploratory analysis, we analyzed the rate of CDI recurrence among SER-109 treated subjects compared to placebo in subgroups defined by rCDI baseline risk factors: proton-pump inhibitor use, number of CDI recurrences, prior FMT history, presence of comorbid conditions and exposure to non-CDI antibiotics after dosing. We also analyzed the rate of CDI recurrence among SER-109 treated subjects by age (≥ 65 and ≤ 65) and gender, which were pre-specified. Results Of 281 patients screened,182 were enrolled. Overall recurrence rates were lower in SER-109 treated patients compared to placebo (12.4% vs 39.8%, respectively); relative risk (RR), 0.32 [95% CI, 0.18-0.58; P&amp;lt; 0.001 for RR&amp;lt; 1.0:P&amp;lt; 0.001 for RR&amp;lt; 0.833]. Co-morbidities including diabetes, renal disease, malignancy, cardiac disease, COPD/asthma, colitis, or immunocompromised status were observed in most patients in the overall study population; 33.5%, 32.4% and 34.1% had 0, 1, or ≥ 2 comorbidities. SER-109 was consistently observed to show greater benefit than placebo in reducing CDI recurrence in all subgroups regardless of the presence or absence of the rCDI risk factor (Fig 1). Conclusion Regardless of risk factor status, SER-109 reduced recurrence of CDI compared to placebo. Most subjects in ECOSPOR III had co-morbidities consistent with the broad inclusion criteria in this Phase 3 trial. Despite a high proportion of patients with co-morbidities in ECOSPOR III, SER-109 significantly reduced the risk of recurrence compared to placebo. Disclosures Stuart H. Cohen, MD, Seres (Research Grant or Support) Thomas J. Louie, MD, Artugen (Advisor or Review Panel member)Crestone (Consultant, Grant/Research Support)Da Volterra (Advisor or Review Panel member)Finch Therapeutics (Grant/Research Support, Advisor or Review Panel member)MGB Biopharma (Grant/Research Support, Advisor or Review Panel member)Rebiotix (Consultant, Grant/Research Support)Seres Therapeutics (Consultant, Grant/Research Support)Summit PLC (Grant/Research Support)Vedanta (Grant/Research Support, Advisor or Review Panel member) Matthew Sims, MD, PhD, Astra Zeneca (Independent Contractor)Diasorin Molecular (Independent Contractor)Epigenomics Inc (Independent Contractor)Finch (Independent Contractor)Genentech (Independent Contractor)Janssen Pharmaceuticals NV (Independent Contractor)Kinevant Sciences gmBH (Independent Contractor)Leonard-Meron Biosciences (Independent Contractor)Merck and Co (Independent Contractor)OpGen (Independent Contractor)Prenosis (Independent Contractor)Regeneron Pharmaceuticals Inc (Independent Contractor)Seres Therapeutics Inc (Independent Contractor)Shire (Independent Contractor)Summit Therapeutics (Independent Contractor) Elaine E. Wang, MD, Seres Therapeutics (Employee) Elaine E. Wang, MD, Seres Therapeutics (Employee, Shareholder) Barbara McGovern, MD, Seres Therapeutics (Employee, Shareholder) Kelly Brady, MS, Seres Therapeutics (Employee, Shareholder) Lisa von Moltke, MD, Seres Therapeutics (Employee, Shareholder)

129. Antimicrobial Resistance Genes Were Reduced Following Administration of Investigational Microbiota-Based Live Biotherapeutic RBX2660 to Individuals with Recurrent Clostridioides difficile Infection

BackgroundIntestinal colonization by antimicrobial resistant (AMR) pathogens is a known health and infection risk, and is common among individuals with recurrent Clostridioides difficile infections (rCDI). Accordingly, therapeutic approaches that decolonize the gut of AMR pathogens could be valuable to patients to reduce risk of associated illnesses. Herein, we assessed gut colonization with AMR bacteria before and after treatment with RBX2660—a microbiota-based investigational live biotherapeutic—in the PUNCH CD3 Phase 3 trial for reducing CDI recurrence.MethodsrCDI participants enrolled in PUNCH CD3 received a blinded single dose of RBX2660 or placebo within 24 to 72 hours after completing antibiotic treatment for the most recent rCDI episode. Clinical response was the absence of CDI recurrence at eight weeks after treatment, and participants were asked to submit stool samples prior to RBX2660 or placebo treatment (baseline) and 1, 4 and 8 weeks, 3 and 6 months after study treatment. Samples were extracted and sequenced using a shallow shotgun method. The presence and number of AMR genes was determined for 175 participant samples and 116 RBX2660 samples using 90% K-mer sequence coverage based on the MEGARes database. AMR gene count data were collapsed into count columns to adjust for sparseness in the matrices and were analyzed using a Generalized Linear Mixed Model.ResultsClinically, RBX2660 demonstrated superior efficacy versus placebo (70.4% and 58.1%, respectively), and the total AMR genes per participant decreased significantly from before to after treatment in RBX2660-treated responders (p< .05, Figure 1) and remained low to at least 6 months. Among genes that decreased in RBX2660 responders were clinically important extended-spectrum beta-lactamase (blaTEM, blaSHV, blaCTX-M), vancomycin resistance (vanA, vanB), and fluoroquinolone resistance genes (gyrA, parC). Total AMR genes per PUNCH CD3 participant among RBX2660-treated responders at the indicated time points and in the RBX2660 investigational product. The red lines indicate timepoint group medians.ConclusionIn the PUNCH CD3 Phase 3 trial of RBX2660 for rCDI, AMR gene content decreased after RBX2660 treatment and remained low to at least 6 months, consistent with prior RBX2660 trials. This underscores the potential of microbiota-based biotherapeutics for decolonizing AMR bacteria from gut microbiota and thereby reducing AMR infection risks.Disclosures Heidi Hau, PhD, Rebiotix Inc. (Employee) Dana M. Walsh, PhD, Rebiotix (Employee) Ken Blount, PhD, Rebiotix Inc., a Ferring Company (Employee)

1064. Treatment Success in Reducing Recurrent Clostridioides difficile Infection with Investigational Live Biotherapeutic RBX2660 Is Associated with Microbiota Restoration: Consistent Evidence from a Phase 3 Clinical Trial

BackgroundSeveral investigational microbiota-based live biotherapeutics are in clinical development for reducing recurrence of Clostridioides difficile infection (rCDI), including RBX2660 a liquid suspension of a broad consortium of microbiota, which includes Bacteridetes and Firmicutes. RBX2660 has been evaluated in >600 participants in 6 clinical trials. Here we report that RBX2660 induced significant shifts to the intestinal microbiota of treatment-responsive participants in PUNCH CD3—a Phase 3 randomized, double-blinded, placebo-controlled trial.MethodsPUNCH CD3 participants received a single dose of RBX2660 or placebo between 24 to 72 hours after completing rCDI antibiotic treatment. Clinical response was the absence of CDI recurrence at eight weeks after treatment. Participants voluntarily submitted stool samples prior to blinded study treatment (baseline), 1, 4 and 8 weeks, 3 and 6 months after receiving study treatment. Samples were extracted and sequenced using shallow shotgun methods. Operational taxonomic unit (OTU) data were used to calculate relative taxonomic abundance, alpha diversity, and the Microbiome Health Index (MHI)—a biomarker of antibiotic-induced dysbiosis and restoration.ResultsClinically, RBX2660 demonstrated superior efficacy versus placebo (70.4% versus 58.1%). From before to after treatment, RBX2660-treated clinical responders’ microbiome diversity shifted significantly (Mann-Whitney), and so did microbiome composition (Generalized Wald Test). Post-treatment changes were characterized by increased Bacteroidia and Clostridia and decreased Gammaproteobacteria and Bacilli, changes and were durable to at least 6 months. Repeated measures analysis confirmed that shifts were greater among RBX2660 responders compared to placebo responders (DMRepeat). The majority of responders’ MHI values shifted from a range common to antibiotic dysbiosis to a range common in healthy populations.Figure 1 Left panel. Mean relative abundance taxonomic class level at timepoints for participants in PUNCH CD3 before and after RBX2660 treatment, and for doses of RBX2660 administered in PUNCH CD3. The four taxonomic classes that change most from before to after treatment are shown with the mean and confidence intervals based on fitting OTU data to a Dirichlet multinomial distribution. Right panel, MHI biomarker for the same time points and investigational product groups, shown as median (red) and individual samples. A previously calculated threshold of MHI = 7.2 is shown (dotted line), above which MHI values predict healthy, below which MHI values predict antibiotic-induced dysbiosis.ConclusionAmong PUNCH CD3 clinical responders, RBX2660 significantly restored microbiota from less to more healthy compositions, and this restoration was durable to at least 6 months. These clinically-correlated microbiome shifts are highly consistent with results from multiple prior trials of RBX2660.Disclosures Ken Blount, PhD, Rebiotix Inc., a Ferring Company (Employee) Dana M. Walsh, PhD, Rebiotix (Employee)

LB15. SER-109, an Investigational Microbiome Therapeutic, Reduces Abundance of Antimicrobial Resistance Genes in Patients with Recurrent Clostridioides difficile Infection (rCDI) after Standard-of-Care Antibiotics

Abstract Background The gastrointestinal microbiota is the first line of defense against colonization with antimicrobial resistant (AR) bacteria, particularly in vulnerable hosts with frequent antibiotic exposure. In a double-blind Phase 3 trial of rCDI patients, SER-109, an orally formulated consortia of purified Firmicutes spores, was superior to placebo in reducing CDI recurrence at week 8 post clinical resolution on standard-of-care (SoC) antibiotics. Overall recurrence rates were lower in SER-109 vs placebo (12.4% vs 39.8%, respectively) relative risk, 0.32 [95% CI, 0.18–0.58; p&amp;lt; 0.001 for RR&amp;lt; 1.0; p&amp;lt; 0.001 for RR&amp;lt; 0.833]. This is a post-hoc analysis examining the impact of SER-109 on antimicrobial resistance genes (ARGs) abundance in the intestinal microbiota compared to placebo. Methods Subjects with rCDI received SoC antibiotics, then were randomized 1:1 to SER-109 or placebo at baseline. Of 182 subjects, 140 who had paired stool samples at baseline and 1-week post-treatment were included in this analysis. ARG abundances and taxonomic profiles were generated from whole metagenomic shotgun sequencing. t-tests were used to compare changes in ARG abundance from baseline; mixed linear models were used to associate ARG and taxon abundances across time points. Results ARG abundance was reduced overall by week 1, with a significantly greater decrease in SER-109 subjects vs. placebo at week 1 (Fig. 1). Proteobacteria relative abundance were positively correlated with ARG abundance across all samples (Fig. 2), with the Enterobacteriaceae family associated with the abundance of 95 ARGs (all p &amp;lt; 0.05). Enterococcaceae relative abundance was associated with glycopeptide AR abundance (p &amp;lt; 0.001). At week 1, Proteobacteria relative abundance was significantly decreased from baseline in SER-109 subjects vs. placebo (p &amp;lt; 0.001). Enterobacteriaceae and Enterococcaceae relative abundances were also decreased from baseline in SER-109 subjects vs. placebo (p &amp;lt; 0.001 and p = 0.007, respectively). Figure 1. Significant reduction in ARG abundance at week 1 from baseline in SER-109 treatment compared to placebo. Figure 2. Total ARG abundance is associated with the relative abundance of Proteobacteria in SER-109 and placebo subjects at baseline and week 1. Conclusion SER-109 was associated with significantly greater reduction of ARGs and AR bacteria abundances compared to placebo at 1 week post treatment. These findings support a potential role of microbiome therapeutics in rapid decolonization of AR bacteria with implications for infection prevention. Disclosures Timothy J. Straub, MS, Seres Therapeutics (Employee) Liyang Diao, PhD, Seres Therapeutics (Employee) Christopher Ford, PhD, Seres Therapeutics (Employee, Shareholder) Matthew Sims, MD, PhD, Astra Zeneca (Independent Contractor)Diasorin Molecular (Independent Contractor)Epigenomics Inc (Independent Contractor)Finch (Independent Contractor)Genentech (Independent Contractor)Janssen Pharmaceuticals NV (Independent Contractor)Kinevant Sciences gmBH (Independent Contractor)Leonard-Meron Biosciences (Independent Contractor)Merck and Co (Independent Contractor)OpGen (Independent Contractor)Prenosis (Independent Contractor)Regeneron Pharmaceuticals Inc (Independent Contractor)Seres Therapeutics Inc (Independent Contractor)Shire (Independent Contractor)Summit Therapeutics (Independent Contractor) Thomas J. Louie, MD, Artugen (Advisor or Review Panel member)Crestone (Consultant, Grant/Research Support)Da Volterra (Advisor or Review Panel member)Finch Therapeutics (Grant/Research Support, Advisor or Review Panel member)MGB Biopharma (Grant/Research Support, Advisor or Review Panel member)Rebiotix (Consultant, Grant/Research Support)Seres Therapeutics (Consultant, Grant/Research Support)Summit PLC (Grant/Research Support)Vedanta (Grant/Research Support, Advisor or Review Panel member) Colleen S. Kraft, MD, MSc, Rebiotix (Individual(s) Involved: Self): Advisor or Review Panel member Stuart H. Cohen, MD, Seres (Research Grant or Support) Stuart H. Cohen, MD, Nothing to disclose Mary-Jane Lombardo, PhD, Seres Therapeutics (Employee, Shareholder) Barbara McGovern, MD, Seres Therapeutics (Employee, Shareholder) Lisa von Moltke, MD, Seres Therapeutics (Employee, Shareholder) Matt Henn, PhD, Seres Therapeutics (Employee, Shareholder)

1039. Rapid Restoration of Bile Acid Compositions After Treatment with RBX2660 for Recurrent Clostridioides difficile Infection—Results from the PUNCH CD3 Phase 3 Trial

BackgroundMicrobiota-based treatments are increasingly evaluated as a strategy to reduce recurrence of Clostridioides difficile infection (rCDI), and their proposed mechanisms include restoration of the microbiota and microbiota-mediated functions, including bile acid metabolism. RBX2660—a broad-consortium investigational live biotherapeutic—has been evaluated in >600 participants in 6 clinical trials, with consistent reduction of rCDI recurrence. Here we report that fecal bile acid compositions were significantly restored in treatment-responsive participants in PUNCH CD3—a Phase 3 randomized, double-blinded, placebo-controlled trial of RBX2660.MethodsPUNCH CD3 participants received a single dose of RBX2660 or placebo between 24 to 72 hours after completing rCDI antibiotic treatment. Clinical response was the absence of CDI recurrence at eight weeks after treatment. Participants voluntarily submitted stool samples prior to blinded study treatment (baseline), 1, 4 and 8 weeks, 3 and 6 months after receiving study treatment. A liquid chromatography tandem mass spectrometry method was developed to extract and quantify 33 bile acids from all participant fecal samples received up to the 8-week time point. Mean bile acid compositions were fit to a Dirichlet multinomial distribution and compared across time points and between RBX2660- and placebo-treated participants.ResultsClinically, RBX2660 demonstrated superior efficacy versus placebo (70.4% versus 58.1%). RBX2660-treated clinical responders’ bile acid compositions shifted significantly from before to after treatment. Specifically, primary bile acids predominated before treatment, whereas secondary bile acids predominated after treatment (Figure 1A). These changes trended higher among RBX2660 responders compared to placebo responders. Importantly, median levels of lithocholic acid (LCA) and deoxycholic acid (DCA) showed large, significant increases after treatment (Figure 1B). A. Bile acid compositions before (BL) and up to 8 weeks after RBX2660 treatment among treatment responders. Compositions are shown as the fraction of total bile acids classified as primary or secondary conjugated or deconjugated bile acids. B. Concentrations of lithocholic acid (LCA) and deoxycholic acid (DCA) among RBX2660 treatment responders, shown with individual samples and time point group median with interquartile ranges.ConclusionAmong PUNCH CD3 clinical responders, RBX2660 significantly restored bile acids from less to more healthy compositions. These clinically correlated bile acid shifts are highly consistent with results from a prior trial of RBX2660.Disclosures Romeo Papazyan, PhD, Ferring Research Institute (Employee) Bryan Fuchs, PhD, Ferring Pharmaceuticals (Employee) Ken Blount, PhD, Rebiotix Inc., a Ferring Company (Employee)

S207 Concomitant Cephalosporins or Vancomycin During or After Treatment of Clostridioides difficile Infection Increases Risk of 3-Month CDI Recurrence

S207 Concomitant Cephalosporins or Vancomycin During or After Treatment of Clostridioides difficile Infection Increases Risk of 3-Month CDI Recurrence

S208 RBX2660, an Investigational Live Microbiota-based Biotherapeutic, Improves Outcomes of Clostridioides difficile Infection in a Real-World Population: A Retrospective Study of Use Under Enforcement Discretion

Introduction: Recurrent Clostridioides difficile infection (rCDI) is an urgent public health threat. RBX2660 is a standardized, stabilized, investigational microbiota-based live biotherapeutic that has been evaluated in 5 prospective clinical trials. Eligibility criteria in clinical trials are often narrowly defined, excluding broader patient populations. Herein, we report a retrospective analysis of safety and efficacy of RBX2660 given under FDA enforcement discretion (ED) in a cohort with broad eligibility criteria. Methods: Participants were ≥18 years old with rCDI and received RBX2660 rectally. The investigator determined the number of doses administered. Participant data were collected from electronic health records. The primary safety set (PSS) population included participants who had not been previously treated with RBX2660 and who had continuously comprehensive medical records for 6 months after therapy. Safety, treatment success (absence of CDI recurrence within 8 weeks post-RBX2660), and clinical response duration were evaluated. Results: 94 participants were enrolled from 5 sites between November 2015 and September 2019. Comorbid conditions included gastroesophageal reflux disease (47.9%), irritable bowel syndrome (17%), gastritis (11.7%), constipation (8.5%), microscopic colitis (7.4%), diverticulitis (6.4%), Crohn’s disease (5.3%), and ulcerative colitis (4.3%). 16% of patients were using concomitant immunosuppressant’s such as glucocorticoids (7%) and monoclonal antibodies (6%) at the time of RBX2660 administration. 64 of the 94 participants were in the PSS, with a treatment success rate of 82.8% (53/64), with no difference observed between participants who received 1 dose (83.3%; 20/24) versus 2 doses (82.5%; 33/40) after the qualifying CDI diagnosis. Of those that responded initially, sustained clinical response to 6 months was 88.7% (47/53). Safety outcomes were comparable to prospective studies for RBX2660, with most (92.2%) adverse events being mild to moderate in severity, including participants with immune-mediated/autoimmune disorders and non-specific inflammation conditions. Conclusion: In this retrospective analysis, RBX2660 administered to participants under ED demonstrated high clinical efficacy to reduce rCDI with a sustained clinical response to 6 months. Safety results were consistent with prospective trials. The results substantiate the potential safety and efficacy of RBX2660 in “real world” populations with common rCDI comorbidities.

A budget impact analysis of bezlotoxumab versus standard of care antibiotics only in patients at high risk of CDI recurrence from a hospital management perspective in Germany

BackgroundClostridioides difficile infection (CDI) is one of the leading nosocomial infections, resulting in increased hospital length of stay and additional treatment costs. Bezlotoxumab, the first monoclonal antibody against CDI, has an 1 A guideline recommendation for prevention of CDI, after randomized clinical trials demonstrated its superior efficacy vs. placebo.MethodsThe budget impact analysis at hand is focused on patients at high risk of CDI recurrence. Treatment with standard of care (SoC) + bezlotoxumab was compared with current SoC alone in the 10 most associated Diagnosis Related Groups to identify, analyze, and evaluate potential cost savings per case from the German hospital management perspective. Based on variation in days to rehospitalization, three different case consolidation scenarios were assessed: no case consolidation, case consolidation for the SoC + bezlotoxumab treatment arm only, and case consolidation for both treatment arms.ResultsOn average, the budget impact amounted to € 508.56 [range: € 424.85 - € 642.19] for no case consolidation, € 470.50 [range: € 378.75 - € 601.77] for case consolidation in the SoC + bezlotoxumab treatment arm, and € 618.00 [range: € 557.40 - € 758.41] for case consolidation in both treatment arms.ConclusionsThe study demonstrated administration of SoC + bezlotoxumab in patients at high risk of CDI recurrence is cost-saving from a hospital management perspective. Reduced length of stay in bezlotoxumab treated patients creates free spatial and personnel capacities for the treating hospital. Yet, a requirement for hospitals to administer bezlotoxumab is the previously made request for additional fees and a successful price negotiation.

Add-on interventions for the prevention of recurrent Clostridioides Difficile infection: A systematic review and network meta-analysis

ObjectivesWe aimed to assess the comparative efficacy and safety of adjunctive interventions for the prevention of Clostridioides difficile recurrence. MethodsWe searched Medline, Embase, CENTRAL, and clinicaltrials.gov up to May 2021. We included randomized controlled trials comparing interventions added to antibiotic therapy for prevention of CDI recurrence, to placebo or each other. Efficacy outcomes were CDI and diarrhea recurrence. Safety outcomes included the incidence of any adverse event (AE), serious AEs, and discontinuation due to AEs. We performed random-effects network meta-analysis. We ranked interventions based on SUCRA (surface under the cumulative ranking curve) probabilities. We assessed confidence in estimates utilizing the CINeMA (Confidence in Network Meta-Analysis) framework. ResultsFifteen trials (3909 patients) assessed 9 interventions. Oligofructose (OR 0.17; 95% CI, 0.07 to 0.46), NTCD-M3 (OR 0.29; 95% CI, 0.12 to 0.68), rifaximin (OR 0.47; 95% CI, 0.24 to 0.93), RBX2660 (OR 0.47; 95% CI, 0.22 to 0.99), the combination bezlotoxumab/actoxumab (OR 0.47; 95% CI, 0.37 to 0.60), and bezlotoxumab (OR, 0.53; 95% CI, 0.42 to 0.68) were associated with lower incidence of CDI recurrence than placebo (moderate confidence). Oligofructose was ranked highest, however data for oligofructose were derived solely from one small trial. Probiotics, actoxumab and SER-109 were not superior to placebo (low confidence). Probiotics were not well tolerated (low confidence) and actoxumab showed high rates of serious AEs (moderate confidence). ConclusionAdd-on treatment with oligofructose, NTCD-M3 spores, rifaximin, RBX2660, and bezlotoxumab likely reduces the risk of CDI. Evidence on probiotics and SER-109 are uncertain, thus adequately powered trials are warranted.

Fecal Microbiota Transplantation in Patients With Recurrent Clostridium difficile Infection: A Four-Year Single-Center Retrospective Review.

BackgroundClostridium difficile infection (CDI) is a common cause of hospital and community-acquired diarrhea with an annual incidence of 453,000 cases in the USA. The white race, female gender, and age over 65 years are known risk factors. Recurrence of CDI is a major problem in patients taking antibiotics for prolonged periods. These patients are observed to have reduced diversity of the intestinal microbiome. Fecal microbiota transplantation (FMT) can restore the healthy flora in the gut, thus breaking the cycle of recurrent infection. Our study aimed to analyze the efficacy of FMT and the recurrence of CDI after FMT. We also aimed to investigate the effects of comorbidities on the outcome of FMT.MethodsAfter obtaining approval from the institutional review board, we included 64 patients who had received FMT at our institution from October 2015 to November 2019. All the patients over 16 years of age in both inpatient and outpatient settings were included. Patients under 16 years of age and patients treated without FMT were excluded. Frozen stool from a standardized stool bank (OpenBiome) was used. The thawed specimen was instilled into the terminal ileum or the cecum. Patients were followed up for the next 1 year for analysis of improvement in symptoms, recurrence, and repeat FMT.ResultsOn the 2-months follow-up, 75% of patients reported symptomatic improvement, 15.6% reported no improvement while 9.4% did not follow up. Twenty-six (40.6%) patients had CDI recurrence in the following year; and 69.2% of patients with recurrence underwent a repeat FMT. There was no statistically significant correlation between CDI recurrence and the age (P value = 0.68), gender (P value = 0.61), previous use of proton pump inhibitors (PPIs, P value = 0.11) or antibiotics (P value = 0.45). There was a statistically significant correlation noted with the use of immunosuppressants and recurrence (P value = 0.04).ConclusionsFMT is a successful treatment modality for refractory and recurrent CDI. Repeat treatments can be beneficial if there is a lack of initial response. Being immunosuppressed with medications is associated with the risk of recurrence.

The need for a holistic view on management of Clostridioides difficile infection

Since the implementation of innovative treatment options for the management of CDIs during the recent decades, controversy exists regarding the most cost-effective treatment pathways. The study by Chen and colleagues, not sponsored by industry, analysed the health-economic impact of using bezlotoxumab and fidaxomicin for initial CDI compared to oral vancomycin, based on the US societal perspective [1]. As one of the main study results, the authors highlighted cost-effectiveness of standard treatment with fidaxomicin, mainly due to a low rate of CDI recurrences (between 13% and 15%) within the observed timeframe of the two clinical trials by Cornely et al.

Evolution of intestinal microbiome in a process of faecal microbiota transplantation in a patient with Clostridioides difficile infection: NGS analysis with different bioinformatics software programs

IntroductionClostridioides difficile infection (CDI) has become a global healthcare challenge due to increases in its incidence and mortality rates. Faecal microbiota transfer (FMT) is postulated as a protocol to prevent CDI recurrence. Material and methodsA donor faecal sample and patient faecal samples (pre-FMT and post-FMT) were analysed. The r16S gene was amplified and sequenced by NGS, and its diversity and taxonomy composition were examined. ResultsMicrobial richness increased in post-FMT samples, and the β diversity studies grouped the samples into two clusters. One included the non-pathological samples (donor and pre-FMT samples), and the other included the pathological sample. The results obtained by Qiime2 and Bioconductor were similar. ConclusionThe analysis showed an increase in taxonomic diversity after the FMT, which suggests its usefulness. Moreover, these results showed that standardisation of bioinformatics analysis is key.

Clostridioides difficile Infection, Still a Long Way to Go.

Clostridioides difficile is an increasingly common pathogen both within and outside the hospital and is responsible for a large clinical spectrum from asymptomatic carriage to complicated infection associated with a high mortality. While diagnostic methods have considerably progressed over the years, the optimal diagnostic algorithm is still debated and there is no single diagnostic test that can be used as a standalone test. More importantly, the heterogeneity in diagnostic practices between centers along with the lack of robust surveillance systems in all countries and an important degree of underdiagnosis due to lack of clinical suspicion in the community, hinder a more accurate evaluation of the burden of disease. Our improved understanding of the physiopathology of CDI has allowed some significant progress in the treatment of CDI, including a broader use of fidaxomicine, the use of fecal microbiota transplantation for multiples recurrences and newer approaches including antibodies, vaccines and new molecules, already developed or in the pipeline. However, the management of CDI recurrences and severe infections remain challenging and the main question remains: how to best target these often expensive treatments to the right population. In this review we discuss current diagnostic approaches, treatment and potential prevention strategies, with a special focus on recent advances in the field as well as areas of uncertainty and unmet needs and how to address them.

Inactivation of Clostridioides Difficile Spores in Carpeting and Upholstery to Reduce Disease Recurrence in Households and Nursing Care Facilities

Objective: Clostridioides difficile (formerly Clostridium difficile) is among the most reported hospital and community-acquired gastrointestinal infections. Spores produced by this bacterium cause the initial disease and recurrent C. difficile infections (rCDI) and survive for long periods in the environment. Killing of C. difficile spores in carpeting and upholstery is very challenging without destruction or alteration of the fiber matrix material. In this study, we evaluated a fiber-safe standardized method for inhibiting germination of C. difficile spores recovered from in carpeting and upholstery material and thereby reduce the risk of disease incidence in households and nursing care facilities. Methods and Results : In this study, we found that the most effective procedure for the recovery of C. difficile spores from short-fiber textile surfaces used an ammonium phosphate-gelatin buffer, stainless steel beads to extract the spores from the carpet samples, and the addition of a heat activation step prior to plating. Virasept®, a known sporicide containing hydrogen peroxide and peroxyacetic acid, was evaluated for marked reduction of viable C. difficile spore number in carpet and fabric models. After a 30 min contact time, application of the sporicide at ~ 75 ml m2 of carpet (or 51.2 ml m2 upholstery fabric) resulted in a 3-log reduction in germination of five different C. difficile spore types (a ~99.9% decrease), representing five different Nap biotypes. Despite effective inhibition of C. difficile spore germination, Virasept treatment did not visibly damage or discolor carpet or fabric fibers. Conclusions: Results of this study show the potential effectiveness of a robust regimen for the practical treatment of carpeting and upholstery fabric in nursing care facilities, and residential homes to prevent community- and environmentally-acquired reinfection and recurrence of CDI in susceptible individuals.

29. Rapid Restoration of Bile Acid Compositions After Treatment with Investigational Microbiota-based Therapeutic RBX2660 for Recurrent clostrioides Difficile Infection

BackgroundRecurrent Clostrioides difficile infection (rCDI) is a public health threat associated with intestinal microbiome disruption (dysbiosis), which is postulated to increase CDI recurrence risk via disruption of bile acid(BA)-mediated resistance to C. difficile colonization. RBX2660 is an investigational microbiota-based therapeutic in clinical development for reducing rCDI recurrence. Herein, we assessed BA composition among participants in a Phase 2 trial of RBX2660 for rCDI.MethodsIn a double-blinded trial (PUNCH CD2), rCDI participants were randomized to receive RBX2660 or placebo. Primary efficacy was defined as absence of CDI recurrence at 8 weeks after the last study treatment. Participants were asked to provide stool samples before (baseline) and up to 24 months after treatment. A liquid chromatography tandem mass spectrometry method was developed to extract and quantify 36 BAs from a total of 167 participant stool samples from 47 participants. Participant-matched samples at baseline and 1, 4, and 8 weeks were compared with a linear mixed effects model.ResultsPrimary BAs predominated at baseline but were significantly reduced (p< .02) as early as 1 week after treatment and remained so to 24 months. Concurrently, secondary BAs, most notably deoxycholic acid (DCA) and lithocholic acid (LCA), were significantly increased (p< .01) after treatment and remained so throughout. Moreover, increases in DCA and LCA were associated with treatment response (p=.05 and p< .01, respectively), recognizing the limited sample size of treatment failures. Observed BA changes coincided with changes in taxonomic compositions—a shift from Gammaproteobacteria and Bacilli predominance before treatment to Clostridia and Bacteroidia predominance after treatment.Figure 1: BA restoration of successfully-treated participants ConclusionIn a trial of RBX2660 for rCDI, participant BA compositions significantly changed from before to after treatment, remained so for at least two years, and correlated with treatment outcome. The resulting predominance of secondary BAs coincided with microbiome compositional changes. Because secondary BA are thought to repress C. difficile colonization, these changes may partly explain how RBX2660 reduced CDI recurrence. Continued evaluation of RBX2660 for rCDI is underway.Disclosures Romeo Papazyan, PhD, Ferring Pharmaceuticals (Employee) Dana Walsh, PhD, Rebiotix Inc. (Employee) Steve Qi, PhD, Ferring Pharmaceuticals (Employee) Ken Blount, PhD, Rebiotix Inc. (Employee) Karthik Srinivasan, PhD, Ferring Pharmaceuticals (Employee) Bryan Fuchs, PhD, Ferring Pharmaceuticals (Employee)

30. Antimicrobial Resistance Genes Are Reduced Following Administration of Investigational Microbiota-based Therapeutic RBX7455 to Individuals with Recurrent clostrioides Difficile Infection

BackgroundAntimicrobial resistance (AMR) is a challenge in individuals at risk for recurrent Clostrioides difficile infection (rCDI). Recognizing that AMR bacteria colonize the intestinal microbiota, therapeutic approaches that decolonize the gut of AMR bacteria would be valuable. Herein, we assessed the microbial resistome before and after treatment with RBX7455—a room temperature-stable, orally-administered investigational microbiota-based therapeutic—in a Phase 1 trial for reducing CDI recurrence.MethodsThis investigator-sponsored trial enrolled 30 rCDI patients in 3 open-label treatment groups (n=10 per group): 1) Four RBX7455 capsules BID for 4 days, 2) Four RBX7455 capsules BID for 2 days, 3) Two RBX7455 capsules BID for 2 days. RBX7455 administration began 48 hours after finishing CDI antibiotics. Participants were asked to submit stool samples at baseline, 1, 7, 28 and 56 days after treatment. These were extracted and sequenced using a shallow shotgun method. Relative taxonomic abundances at the class level and the presence of AMR genes were determined for 148 participant samples and 11 product samples using 90% K-mer sequence coverage based on the MEGARes database.ResultsNinety percent of participants met the primary endpoint of no CDI recurrence through 8 weeks after treatment, and participant microbiome compositions became more similar to RBX7455 after treatment. The total AMR counts per participant decreased from before to after treatment (p< .05, mixed effects model), with the pattern of AMRs identified (resistome) becoming more like the RBX7455 resistome (Figure 1). Most notably, AMRs associated with multi-drug, fluoroquinolone, and betalactam resistance decreased from before to after treatment. There was no significant difference among the groups with respect to clinical response or changes in microbiome composition and AMR content.Figure 1 Average total and per-class AMR gene counts in participant samples before and after RBX7455 treatment. ConclusionIn a Phase 1 trial of RBX7455 for rCDI, AMR gene content decreased after treatment. This underscores the potential of microbiota-based therapies for decolonizing AMR bacteria from the gut microbiota. Continued clinical evaluation of RBX7455 is underway.Disclosures Dana Walsh, PhD, Rebiotix Inc. (Employee) Carlos Gonzalez, MS, BioRankings, LLC (Employee) Bill Shannon, PhD MBA, BioRankings, LLC (Employee) Ken Blount, PhD, Rebiotix Inc. (Employee)

796. Improving Clostridioides difficile Infection Treatment and Outcomes Using a Web-based Tool to Support a Care Coordination Intervention

Background Clostridioides difficile infection (CDI) is a highly burdensome disease, affecting 500,000 Americans each year. Despite extensive efforts to prevent and treat CDI, variability remains in the treatment guidelines, particularly as new medications are released. Treating CDI is particularly difficult, as approximately 25% of infected individuals experience recurrent CDI (rCDI).MethodsWe used a pre-post design to measure the impact of an intervention on rCDI, CDI readmission, and guideline-adherent treatment rates in adult patients who were admitted with or contracted CDI in the hospital. The intervention included the following:• Web-based performance platform delivering education and care coordination support• CDI care coordination for 8 weeks post-discharge (Figure 1)• Education and tools for addressing CDI guidelines, workflow needs, and patient engagement• Best practice sharing through peer-to-peer discussion callsPatient Contacts ResultsAmong the 77 patients consented in the Pre-Intervention period, 12 (15.6%) patients reported a recurrence of CDI, compared to 6 (15.4%) of the 39 Intervention patients who provided a response (P = 0.98). While a total of 55 patients were consented in the Intervention period, none reported a readmission for CDI, however 9 (11.7%) of Pre-Intervention patients reported a readmission for CDI (P = 0.03). There was a significant difference (P < 0.001) between the use of appropriate treatment, as defined by the 2018 SHEA/IDSA guidelines, between the Pre-Intervention and Intervention groups (55.8% vs. 94.3%).ConclusionA comprehensive multi-disciplinary team approach to preventing rCDI, including post-discharge care coordination, provides support to patients and caregivers. Future research is needed to evaluate how web-based tools, like those used in this study, could engage patients in the management of CDI and rCDI. Interventions aimed at improving the care of these patients may reduce recurrences and rehospitalizations.Disclosures All Authors: No reported disclosures