scholarly journals The effect of microbiota-based investigational drug RBX2660 on the gut microbiome and resistome revealed by a placebo-controlled clinical trial

2020 ◽  
Author(s):  
Suryang Kwak ◽  
JooHee Choi ◽  
Tiffany Hink ◽  
Kimberly A. Reske ◽  
Kenneth Blount ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Post Treatment ◽  
Patient Specific ◽  
Controlled Clinical Trial ◽  
Investigational Drug ◽  
Double Blind ◽  
Significant Recovery ◽  
Clostridioides Difficile ◽  
Metabolic Functions ◽  
Clostridioides Difficile Infection

Abstract Background Intestinal microbiota restoration can be achieved by replacing a subject’s perturbed microbiota with that of a healthy donor. Recurrent Clostridioides difficile infection (rCDI) is one key application of such treatment. Another application of interest is depletion of antibiotic resistant genes (ARGs) and organisms (AROs). In this study, we investigated fecal specimens from a multicenter, randomized, double-blind, placebo-controlled phase 2b study of microbiota-based investigational drug RBX2660. Patients were administered either placebo, 1 dose of RBX2660 and 1 placebo, or 2 doses of RBX2660 via enema and longitudinally tracked for changes in their microbiome and antibiotic resistome. Results All patients exhibited significant recovery of gut microbiome diversity and decrease of ARG abundance during the first 7 days post-treatment. However, the microbiome and resistome shifts towards healthier configurations were more significant and longer lasting in RBX2660 recipients compared to placebo. We identified 18 taxa and 21 metabolic functions distinguishing the baseline microbiome of non-transplanted patients, and the majority of features were correlated to intrinsic vancomycin resistance. We also identified 7 patient-specific and 3 RBX2660-specific ARGs and tracked their dynamics post treatment. Whole genome sequencing of AROs cultured from RBX2660 product and patient samples indicate ARO eradication in patients via RBX2660 administration, but also, to a lesser extent, introduction of RBX2660-derived AROs. Conclusions By including a placebo group, we distinguished the effects of RBX2660 from baseline post-antibiotic microbiome dynamics. Antibiotic discontinuation alone resulted in significant recovery of gut microbial diversity and reduced ARG abundance, but RBX2660 administration more rapidly and completely changed the composition of patients’ microbiome, resistome, and ARO colonization by transplanting RBX2660 microbiota into the recipients. Although ARGs and AROs were transmitted through RBX2660, the resistome post-RBX2660 more closely resembled that of the administered product—a proxy for the donor—than an antibiotic perturbed state.

scholarly journals The effect of microbiota-based investigational drug RBX2660 on the gut microbiome and resistome revealed by a placebo-controlled clinical trial

2020 ◽  
Author(s):  
Suryang Kwak ◽  
JooHee Choi ◽  
Tiffany Hink ◽  
Kimberly A. Reske ◽  
Kenneth Blount ◽  
...  
Keyword(s):  
Gut Microbiome ◽  
Post Treatment ◽  
Patient Specific ◽  
Controlled Clinical Trial ◽  
Investigational Drug ◽  
Metagenomic Sequencing ◽  
Double Blind ◽  
Significant Recovery ◽  
Clostridioides Difficile ◽  
Shotgun Metagenomic Sequencing

Abstract Background. Intestinal microbiota restoration can be achieved by replacing a subject’s perturbed microbiota with that of a healthy donor. Recurrent Clostridioides difficile infection (rCDI) is one key application of such treatment. Another emerging application of interest is depletion of antibiotic resistant genes (ARGs) and organisms (AROs). In this study, we investigated fecal specimens from a multicenter, randomized, double-blind, placebo-controlled phase 2b study of microbiota-based investigational drug RBX2660. Patients were administered either placebo, 1 dose of RBX2660 and 1 placebo, or 2 doses of RBX2660 via enema and longitudinally tracked for changes in their microbiome and antibiotic resistome. Results. All patients exhibited significant recovery of gut microbiome diversity and a decrease of ARG abundance during the first 7 days post-treatment. However, the microbiome and resistome shifts towards healthier configurations were more significant and longer-lasting in RBX2660 recipients compared to placebo. We quantified microbiome and resistome modification by RBX2660 using a novel ‘transplantation index’ metric. We identified taxonomic and metabolic features distinguishing the baseline microbiome of non-transplanted patients and taxa specifically enriched during the process of transplantation. We elucidated the correlation between resistome and taxonomic transplantations and post-treatment dynamics of patient-specific and RBX2660-specific ARGs. Whole genome sequencing of AROs cultured from RBX2660 product and patient samples indicate ARO eradication in patients via RBX2660 administration, but also, to a lesser extent, introduction of RBX2660-derived AROs. Conclusions. Through shotgun metagenomic sequencing, we elucidated the effects of RBX2660 in the microbiome and resistome. Antibiotic discontinuation alone resulted in significant recovery of gut microbial diversity and reduced ARG abundance, but RBX2660 administration more rapidly and completely changed the composition of patients’ microbiome, resistome, and ARO colonization by transplanting RBX2660 microbiota into the recipients. Although ARGs and AROs were transmitted through RBX2660, the resistome post-RBX2660 more closely resembled that of the administered product—a proxy for the donor—than an antibiotic perturbed state.

scholarly journals Impact of investigational microbiota therapeutic RBX2660 on the gut microbiome and resistome revealed by a placebo-controlled clinical trial

2020 ◽  
Author(s):  
Suryang Kwak ◽  
JooHee Choi ◽  
Tiffany Hink ◽  
Kimberly A. Reske ◽  
Kenneth Blount ◽  
...  
Keyword(s):  
Relative Abundance ◽  
Gut Microbiome ◽  
Post Treatment ◽  
Patient Specific ◽  
Controlled Clinical Trial ◽  
Investigational Drug ◽  
Metagenomic Sequencing ◽  
Double Blind ◽  
Significant Recovery ◽  
Clostridioides Difficile

Abstract Background. Intestinal microbiota restoration can be achieved by complementing a subject’s perturbed microbiota with that of a healthy donor. Recurrent Clostridioides difficile infection (rCDI) is one key application of such treatment. Another emerging application of interest is reducing antibiotic resistant genes (ARGs) and organisms (AROs). In this study, we investigated fecal specimens from a multicenter, randomized, double-blind, placebo-controlled phase 2b study of microbiota-based investigational drug RBX2660. Patients were administered either placebo, 1 dose of RBX2660 and 1 placebo, or 2 doses of RBX2660 via enema and longitudinally tracked for changes in their microbiome and antibiotic resistome.Results. All patients exhibited significant recovery of gut microbiome diversity and a decrease of ARG relative abundance during the first 7 days post-treatment. However, the microbiome and resistome shifts towards average configurations from unperturbed individuals were more significant and longer-lasting in RBX2660 recipients compared to placebo. We quantified microbiome and resistome modification by RBX2660 using a novel ‘transplantation index’ metric. We identified taxonomic and metabolic features distinguishing the baseline microbiome of non-transplanted patients and taxa specifically enriched during the process of transplantation. We elucidated the correlation between resistome and taxonomic transplantations and post-treatment dynamics of patient-specific and RBX2660-specific ARGs. Whole genome sequencing of AROs cultured from RBX2660 product and patient samples indicate ARO eradication in patients via RBX2660 administration, but also, to a lesser extent, introduction of RBX2660-derived AROs.Conclusions. Through shotgun metagenomic sequencing, we elucidated the effects of RBX2660 in the microbiome and resistome. Antibiotic discontinuation alone resulted in significant recovery of gut microbial diversity and reduced ARG relative abundance, but RBX2660 administration more rapidly and completely changed the composition of patients’ microbiome, resistome, and ARO colonization by transplanting RBX2660 microbiota into the recipients. Although ARGs and AROs were transmitted through RBX2660, the resistome post-RBX2660 more closely resembled that of the administered product—a proxy for the donor—than an antibiotic perturbed state.Trial registration: NCT02299570. Registered 19 November 2014, https://clinicaltrials.gov/ct2/show/NCT02299570

scholarly journals The contribution of bile acid metabolism to the pathogenesis of Clostridioides difficile infection

2021 ◽  
Vol 14 ◽  
pp. 175628482110177
Author(s):  
Benjamin H. Mullish ◽  
Jessica R. Allegretti
Keyword(s):  
Bile Acid ◽  
Bile Acids ◽  
Gut Microbiome ◽  
Acid Metabolism ◽  
Disease Process ◽  
Farnesoid X Receptor ◽  
Bile Acid Metabolism ◽  
Clostridioides Difficile ◽  
Gut Barrier Function ◽  
Clostridioides Difficile Infection

Clostridioides difficile infection (CDI) remains a major global cause of gastrointestinal infection, with significant associated morbidity, mortality and impact upon healthcare system resources. Recent antibiotic use is a key risk factor for the condition, with the marked antibiotic-mediated perturbations in gut microbiome diversity and composition that underpin the pathogenesis of CDI being well-recognised. However, only relatively recently has further insight been gained into the specific mechanistic links between these gut microbiome changes and CDI, with alteration of gut microbial metabolites – in particular, bile acid metabolism – being a particular area of focus. A variety of in vitro, ex vivo, animal model and human studies have now demonstrated that loss of gut microbiome members with bile-metabolising capacity (including bile salt hydrolases, and 7-α-dehydroxylase) – with a resulting alteration of the gut bile acid milieu – contributes significantly to the disease process in CDI. More specifically, this microbiome disruption results in the enrichment of primary conjugated bile acids (including taurocholic acid, which promotes the germination of C. difficile spores) and loss of secondary bile acids (which inhibit the growth of C. difficile, and may bind to and limit activity of toxins produced by C. difficile). These bile acid changes are also associated with reduced activity of the farnesoid X receptor pathway, which may exacerbate C. difficile colitis throughout its impact upon gut barrier function and host immune/inflammatory response. Furthermore, a key mechanism of efficacy of faecal microbiota transplant (FMT) in treating recurrent CDI has been shown to be restoration of gut microbiome bile metabolising functionality; ensuring the presence of this functionality among defined microbial communities (and other ‘next generation’ FMT products) designed to treat CDI may be critical to their success.

scholarly journals Gut microbiome and Clostridioides difficile infection: a closer look at the microscopic interface

2021 ◽  
Vol 14 ◽  
pp. 175628482199473
Author(s):  
Kanika Sehgal ◽  
Sahil Khanna
Keyword(s):  
Gut Microbiota ◽  
Proton Pump Inhibitors ◽  
Proton Pump ◽  
Gut Microbiome ◽  
Gastrointestinal Diseases ◽  
Clostridioides Difficile ◽  
Number Of Factors ◽  
Clostridioides Difficile Infection ◽  
Microbiota Structure

The pathogenesis of Clostridioides difficile infection (CDI) was recognized with its link to the use of antimicrobials. Antimicrobials significantly alter gut microbiota structure and composition, which led to the discovery of the association of this gut perturbation with the development of CDI. A number of factors implicated in its pathogenesis, such as advancing age, proton-pump inhibitors, and gastrointestinal diseases, are linked to gut microbiota perturbations. In an effort to better understand CDI, a multitude of studies have tried to ascertain protective and predictive microbial footprints linked with CDI. It has further been realized that CDI in itself can alter the gut microbiome. Its spore-forming capability poses as an impediment in the management of the infection and contributes to its recurrence. Antibiotic therapies used for its management have also been linked to gut microbiota changes, making its treatment a little more challenging. In an effort to exploit and utilize this association, gut microbial restoration therapies, particularly in the form of fecal microbial transplant, are increasingly being put to use and are proving to be beneficial. In this review, we summarize the association of the gut microbiome and microbial perturbation with initial and recurrent CDI.

scholarly journals Clinical efficacy of Tailin formulation combined with continuous low-dose antimicrobial therapy for recurrent urinary tract infection: study protocol for a multicenter, double-blind, randomized, controlled clinical trial

Trials ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Tonglu Li ◽  
Yingru Xu ◽  
Xuezhong Gong
Keyword(s):  
Clinical Trial ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Post Treatment ◽  
Controlled Clinical Trial ◽  
Double Blind ◽  
Randomized Controlled ◽  
Treatment Changes

Abstract Background Given the increasing rates of antimicrobial resistance (AMR), recurrent urinary tract infection (rUTI) is becoming refractory more and more. Antibiotic prophylaxis including continuous low-dose antibiotic therapy (CLAT), is the common treatment for rUTI of the world. However, the presumably adverse reactions caused by CLAT alone should be paid more attention. Studies indicated that Chinese herbal medicine (CHM) might be an available treatment method for rUTI. Tailin formulation (TLF) is a herbal prescription developed for the treatment of rUTI in the 2000s in Shanghai Municipal Hospital of Traditional Chinese Medicine. Our previous studies have shown TLF could prevent urinary tract infection both in pyelonephritis (PN) rat model and in PN patients. Additionally, our published data demonstrated TLF is helpful to reduce the recurrence of rUTI and protect renal tubular function in clinic. In order to find a novel treating project for rUTI to increase the clinical curative effect, we thus try to combine TLF with CLAT to treat rUTI and design an optimized, pragmatically clinical trial to evaluate the efficacy and safety of this project. Methods/design This is a multicenter, double-blind, randomized, controlled clinical trial. We will enroll 200 eligible patients diagnosed with uncomplicated rUTI and then divide them randomly into two groups with a 1:1 ratio: TLF + CLAT group and placebo + CLAT group. This trial consists of two stages, a 12-week period of treatment and a 12-week period of post-treatment follow-up, respectively. The primary outcome will be the recurrence rate at the 12th week of the follow-up period; the second outcomes will be the post-treatment changes in renal and liver function; furthermore, traditional Chinese medicine (TCM) symptoms, non-infection-related physical signs, and subjective symptoms will be scored, and the number of episodes of each subject will be also recorded; meanwhile, vital signs indicators and serious adverse events (SAEs) will be monitored throughout the trial. Discussion This study will provide convictive research-derived data to evaluate clinical efficacy and safety of TLF combined with CLAT for rUTI, and provide an evidence-based recommendation for clinicians. Moreover, post-treatment changes in non-infection-related physical signs and subjective symptoms were included in the efficacy evaluation, which is important and more significant for assessing the clinical benefits for those rUTI patients. Trial registration Chinese Clinical Trial Registry ChiCTR2100041914. Registered on 10 January 2021. Protocol date and version: September 12, 2020; version 1.

scholarly journals SER-109, an Investigational Microbiome Drug to Reduce Recurrence After Clostridioides difficile Infection: Lessons Learned From a Phase 2 Trial

2020 ◽  
Author(s):  
Barbara H McGovern ◽  
Christopher B Ford ◽  
Matthew R Henn ◽  
Darrell S Pardi ◽  
Sahil Khanna ◽  
...  
Keyword(s):  
Bile Acid ◽  
Statistical Significance ◽  
Standard Of Care ◽  
Lessons Learned ◽  
Metagenomic Sequencing ◽  
Double Blind ◽  
Secondary Bile Acid ◽  
Phase 2 Trial ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection

Abstract Background Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs. Methods In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile–positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed. Results 89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11–2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity. Conclusions Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial. Clinical Trials Registration NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4.

scholarly journals Characterization of Clostridioides difficile Strains, the Disease Severity, and the Microbial Changes They Induce

2020 ◽  
Vol 9 (12) ◽  
pp. 4099
Author(s):  
Hanan Rohana ◽  
Maya Azrad ◽  
Orna Nitzan ◽  
Amos Adler ◽  
Dana Binyamin ◽  
...  
Keyword(s):  
Disease Severity ◽  
Gut Microbiome ◽  
Binary Toxin ◽  
Toxin Gene ◽  
Medical Interventions ◽  
Clostridioides Difficile ◽  
Clostridioides Difficile Infection ◽  
Susceptibility Tests ◽  
Nosocomial Disease ◽  
Different Strains

Background: Clostridioides difficile infection (CDI) is a major nosocomial disease. The characteristics of different strains, the disease severity they cause, their susceptibility to antibiotics, and the changes they inflict on gut microbiome, have not been comprehensively studied in Israel. Methods: A severity score was calculated for 70 patients. Stool samples were tested for toxins presence using a special kit. Bacteria were isolated, identified by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) and antibiotic susceptibility tests were performed for several antibiotics. Strains were classified by Multi-locus sequence typing (MLST), and changes in gut microbiome were tested. Results: ST04 (22.5%) and ST37 (12.7%) were the most frequent strains. Clade (phylogenetic lineage) 1 was the most (81.4%) prevalent. We found significant associations between ST and age (p = 0.024) and between ST and moxifloxacin susceptibility (p = 0.001). At the clade level, we found significant associations with binary toxin gene occurrence (p = 0.002), and with susceptibility to both metronidazole and vancomycin (p = 0.024, 0.035, respectively). Differences in intestine microbiome were affected by age, clades’ distribution and STs. Conclusions: By defining the characteristics of the different strains and clades, clinicians can choose medical interventions based on the predicted response or disease severity associated with each strain, enabling new advances in the field of personalized medicine.

Sign in / Sign up

Export Citation Format

Share Document