Microbiota-Based Live Biotherapeutic Products for Clostridioides Difficile Infection- The Devil is in the Details.

Clostridioides difficile infection (CDI) remains a significant contributor to healthcare costs and morbidity due to high rates of recurrence. Currently, available antibiotic treatment strategies further disrupt the fecal microbiome and do not address the alterations in commensal flora (dysbiosis) that set the stage for CDI. Advances in microbiome-based research have resulted in the development of new agents, classified as live biotherapeutic products (LBPs), for preventing recurrent CDI (rCDI) by restoring eubiosis. Prior to the LBPs, fecal microbiota transplantation (FMT) was available for this purpose; however, lack of large-scale availability and safety concerns have remained barriers to its widespread use. The LBPs are an exciting development, but questions remain. Some are derived directly from human stool while other developmental products contain a defined microbial consortium manufactured ex vivo, and they may be composed of either living bacteria or their spores, making it difficult to compare members of this heterogenous drug class to one another. None have been studied head-to head or against FMT in preventing rCDI. As a class, they have considerable variability in their biologic composition, biopharmaceutic science, route of administration, stages of development, and clinical trial data. This review will start by explaining the role of dysbiosis in CDI, then give the details of the biopharmaceutical components for the LBPs which are approved or in development including how they differ from FMT and from one another. We then discuss the clinical trials of the LBPs currently approved for rCDI and end with the future clinical directions of LBPs beyond C. difficile.

Gut microbiome alpha diversity decreases in relation to body weight, antibiotic exposure, and infection with multidrug-resistant organisms.

BACKGROUND: The human gastrointestinal tract is home to a dense and diverse microbiome, predominated by bacteria. Despite the conservation of critical functionality across most individuals, the composition of the gut microbiome is highly individualized, leading to differential responses to perturbations such as oral antibiotics or multidrug-resistant organism (MDRO) infection. Herein, subject responses to these perturbations based on their body weight were evaluated. METHODS: Fecal samples were collected from 45 subjects at the Detroit Medical Center to evaluate the effects of perturbations on subjects' gut microbiome composition. Bacterial profiling was completed using 16S rRNA gene sequencing. RESULTS: Subjects with multiple MDROs, subjects weighing greater than 80 kg infected with MDRO E coli, and subjects weighing less than 80 kg with exposure to vancomycin and carbapenem antibiotics during hospitalization had significantly decreased gut microbiome richness. CONCLUSIONS: Both administration of oral antibiotics and MDRO infections decreased gut microbiome alpha diversity, but the magnitude of these gut microbiome perturbations was body weight dependent.

Efficacy and Health-Related Quality of Life Impact of Fecal Microbiota, Live-jslm: A Post Hoc Analysis of PUNCH CD3 Patients at First Recurrence of Clostridioides difficile Infection.

INTRODUCTION: Clostridioides difficile infection (CDI) causes symptoms of varying severity and negatively impacts patients' health-related quality of life (HRQL). Despite antibiotic treatment, recurrence of CDI (rCDI) is common and imposes clinical and economic burdens on patients. Fecal microbiota, live-jslm (REBYOTA [RBL]) is newly approved in the USA for prevention of rCDI following antibiotic treatments. We analyzed efficacy and HRQL impact of RBL vs. placebo in patients at first rCDI using data from the phase 3 randomized, double-blind placebo-controlled clinical trial, PUNCH CD3. METHODS: This post hoc analysis included patients at first rCDI fromPUNCH CD3. Treatment success (i.e., absence of diarrhea within 8 weeks post-treatment) was analyzed adjusting for baseline patient characteristics. HRQL was measured using the Clostridioides difficile Quality of Life Survey (Cdiff32); absolute scores and change from baseline in total and domain (physical, mental, and social) scores were summarized and compared between arms. Analyses were conducted for the trial's blinded phase only. RESULTS: Among 86 eligible patients (32.8% of the overall trial population, RBL 53 [61.6%], placebo 33 [38.4%]), RBL-treated patients had significantly lower odds of recurrence (i.e., greater probability of treatment success) at week 8 vs. placebo (odds ratio 0.35 [95% confidence interval 0.13, 0.98]). Probability of treatment success at week 8 was 81% for RBL and 60% for placebo, representing 21% absolute and 35% relative increases for RBL (crude proportions 79.2% vs. 60.6%; relative risk 0.53, p = 0.06). Additionally, RBL was associated with significantly higher Cdiff32 total (change score difference 13.5 [standard deviation 5.7], p < 0.05) and mental domain (16.2 [6.0], p < 0.01) scores vs. placebo from baseline to week 8. CONCLUSION: Compared to placebo, RBL demonstrated a significantly higher treatment success in preventing further rCDI and enhanced HRQL among patients at first recurrence, establishing RBL as an effective treatment to prevent further recurrences in these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT03244644.

Bacteroides and related species: The keystone taxa of the human gut microbiota.

Microbial communities play a significant role in maintaining ecosystems in a healthy homeostasis. Presently, in the human gastrointestinal tract, there are certain taxonomic groups of importance, though there is no single species that plays a keystone role. Bacteroides spp. are known to be major players in the maintenance of eubiosis in the human gastrointestinal tract. Here we review the critical role that Bacteroides play in the human gut, their potential pathogenic role outside of the gut, and their various methods of adapting to the environment, with a focus on data for B. fragilis and B. thetaiotaomicron. Bacteroides are anaerobic non-sporing Gram negative organisms that are also resistant to bile acids, generally thriving in the gut and having a beneficial relationship with the host. While they are generally commensal organisms, some Bacteroides spp. can be opportunistic pathogens in scenarios of GI disease, trauma, cancer, or GI surgery, and cause infection, most commonly intra-abdominal infection. B. fragilis can develop antimicrobial resistance through multiple mechanisms in large part due to its plasticity and fluid genome. Bacteroidota (formerly, Bacteroidetes) have a very broad metabolic potential in the GI microbiota and can rapidly adapt their carbohydrate metabolism to the available nutrients. Gastrointestinal Bacteroidota species produce short-chain fatty acids such as succinate, acetate, butyrate, and occasionally propionate, as the major end-products, which have wide-ranging and many beneficial influences on the host. Bacteroidota, via bile acid metabolism, also play a role in in colonization-resistance of other organisms, including Clostridioides difficile, and maintenance of gut integrity.

A narrative review of nontuberculous mycobacterial pulmonary disease: microbiology, epidemiology, diagnosis, and management challenges.

INTRODUCTION: Nontuberculous mycobacteria (NTM) are a diverse group of mycobacterial species that are ubiquitous in the environment. They are opportunistic pathogens that can cause a range of diseases, especially in individuals with underlying structural lung disease or compromised immune systems. AREAS COVERED: This paper provides an in-depth analysis of NTM infections, including microbiology, environmental sources and transmission pathways, risk factors for disease, epidemiology, clinical manifestations and diagnostic approaches, guideline-based treatment recommendations, drugs under development, and management challenges. EXPERT OPINION: Future approaches to the management of NTM pulmonary disease will require therapies that are well tolerated, can be taken for a shorter time period and perhaps less frequently, have few drug-drug interactions, and are active against the various strains of pathogens. As the numbers of infections increase, such therapies will be welcomed by clinicians and patients.

Fecal Microbiota, Live-jslm for the Prevention of Recurrent Clostridioides difficile Infection : Subgroup Analysis of PUNCH CD2 and PUNCH CD3.

GOALS: To assess fecal microbiota, live-jslm (REBYOTA, abbreviated as RBL, formerly RBX2660) efficacy and safety in participants grouped by recurrent Clostridioides difficile infection (rCDI) risk factors and treatment-related variables. BACKGROUND: RBL is the first microbiota-based live biotherapeutic approved by the US Food and Drug Administration for the prevention of rCDI in adults after antibiotic treatment for rCDI. STUDY: Treatment success rates across subgroups for PUNCH CD3 (NCT03244644) were estimated using a Bayesian hierarchical model, borrowing data from PUNCH CD2 (NCT02299570). Treatment-emergent adverse events were summarized for the double-blind treatment period within 8 weeks. RESULTS: Treatment differences between RBL and placebo at 8 weeks were similar to the total population for most subgroups. Treatment effect sizes were similar between CDI tests, higher for oral vancomycin courses >14 days versus ≤14 days and higher for antibiotic washout periods of 3 days versus ≤2 days. The largest reductions in the rate of rCDI with RBL versus placebo were observed for participants with a 3-day CDI antibiotic washout period and participants with ≥4 previous CDI episodes. Most RBL-treated participants experienced TEAEs that were mild or moderate in severity and related to preexisting conditions. CONCLUSION: This analysis provides further evidence of RBL efficacy and safety across subgroups, including those at high risk for rCDI.

Patient Perception of Route of Rectal Administration of Live Biotherapeutic Product for Recurrent Clostridioides difficile Infection.

Introduction: CDI is a recurrent disease that is treated with antibiotics, but patients commonly experience repeat infections with significant impacts on hospital budgets and patient health quality. Standard of care management includes the antibiotics, vancomycin and fidaxomicin, which frequently provide clinical response, but do not avoid recurrence of Clostridioides difficile infection (rCDI). These recurrent infections occur due to dysbiosis of the colonic microbiota. One adjunctive therapeutic approach is to restore the deficient gastrointestinal flora using fecal microbiota transplantation (FMT) or live biotherapeutic products (LBP) when given after standard of care antimicrobials, which have been successful in reducing repeat infections with success rates up to 88%. FMT or LBP can be given by various routes. Methods: Two groups of subjects aged ≥18 years with at least one previous CDI episode within the previous 36 months completed self-administered online surveys to assess the acceptability of an LBP administered rectally. Group 1 consisted of LBP-recipients who had received RBL (REBYOTA) rectally as part of the Phase III PUNCH CD3 clinical trial. Group 2 consisted of LBP-naïve subjects who volunteered to participate and had experienced CDI within the prior 36 months but had no history of receiving FMT or LBP therapy. Results: LBP-recipients considered rectal administration easy (96%) and quick (94%), while 98% of respondents considered the lack of need for bowel preparation appealing. Most LBP-recipients (96%) wished they had earlier access to RBL. Most LBP-naïve subjects (87%) were likely or somewhat likely to consider a rectally administered treatment and 80% preferred a treatment option that does not require bowel preparation. Many of these subjects (76%) expressed interest in finding out about new treatment options for rCDI. Discussion: LBP-recipients and LBP-naïve subjects alike felt that rectal delivery of microbiome therapy is not only acceptable but highly interesting as a treatment avenue.

Effect of Fecal Microbiota, Live-Jslm (REBYOTA [RBL]) on Health-Related Quality of Life in Patients With Recurrent Clostridioides difficile Infection: Results From the PUNCH CD3 Clinical Trial.

Background: Recurrence of Clostridioides difficile infection (rCDI) is common, prolonging disease morbidity and leading to poor quality of life. We evaluated disease-specific health-related quality of life (HRQL) in patients with rCDI treated with fecal microbiota, live-jslm (REBYOTA [RBL]; Rebiotix) versus placebo. Methods: This was a secondary analysis of a randomized, double-blind, placebo-controlled phase 3 study (PUNCH CD3). The disease-specific Clostridioides difficile Quality of Life Survey (Cdiff32) was administered at baseline and at weeks 1, 4, and 8. Changes in Cdiff32 total and domain (physical, mental, social) scores from baseline to week 8 were compared between RBL and placebo and for responders and nonresponders. Results: Findings were analyzed in a total of 185 patients (RBL, n = 128 [69.2%]; placebo, n = 57 [30.8%]) with available Cdiff32 data. Patients from both arms showed significant improvements in Cdiff32 scores relative to baseline across all outcomes and at all time points (all P < .001); RBL-treated patients showed significantly greater improvements in mental domain than those receiving placebo. In adjusted analyses, RBL-treated patients showed greater improvements than placebo in total score and physical and mental domains (all P < .05). Similar improvement in mental domain was observed among responders, while nonresponders showed numerical improvements with RBL but not placebo. Conclusions: In a phase 3 double-blinded clinical trial, RBL-treated patients reported more substantial and sustained disease-specific HRQL improvements than placebo-treated patients. Clinical Trials Registration: ClinicalTrials.gov NCT03244644 (https://clinicaltrials.gov/ct2/show/NCT03244644).

Economic Impact of Recurrent Clostridioides difficile Infection in the USA: A Systematic Literature Review and Cost Synthesis.

INTRODUCTION: Up to 35% of patients with a first episode of Clostridioides difficile infection (CDI) develop recurrent CDI (rCDI), and of those, up to 65% experience multiple recurrences. A systematic literature review (SLR) was conducted to review and summarize the economic impact of rCDI in the United States of America. METHODS: English-language publications reporting real-world healthcare resource utilization (HRU) and/or direct medical costs associated with rCDI in the USA were searched in MEDLINE, MEDLINE In-Process, Embase, and the Cochrane Library databases over the past 10 years (2012-2022), as well as in selected scientific conferences that publish research on rCDI and its economic burden over the past 3 years (2019-2022). HRU and costs identified through the SLR were synthesized to estimate annual rCDI-attributable direct medical costs to inform the economic impact of rCDI from a US third-party payer's perspective. RESULTS: A total of 661 publications were retrieved, and 31 of them met all selection criteria. Substantial variability was found across these publications in terms of data source, patient population, sample size, definition of rCDI, follow-up period, outcomes reported, analytic approach, and methods to adjudicate rCDI-attributable costs. Only one study reported rCDI-attributable costs over 12 months. Synthesizing across the relevant publications using a component-based cost approach, the per-patient per-year rCDI-attributable direct medical cost was estimated to range from $67,837 to $82,268. CONCLUSIONS: While real-world studies on economic impact of rCDI in the USA suggested a high-cost burden, inconsistency in methodologies and results reporting warranted a component-based cost synthesis approach to estimate the annual medical cost burden of rCDI. Utilizing available literature, we estimated the average annual rCDI-attributable medical costs to allow for consistent economic assessments of rCDI and identify the budget impact on US payers.

The burden of CDI in the United States: a multifactorial challenge.

Clostridioides difficile infection (CDI) affects approximately 500,000 patients annually in the United States, of these around 30,000 will die. CDI carries significant burdens including clinical, social and economic. While healthcare-associated CDI has declined in recent years, community-associated CDI is on the rise. Many patients are also impacted by recurrent C. difficile infections (rCDI); up to 35% of index CDI will recur and of these up to 60% will further recur with multiple recurrences observed. The range of outcomes adversely affected by rCDI is significant and current standard of care does not alter these recurrence rates due to the damaged gut microbiome and subsequent dysbiosis. The clinical landscape of CDI is changing, we discuss the impact of CDI, rCDI, and the wide range of financial, social, and clinical outcomes by which treatments should be evaluated.

Microbiota-Based Live Biotherapeutic RBX2660 for the Reduction of Recurrent Clostridioides difficile Infection in Older Adults With Underlying Comorbidities.

Background: Advanced age and underlying comorbidities are associated with greater rates of recurrence in patients with Clostridioides difficile infection (CDI). Reducing the likelihood of recurrence through treatment with an antimicrobial followed by a microbiota replacement therapy can decrease the burden of this infection and improve patient outcomes. We report the efficacy and safety of RBX2660, a microbiota-based live biotherapeutic, in older adults with recurrent CDI, grouped by comorbidities. Methods: In this post hoc subgroup analysis of the PUNCH CD3 trial, we assessed outcomes in older adults (age ≥65 years) grouped by Charlson Comorbidity Index severity scores at screening (moderate [3-4] and severe [≥5]) and by the presence of underlying cardiac, renal, or gastrointestinal disorders. Results: RBX2660 treatment success rates in older adults with comorbidities were consistent across subgroups and similar to those in the total RBX2660-treated population. A greater percentage of RBX2660-treated older adults remained free of CDI recurrence through 8 weeks following treatment compared with placebo-treated participants in all but 2 subgroups assessed. Across all subgroups, most treatment-emergent adverse events (TEAEs) were mild or moderate in severity and related to a preexisting condition. None of the serious or life-threatening TEAEs that occurred were related to RBX2660 or its administration. Occurrence of TEAEs did not cluster in any subgroup. Conclusions: RBX2660 is efficacious and safe in older adults with recurrent CDI and underlying comorbidities.

Reducing Recurrence and Complications Related to Clostridioides difficile Infection: A Panel Discussion Summary.

BACKGROUND: The Centers for Disease Control and Prevention identifies Clostridioides difficile infection (CDI) as an urgent threat to people and health care systems. CDI leads to high health care utilizations and results in significantly reduced quality of life for patients. The high burden of disease is seen across all health care settings, outside of the hospital, in the community, and in younger people. Individuals with CDI transition from hospitals to long-term care facilities to the community, and management of these transitions can reduce the incidence of recurrence and rehospitalization. PURPOSE: The most common cause of diarrhea occurring in a health care setting is Clostridioides difficile and is also the cause of antibiotic-associated colitis (L. C. McDonald, 2021). The infection results from a disruption in the microbial flora of the gastrointestinal tract, mostly after antibiotic use or other medications such as proton pump inhibitors (PPIs). As a result, infected individuals are colonized and shed the spores into the environment, exposing others-goals of treatment focus on reducing the exposure and individual susceptibility. Although the incidence of C. diff is stable, recurrence is increasing significantly, with severe complications also a concern. The increased incidence and potential for life-threatening conditions require reducing initial exposure, supporting prescribed treatment, and preventing recurrence. PRIMARY PRACTICE SETTINGS: C. diff infection can be contracted in health care facilities and in the community. Case managers from nearly all practice settings may encounter patients with the infection. FINDINGS/CONCLUSIONS: To avert the devastating complications of Clostridioides difficile infection, case managers play an essential role in the prevention of recurrence with education, advocacy of best practices, effective care coordination, and thorough transitions of care. Each recurrence of C. diff infection leaves the patient vulnerable to the potential for surgical intervention, sepsis, and death. IMPLICATIONS FOR CASE MANAGEMENT: Mitigating the risk for readmission and recurrence will enhance C. diff infection care, safety, and outcomes to improve a patient's health care journey and quality of life. Case managers need to take a primary role in the transition and care coordination processes, including patient and support system education, coordination of any postdischarge services, connection to providers, adherence support activities, and follow-up for improvement or changes in condition. Supportive adherence activities and prevention education can result in the avoidance of recurrence. Case managers are well-equipped to locate resources to assist those patients challenged with the cost of medications, inability to attend appointments, or access basic needs. Although not directly related to C. diff, these challenges contribute to recurrence and readmission. Mitigating risk for readmission and recurrence results in an improved quality of life.

It's about the patients: Practical antibiotic stewardship in outpatient settings in the United States.

Antibiotic-resistant pathogens cause over 35,000 preventable deaths in the United States every year, and multiple strategies could decrease morbidity and mortality. As antibiotic stewardship requirements are being deployed for the outpatient setting, community providers are facing systematic challenges in implementing stewardship programs. Given that the vast majority of antibiotics are prescribed in the outpatient setting, there are endless opportunities to make a smart and informed choice when prescribing and to move the needle on antibiotic stewardship. Antibiotic stewardship in the community, or "smart prescribing" as we suggest, should factor in antibiotic efficacy, safety, local resistance rates, and overall cost, in addition to patient-specific factors and disease presentation, to arrive at an appropriate therapy. Here, we discuss some of the challenges, such as patient/parent pressure to prescribe, lack of data or resources for implementation, and a disconnect between guidelines and real-world practice, among others. We have assembled an easy-to-use best practice guide for providers in the outpatient setting who lack the time or resources to develop a plan or consult lengthy guidelines. We provide specific suggestions for antibiotic prescribing that align real-world clinical practice with best practices for antibiotic stewardship for two of the most common bacterial infections seen in the outpatient setting: community-acquired pneumonia and skin and soft-tissue infection. In addition, we discuss many ways that community providers, payors, and regulatory bodies can make antibiotic stewardship easier to implement and more streamlined in the outpatient setting.

The Practical Problem With Carbapenem Testing and Reporting Accurate Bacterial Susceptibilities.

Background: Antibiotic resistance is an evolving issue which requires constant review. Susceptibility breakpoints are revised in line with new microbiological and pharmacological data. Susceptibility breakpoints for carbapenems and Enterobacterales were revised in response to the rise in resistance and the potential for standard doses of carbapenems to provide the necessary antibiotic exposure and to accurately identify rates of carbapenem resistance. Objectives: This review sought to identify real-world implications associated with lack of testing and reporting current carbapenem breakpoints and potential barriers that may impede implementation of these strategies. Methods: A literature review was conducted using PubMed and Google Scholar electronic databases. Results: The failure to adopt revised breakpoints incurs negative clinical outcomes and carries increased cost implications. However, there were several impediments highlighted which are barriers for laboratories to implement breakpoint updates. Conclusion: Possible practical steps to implement revised breakpoints which apply to carbapenems and Enterobacterales are proposed. The challenge for laboratories is to be aware and implement these changes to provide accurate and relevant susceptibility results for clinicians.

Transitions of care in Clostridioides difficile infection: a need of the hour.

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