Microbiota restoration therapies for recurrent Clostridioides difficile infection reach an important new milestone.

Microbiota restoration therapy has become a standard treatment for recurrent Clostridioides difficile infection (rCDI). In this article, we review the studies supporting the licensure of two live biotherapeutic products (LBPs) designed to prevent rCDI and to provide clinicians with a perspective on their differences. PubMed was reviewed on 1 October 2023, for all papers published concerning the current Food and Drug Administration allowance of the use of fecal microbiota transplantation (FMT) and the studies that led to the licensure of RBX2660 (REBYOTA™), generic name, fecal microbiota, live-jslm, and SER-109 (VOWST™), generic name, fecal microbiota spores, live-brpk. OpenBiome continues to produce fecal products for patients with rCDI at their treatment sites, and the American Gastroenterology Association has a National Registry focused on long-term safety of administering fecal microbiota products. The science behind the licensing of fecal microbiota, live-jslm, a consortium of fecal anaerobes found in stool augmented with strains of Bacteroidetes and fecal microbiota spores, live-brpk, a mixture of 50 species of purified Firmicutes spores is reviewed. Both products appear to be safe in clinical trials and effective in reducing rCDI episodes by mechanisms established for FMT, including normalization of α- and ß-diversity of the microbiome and by increasing fecal secondary bile acids. The different makeup of the two LBPs suggests that rCDI responds to a variety of engrafting microbiota which explains why nearly all donors in FMT of rCDI are generally effective. Fecal microbiota, live-jslm has also been shown to successfully treat rCDI in elderly patients with advanced comorbidities. With the licensure of two novel LBPs, we are entering a new phase of microbiota replacement therapy. Having standardized manufacturing and proper monitoring of products, harnessing the microbiome to control and prevent disease has a new beginning.

Licensure of two new live biotherapeutic products to treat recurrent C difficile infection is changing the landscape for treatment of this common and often serious infection Microbiota replacement therapy is the most effective way to prevent multiple recurrences of C difficile infection. The article discusses where fecal microbiota transplantation is available in North America. The major focus is on two recently licensed live biotherapeutic products, RBX2660 (REBYOTA), generic name fecal microbiota, live-jslm and SER-109 (VOWST), generic fecal microbiota spores, live-brpk, manufactured under standardized methods which should be safer and more standardized in response. The article compares the new LBPs for safety, effectiveness, cost to help clinicians make decisions. The licensure and availability of two safe and effective standardized and regulated biotherapies, fecal microbiota, live-jslm and fecal microbiota spores, live-brpk, for preventing rCDI is a critical advance in medical management. Both treatments were shown to cure rCDI, to normalize the microbiome of the treated patients by reducing proportions of proinflammatory Enterobacteriaceae and increasing the α- and ß-diversity of the microbiome, and to convert primary bile acids to C. difficile-inhibiting secondary bile acids in fecal samples. Both products included follow-up studies show durable cure without important short-term adverse events. The two recently licensed LBP differ in a number of ways. Fecal microbiota, live-jslm is a broad consortium of microbiota expected in a healthy donor fecal samples, including all the major phyla including Firmicutes. It is augmented with strains of Bacteroidetes, while fecal microbiota spores, live-brpk is ethanol washed spores exclusively within the phylum of Firmicutes. The fact that both products are effective in preventing rCDI support the idea that bacterial restoration in rCDI can be achieved by transplantation of a variety of different microbiota. This is seen in FMT for rCDI where it is generally accepted that all healthy adults are suitable donors and large number of donors can be included unscreened for microbiome diversity in a stool bank such as OpenBiome. When treating conditions other than CDI, the specific makeup of an LBP may need to be adjusted. One way around the unique microbiome requirements of non-CDI illnesses with dysbiosis is to administer FMT product derived from multiple donors. Evidence developed and presented here indicate that the two new LBPs are effective in treating rCDI, although head-to-head comparisons have not been carried out. fecal microbiota, live-jslm is a more traditional microbiome restoration product employing a full range of microbiota. fecal microbiota spores, live-brpk is novel in design and is based on the selection of Firmicutes spores with a narrower range of bioactivity. The future of microbiota-therapy has gotten brighter with the licensure of fecal microbiota, live-jslm and fecal microbiota spores, live-brpk.

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).

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.

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.

Clostridioides difficile Infection: The Challenge, Tests, and Guidelines.

Clostridioides difficile is a dangerous human pathogen because it can grow to high numbers in the intestine, cause colitis with its potent toxins, and persist as spores. C. difficile infection (CDI) is the primary hospital-acquired infection in North America and Europe, and it now is a global disease. Even with newer laboratory tests, there still is confusion on accurately diagnosing this disease. Three guidelines from three different healthcare-affiliated societies have recently been published. Consensus consolidated recommendations from these guidelines should be recognized by healthcare professionals, who need to understand why this disease continues to be difficult to diagnose and need a clear understanding of the advantages and limitations of current tests. Hopefully, these combined efforts will lead to an improvement in the recognition of this pathogen and a reduction in the suffering and economic loss caused by CDI.

The Role of Delafloxacin in Patients with Community-Acquired Bacterial Pneumonia in the Outpatient Setting: A Budget Impact Model.

BACKGROUND AND OBJECTIVE: Community-acquired bacterial pneumonia (CABP) affects millions of people each year in the USA. The majority of patients with CABP are treated in the community setting with empirical antimicrobial therapy. Delafloxacin is an anionic fluoroquinolone approved for the treatment of adult patients with CABP. This de novo analysis sought to estimate the budget impact of delafloxacin in the treatment of adult patients with CABP in the outpatient setting from the payer's perspective. METHODS: A budget impact model (BIM) was developed from the perspective of a US third-party payer to estimate the cost of introducing delafloxacin for the outpatient treatment of CABP over a 1-year time horizon. Population, clinical, and cost inputs were based on the available literature, clinical trial data, and real-world evidence studies. Scenario analyses were conducted to evaluate the potential budget impact among COPD/asthma patients based on the findings from the phase III trial of delafloxacin for CABP, which indicated that patients with COPD or asthma may experience improved effectiveness with delafloxacin compared to moxifloxacin. RESULTS: In the base-case analysis, with a hypothetical plan of 1,000,000 members, the model estimated that adding delafloxacin to the formulary resulted in a total budget impact of $58,987. This increase was mainly attributed to treatment acquisition costs. In the scenario analysis that was restricted to COPD/asthma patients, adding delafloxacin to the formulary was estimated to result in a total budget impact of $5,042. CONCLUSION: The results of the budget impact analyses provide conservative estimates of the impact of adding delafloxacin to outpatient formularies in substitution of moxifloxacin.

Real-World Use of Oritavancin for the Treatment of Osteomyelitis.

Osteomyelitis is a difficult-to-treat disease that can require both surgical debridement and a prolonged course of antimicrobial therapy. Current standard of care for the antimicrobial treatment of osteomyelitis is fraught with multiple challenges and limitations. Patients typically require the insertion of an indwelling catheter for single or multiple daily intravenous antibiotic infusions for up to 6 weeks. Currently, there are treatment guidelines for only vertebral osteomyelitis, indicating the complexity of the condition. Oritavancin is a long-acting, second-generation lipoglycopeptide, administered intravenously once per week, which has potential to be a useful alternative in the treatment of osteomyelitis. This article reviews occurrence and outcomes of off-label oritavancin use for treatment of osteomyelitis as described in case reports. Analysis included 23 patients treated for osteomyelitis with single- or multiple-dose oritavancin. Overall, clinical cure or improvement was achieved in 87% of patients, and adverse events were mild and reported in only two patients. Clinical efficacy was demonstrated in 81.8% of methicillin-resistant Staphylococcus aureus (MRSA), 71.4% of methicillin-sensitive S. aureus (MSSA), 50% of vancomycin-resistant Enterococcus (VRE), and in the single case of Streptococcus pyogenes. Oritavancin has shown efficacy against Gram-positive pathogens in osteomyelitis, and offers a possible outpatient treatment option for osteomyelitis patients. Future studies are needed to determine dosing frequency in osteomyelitis patients.

The Real-World Economic and Clinical Management of Adult Patients with Skin and Soft Tissue Infections (SSTIs) with Oritavancin: Data from Two Multicenter Observational Cohort Studies.

BACKGROUND: Oritavancin is a FDA-approved single-dose IV therapy for the treatment of acute bacterial skin and skin structure infections caused (or suspected to be caused) by certain Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). Published data describing the outcomes of patients with skin and soft tissue infections (SSTIs) who received oritavancin beyond its pivotal phase III clinical trials are scant. OBJECTIVE: The purpose of this report was to describe the results of two separate multicenter observational cohort studies that described the outcomes associated with two unique real-world usage patterns of oritavancin. METHODS: The first cohort (n = 115) examined patients 18 years or older who were treated with oritavancin at three outpatient sites for SSTIs caused by suspected or confirmed Gram-positive pathogens, including MRSA, to avoid hospital admission. Patients were included if they had not been discharged from the inpatient setting within the previous 24 h and received their single-dose oritavancin treatment at a hospital-based outpatient infusion center. The primary outcomes measured were 30-day healthcare costs and admissions (all cause and infection related). The second cohort (n = 151) was a multicenter, retrospective chart review of adult patients who were discharged early from seven hospitals in 2015 on oritavancin for SSTIs. The primary outcome was readmission of patients within 30 days (all cause and infection related). RESULTS: In cohort 1, 30-day mean healthcare costs were USD 3698. In the study of patients who started oritavancin in the outpatient setting, 7 patients (6.1%) were admitted to hospital within 30 days of the index treatment, and 3 of those (2.6% overall) were deemed to be due to an infection. In cohort 2, all-cause and infection-related 30-day readmission rates were 6.6% and 2.6%, respectively, among patients who received oritavancin at hospital discharge. CONCLUSIONS: Findings from these studies suggest that oritavancin may be a potentially useful agent to avoid hospitalization or shorten hospital length of stay among appropriate SSTI patients. Future comparator studies are required to properly ascertain the outcomes and potential benefits associated with oritavancin relative to other commonly used antibiotics in patients with SSTIs.

Combating resistance while maintaining innovation: the future of antimicrobial stewardship.

Antimicrobial resistance represents a significant global health threat. However, a commercial model that does not offer a return on investment resulting in a lack of investment in antibiotic R&D, means that the current pipeline of antibiotics lacks sufficient innovation to meet this challenge. Those responsible for defining, promoting and monitoring the rationale use of antibiotics (the antimicrobial stewardship programme) are key to addressing current shortcomings. In this personal perspective, we discuss the future role stewardship can play in stimulating innovation, a need to move away from a pharmacy budget dominated view of antibiotic use, and the impact of the ever-increasing sophistication and interdisciplinary nature of antimicrobial control programs. Changes are needed to optimize clinical outcomes for patients.

The burden of community-acquired bacterial pneumonia in the era of antibiotic resistance.

INTRODUCTION: Community-acquired pneumonia (CAP) is a significant global health problem and leading cause of death and hospitalization in both the US and abroad. Increasing macrolide resistance among Streptococcus pneumoniae and other pathogens results in a greater disease burden, along with changing demographics and a higher preponderance of comorbid conditions. Areas covered: This review summarizes current data on the clinical and economic burden of CAP, with particular focus on community-acquired bacterial pneumonia (CABP). Incidence, morbidity and mortality, and healthcare costs for the US and other regions of the world are among the topics covered. Major factors that are believed to be contributing to the increased impact of CABP, including antimicrobial resistance, the aging population, and the incidence of comorbidities are discussed, as well as unmet needs in current CABP management. Expert commentary: The clinical and economic burden of CABP is staggering, far-reaching, and expected to increase in the future as new antibiotic resistance mechanisms emerge and the world's population ages. Important measures must be initiated to stabilize and potentially decrease this burden. Urgent needs in CABP management include the development of new antimicrobials, adjuvant therapies, and rapid diagnostics.

Burden of antimicrobial resistance in an era of decreasing susceptibility.

INTRODUCTION: Antimicrobial resistance has become a global problem. Many pathogens are becoming multidrug-resistant with the attendant increased risk of failure of standard therapies and the under-recognised outcomes such as increased morbidity, mortality, length of hospitalization and costs of treatment. Areas covered: We undertook a review of the literature using standard search engines including PubMed, Google Scholar, Scopus and internet sources. Key search terms included antimicrobial resistance, antibiotic resistance, bacterial resistance, clinical outcomes, economic consequences, Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae and Staphylococcus aureus. Expert commentary: Antimicrobial resistance among the five-species presented demonstrates a major, and increasing, deleterious impact seen in each of the key outcomes measured. These negative changes, at a personal, health system and Societal levels, further emphasise the growing problem of increasing antimicrobial resistance at a global level and the vital need for new antimicrobials.

Efficacy and safety of ridinilazole compared with vancomycin for the treatment of Clostridium difficile infection: a phase 2, randomised, double-blind, active-controlled, non-inferiority study.

BACKGROUND: Clostridium difficile infection is the most common health-care-associated infection in the USA. We assessed the safety and efficacy of ridinilazole versus vancomycin for treatment of C difficile infection. METHODS: We did a phase 2, randomised, double-blind, active-controlled, non-inferiority study. Participants with signs and symptoms of C difficile infection and a positive diagnostic test result were recruited from 33 centres in the USA and Canada and randomly assigned (1:1) to receive oral ridinilazole (200 mg every 12 h) or oral vancomycin (125 mg every 6 h) for 10 days. The primary endpoint was achievement of a sustained clinical response, defined as clinical cure at the end of treatment and no recurrence within 30 days, which was used to establish non-inferiority (15% margin) of ridinilazole versus vancomycin. The primary efficacy analysis was done on a modified intention-to-treat population comprising all individuals with C difficile infection confirmed by the presence of free toxin in stool who were randomly assigned to receive one or more doses of the study drug. The study is registered with ClinicalTrials.gov, number NCT02092935. FINDINGS: Between June 26, 2014, and August 31, 2015, 100 patients were recruited; 50 were randomly assigned to receive ridinilazole and 50 to vancomycin. 16 patients did not complete the study, and 11 discontinued treatment early. The primary efficacy analysis included 69 patients (n=36 in the ridinilazole group; n=33 in the vancomycin group). 24 of 36 (66·7%) patients in the ridinilazole group versus 14 of 33 (42·4%) of those in the vancomycin group had a sustained clinical response (treatment difference 21·1%, 90% CI 3·1-39·1, p=0·0004), establishing the non-inferiority of ridinilazole and also showing statistical superiority at the 10% level. Ridinilazole was well tolerated, with an adverse event profile similar to that of vancomycin: 82% (41 of 50) of participants reported adverse events in the ridinilazole group and 80% (40 of 50) in the vancomycin group. There were no adverse events related to ridinilazole that led to discontinuation. INTERPRETATION: Ridinilazole is a targeted-spectrum antimicrobial that shows potential in treatment of initial C difficile infection and in providing sustained benefit through reduction in disease recurrence. Further clinical development is warranted. FUNDING: Wellcome Trust and Summit Therapeutics.

Antibiotic treatment patterns, costs, and resource utilization among patients with community acquired pneumonia: a US cohort study.

OBJECTIVES: The current treatment options for patients with community-acquired pneumonia (CAP) often present a trade-off between the potential for treatment failure and safety concerns. We set out to investigate real-world outcomes associated with the use of currently available antimicrobial treatment options for CAP in both the outpatient and inpatient (non-intensive care unit [ICU]) settings. METHODS: This claims-based retrospective study included adult patients diagnosed with CAP and treated with antibiotic therapies, including any oral fluoroquinolone, macrolide, or beta-lactam monotherapy in the outpatient setting, and intravenous (IV) levofloxacin or IV azithromycin/ceftriaxone in the inpatient setting. Generalized linear model (GLM) regression was used to determine total charges for inpatient stay, the length of stay, and days of inpatient therapy. For outpatients, rates of adverse events (AEs), treatment failure, and hospitalization were compared by type of initial antibiotic therapy using logistic regression multivariate models that controlled for baseline characteristics. RESULTS: A total of 441,820 outpatients and 33,287 inpatients treated for CAP between 2007 and 2012 were included in this analysis. In the outpatient setting, fluoroquinolone therapy led to a higher rate of documented AEs (adjusted odds ratio [OR]: 1.23; 95% confidence interval [CI]: 1.20-1.25; p < 0.0001) but a lower rate of retreatment (adjusted OR: 0.9; 95% CI: 0.87-0.94; p < 0.0001) compared with macrolides. Both AEs and retreatment in these patients were associated with increased costs. For patients treated with the IV macrolide/beta-lactam combination compared with IV fluoroquinolone in the inpatient setting, a significantly longer length of stay in hospital (4.71 vs. 4.38 days; p < 0.0001) and greater overall costs ($3,535 more per stay; p < 0.0001) were observed. CONCLUSION: In both the inpatient and outpatient settings, the development of additional efficacious treatment options that have a reduced AE burden for patients with CAP may be warranted.

Trojan Horse Antibiotics-A Novel Way to Circumvent Gram-Negative Bacterial Resistance?

Antibiotic resistance has been emerged as a major global health problem. In particular, gram-negative species pose a significant clinical challenge as bacteria develop or acquire more resistance mechanisms. Often, these bacteria possess multiple resistance mechanisms, thus nullifying most of the major classes of drugs. Novel approaches to this issue are urgently required. However, the challenges of developing new agents are immense. Introducing novel agents is fraught with hurdles, thus adapting known antibiotic classes by altering their chemical structure could be a way forward. A chemical addition to existing antibiotics known as a siderophore could be a solution to the gram-negative resistance issue. Siderophore molecules rely on the bacterial innate need for iron ions and thus can utilize a Trojan Horse approach to gain access to the bacterial cell. The current approaches to using this potential method are reviewed.