The potential for development of clinically relevant microbial resistance to rifaximin-α: a narrative review.

Rifaximin-α is a gut-targeted antibiotic indicated for numerous gastrointestinal and liver diseases. Its multifaceted mechanism of action goes beyond direct antimicrobial effects, including alterations in bacterial virulence, cytoprotective effects on host epithelial cells, improvement of impaired intestinal permeability, and reduction of proinflammatory cytokine expression via activation of the pregnane X receptor. Rifaximin-α is virtually non-absorbed, with low systemic drug levels contributing to its excellent safety profile. While there are high concentrations of drug in the colon, low water solubility leads to low colonic drug bioavailability, protecting the gut microbiome. Rifaximin-α appears to be more active in the bile-rich small bowel. Its important biologic effects are largely at sub-inhibitory concentration. Although in vitro testing of clinical isolates from rifaximin recipients has revealed rifaximin-resistant strains in some studies, the risk of emergent rifaximin-α resistance appears to be lower than for many other antibiotics. Rifaximin-α has been used for many years for traveler's diarrhea with no apparent increase in resistance levels in causative pathogens. Further, rifaximin-α retains its efficacy after long-term and recurrent usage in chronic gastrointestinal disorders. There are numerous reasons why the risk of microbial resistance to rifaximin-α may be lower than that for other agents, including low intestinal bioavailability in the aqueous colon, the mechanisms of action of rifaximin-α not requiring inhibitory concentrations of drug, and the low risk of cross transmission of rifaximin-α resistance between bacterial species. Reported emergence of vancomycin-resistant Enterococcus in liver-disease patients maintained on rifaximin needs to be actively studied. Further studies are required to assess the possible correlation between in vitro resistance and rifaximin-α efficacy.

Emergence of Clinical Clostridioides difficile Isolates With Decreased Susceptibility to Vancomycin.

BACKGROUND: Clostridioides difficile infection (CDI) is a leading cause of hospital-associated antibiotic-related diarrhea and deaths worldwide. Vancomycin is one of the few antibiotics recommended for both nonsevere and severe CDI cases. We sought to determine whether vancomycin nonsusceptible C. difficile strains are circulating in the patient population. METHODS: Stool samples from patients with CDI were collected from 438 and 98 patients at a large university hospital in Houston, Texas, and Nairobi, Kenya, respectively. The stools were examined for the presence of vancomycin and metronidazole nonsusceptible C. difficile using broth dilution culture, Etest (BioMérieux, France), polymerase chain reaction (PCR), whole-genome sequencing, and in vivo testing in a CDI mouse model. RESULTS: Of the Houston stool samples, 114/438 (26%) had vancomycin nonsusceptible C. difficile isolates and 128/438 (29%) were metronidazole nonsusceptible. Similarly, 66 out of 98 (67%) and 83/98 (85%) of the Nairobi patients harbored vancomycin and metronidazole nonsusceptible isolates, respectively. Vancomycin treatment of a CDI mouse model infected with a vancomycin nonsusceptible isolate failed to eradicate the infection. Whole-genome sequencing analyses did not identify vanA genes, suggesting a different mechanism of resistance. CONCLUSIONS: C. difficile strains exhibiting reduced susceptibility to vancomycin are currently circulating in patient populations. The spread of strains resistance to vancomycin, a first-line antibiotic for CDI, poses a serious therapeutic challenge. Routine susceptibility testing may be necessary.

Durable reduction of Clostridioides difficile infection recurrence and microbiome restoration after treatment with RBX2660: results from an open-label phase 2 clinical trial.

BACKGROUND: Effective treatment options for recurrent Clostridioides difficile infection (rCDI) are limited, with high recurrence rates associated with the current standard of care. Herein we report results from an open-label Phase 2 trial to evaluate the safety, efficacy, and durability of RBX2660-a standardized microbiota-based investigational live biotherapeutic-and a closely-matched historical control cohort. METHODS: This prospective, multicenter, open-label Phase 2 study enrolled patients who had experienced either ≥ 2 recurrences of CDI, treated by standard-of-care antibiotic therapy, after a primary CDI episode, or ≥ 2 episodes of severe CDI requiring hospitalization. Participants received up to 2 doses of RBX2660 rectally administered with doses 7 days apart. Treatment success was defined as the absence of CDI diarrhea without the need for retreatment for 8 weeks after completing study treatment. A historical control group with matched inclusion and exclusion criteria was identified from a retrospective chart review of participants treated with standard-of-care antibiotics for recurrent CDI who matched key criteria for the study. The primary objective was to compare treatment success of RBX2660 to the historical control group. A key secondary outcome was the safety profile of RBX2660, including adverse events and CDI occurrence through 24 months after treatment. In addition, fecal samples from RBX2660-treated participants were sequenced to evaluate microbiome composition and functional changes from before to after treatment. RESULTS: In this Phase 2 open-label clinical trial, RBX2660 demonstrated a 78.9% (112/142) treatment success rate compared to a 30.7% (23/75) for the historical control group (p < 0.0001; Chi-square test). Post-hoc analysis indicated that 91% (88/97) of evaluable RBX2660 responders remained CDI occurrence-free to 24 months after treatment demonstrating durability. RBX2660 was well-tolerated with mostly mild to moderate adverse events. The composition and diversity of RBX2660 responders' fecal microbiome significantly changed from before to after treatment to become more similar to RBX2660, and these changes were durable to 24 months after treatment. CONCLUSIONS: In this Phase 2 trial, RBX2660 was safe and effective for reducing rCDI recurrence as compared to a historical control group. Microbiome changes are consistent with restorative changes implicated in resisting C. difficile recurrence. Clinical Trials Registration NCT02589847 (10/28/2015).

Potential role of probiotics in reducing Clostridioides difficile virulence: Interference with quorum sensing systems.

Opportunistic pathogenic bacteria may cause disease after the normally protective microbiome is disrupted (typically by antibiotic exposure). Clostridioides difficile is one such pathogen having a severe impact on healthcare facilities and increasing costs of medical care. The search for new therapeutic strategies that are not reliant on additional antibiotic exposures are currently being explored. One such strategy is to disrupt the production of C. difficile virulence factors by interfering with quorum sensing (QS) systems. QS has been well studied in other bacteria, but our understanding in C. difficile is not so well understood. Some probiotic strains or combinations of strains have been shown to be effective in the treatment or primary prevention of C. difficile infections and may possess multiple mechanisms of action. One mechanism of probiotics might be the inhibition of QS, but their role has not been clearly defined yet. A literature search was conducted using standard databases (PubMed, Google Scholar) from database inception to August 2020. The objective of this paper is to update our understanding of how QS leads to toxin production by C. difficile, which is important in pathogenesis, and how QS inhibitors or probiotics may disrupt this pathway. We found two main QS systems for C. difficile (Agr and Lux systems) that are involved in C. difficile pathogenesis by regulating toxin production, motility and adherence. Probiotics and other QS inhibitors targeting QS systems may represent important new directions of therapy and prevention of CDI.

Approach to the patient with infectious colitis: clinical features, work-up and treatment.

PURPOSE OF REVIEW: To provide the definition, causes, and current recommendations for workup and treatment of acute infectious colitis in adults, a common medical problem of diverse cause. RECENT FINDINGS: The management of acute colitis in adults depend upon establishment of cause. Most forms of infectious colitis are treatable with antimicrobials. Multiplex polymerase chain reaction (PCR) followed by guided culture on PCR-positive pathogens can often confirm active infection while standard culture methods provide isolates for antibiotic susceptibility testing, subtyping, and Whole Genome Sequencing. SUMMARY: Patients with colitis may be suffering from a range of etiologies including infectious colitis, neutropenic colitis, drug-induced colitis, and inflammatory bowel disease. The present review was prepared to provide an approach to prompt diagnosis and management of acute colitis to prevent severe complications (e.g. dehydration and malnutrition, or toxic megacolon) and provide recommendations for antimicrobial therapy.

Impact of Diabetes on the Gut and Salivary IgA Microbiomes.

Mucosal surfaces like those present in the lung, gut, and mouth interface with distinct external environments. These mucosal gateways are not only portals of entry for potential pathogens but also homes to microbial communities that impact host health. Secretory immunoglobulin A (SIgA) is the single most abundant acquired immune component secreted onto mucosal surfaces and, via the process of immune exclusion, shapes the architecture of these microbiomes. Not all microorganisms at mucosal surfaces are targeted by SIgA; therefore, a better understanding of the SIgA-coated fraction may identify the microbial constituents that stimulate host immune responses in the context of health and disease. Chronic diseases like type 2 diabetes are associated with altered microbial communities (dysbiosis) that in turn affect immune-mediated homeostasis. 16S rRNA gene sequencing of SIgA-coated/uncoated bacteria (IgA-Biome) was conducted on stool and saliva samples of normoglycemic participants and individuals with prediabetes or diabetes (n = 8/group). These analyses demonstrated shifts in relative abundance in the IgA-Biome profiles between normoglycemic, prediabetic, or diabetic samples distinct from that of the overall microbiome. Differences in IgA-Biome alpha diversity were apparent for both stool and saliva, while overarching bacterial community differences (beta diversity) were also observed in saliva. These data suggest that IgA-Biome analyses can be used to identify novel microbial signatures associated with diabetes and support the need for further studies exploring these communities. Ultimately, an understanding of the IgA-Biome may promote the development of novel strategies to restructure the microbiome as a means of preventing or treating diseases associated with dysbiosis at mucosal surfaces.

THE INTESTINAL MICROBIOME IN HUMAN HEALTH AND DISEASE.

The Human Microbiome Initiative of NIH, begun in 2007, has opened the door to the power of the intestinal microbiome in health and disease. The 100 trillion gut microbes influence body function through three pathways: (1) via the neural route where 500 million neurons of the enteric nervous system (the body's second brain) connect to the brain and spinal cord, (2) via the immune route where the gut-immune capacity prevents infection and elicits immune response to vaccines, and (3) by the hormonal route wherein biologically active chemicals are released from enteroendocrine cells to control mood and body functions. Through research, the identification of diseases and disorders associated with abnormal microbiome ("dysbiosis") has increased in number with potential for reversibility. Our team has developed an orally administered fecal microbiota transplantation product that is effective in reversing dysbiosis in recurrent Clostridioides difficile (C. difficile) and is being used to reverse abnormal microbiomes in chronic dysbiotic disorders.

Abnormal Intestinal Microbiome in Medical Disorders and Potential Reversibility by Fecal Microbiota Transplantation.

Reduction in diversity of the intestinal microbiome (dysbiosis) is being identified in many disease states, and studies are showing important biologic contributions of microbiome to health and disease. Fecal microbiota transplantation (FMT) is being evaluated as a way to reverse dysbiosis in diseases and disorders in an attempt to improve health. The published literature was reviewed to determine the value of FMT in the treatment of medical disorders for which clinical trials have recently been conducted. FMT is effective in treating recurrent C. difficile infection in one or two doses, with many healthy donors providing efficacious fecal-derived products. In inflammatory bowel disease (IBD), FMT may lead to remission in approximately one-third of moderate-to-severe illnesses with one study suggesting that more durable FMT responses may be seen when used once medical remissions have been achieved. Donor products differ in their efficacy in treatment of IBD. Combining donor products has been one way to increase the potential value of FMT in treating chronic disorders. FMT is being explored in a variety of clinical settings affecting different organ systems outside CDI, with positive preliminary signals, in treatment of functional constipation, immunotherapy-induced colitis, neurodegenerative disease, as well as prevention of cancer-related disorders like graft versus host disease and decolonization of patients with recurrent urinary tract infection due to antibiotic-resistant bacteria. Currently, intense research is underway to see how the microbiome products like FMT can be harnessed for health benefits.

Activity of Hospital Disinfectants against Vegetative Cells and Spores of Clostridioides difficile Embedded in Biofilms.

Clostridioides difficile spores can survive in the environment in either mono- or mixed-species biofilms. However, no previous studies have investigated chemical disinfection of C. difficile spores embedded in biofilms. Thus, the purpose of this study was to assess the in vitro effectiveness of hospital disinfectants against C. difficile spores embedded within biofilms. Five unique C. difficile strains embedded in three different biofilm types grown for 72 or 120 h were exposed to seven different hospital disinfectants. C. difficile abundance [as log(number of CFU/milliliter)] was calculated after manufacturer-determined contact times along with biofilm biomass and microscopy. The primary analysis compared differences between C. difficile vegetative cell and spore counts as well as amounts of biomass after exposure to disinfectants. C. difficile vegetative cells and spores were recovered from biofilms regardless of the type of biofilm growth or biofilm growth time. No disinfectant was able to completely eliminate C. difficile from the biofilms. Overall, Clorox, ortho-phthalaldehyde (OPA), and Virex were most effective at killing C. difficile spores regardless of biofilm age, ribotype, or wash conditions (whether biofilms are washed or unwashed) (P = 0.001, each). Clorox and OPA were also effective at killing total vegetative cell growth (P = 0.001, each), but Virex was found to be ineffective against vegetative cell growth in biofilms (P = 0.77). Clorox and Virex were most effective in reducing biomass, followed by Nixall, OPA, and Vital Oxide. No disinfectant was able to completely eliminate C. difficile embedded within biofilms although differences among disinfectants were noted. Future research will be required to determine methods to eradicate this persister reservoir.

Estimating the incidence of norovirus acute gastroenteritis among US and European international travelers to areas of moderate to high risk of traveler's diarrhea: a prospective cohort study protocol.

BACKGROUND: Acute gastroenteritis (AGE) is the leading cause of illness among returning travelers seeking medical care. Multiple types of enteric pathogens can cause travel-acquired AGE and, while bacterial pathogens have a predominant role, the importance of viruses, such as norovirus, is increasingly recognized. There is a lack of information on travel-acquired norovirus incidence among symptomatic and asymptomatic individuals irrespective of healthcare-seeking behavior. Our aim is to estimate the incidence of travel-acquired AGE due to norovirus and to characterize the burden of disease among international travelers from the United States and Europe. METHODS: We describe a prospective cohort study implemented in five US and European sites to estimate the role of AGE due to norovirus among adult international travelers. We enrolled individuals aged 18 years and older who are traveling to regions of moderate-high risk of AGE, or via cruise ship with an international port stop, with a trip duration of 3-15 days. The study will generate a wide range of health and travel-related data for pre-, during, and up to 6-months post-travel. We will identify laboratory-confirmed travel-acquired norovirus infections among both symptomatic and asymptomatic individuals from self-collected whole stool samples tested via quantitative RT-PCR. Coinfections will be identified in a subset of travelers with AGE using a multiplex molecular-based assay. DISCUSSION: This study is unique in design and breadth of data collected. The prospective collection of health and behavioral data, as well as biologic samples from travelers irrespective of symptoms, will provide useful data to better understand the importance of norovirus AGE among international travelers. This study will provide data to estimate the incidence of norovirus infections and AGE and the risk of post-infectious sequelae in the 6-month post-travel period serving as a baseline for future norovirus AGE vaccination studies. This study will contribute valuable information to better understand the role of norovirus in travel-acquired AGE risk and the impact of these infections on a broad set of outcomes.

Stability and efficacy of frozen and lyophilized fecal microbiota transplant (FMT) product in a mouse model of Clostridium difficile infection (CDI).

Freezing donor fecal microbiota has simplified fecal microbiota transplantation (FMT) in the treatment of recurrent C. difficile infection (CDI). However, the optimal storage time for the frozen FMT products remains unknown. Using an established murine model of CDI, stability and efficacy of frozen and lyophilized FMT product was studied at time points from 2 months to 15 months. DNA was extracted from fecal samples from the mice with identification of specific bacterial species by real-time quantitative PCR (qPCR). FMT product stability and efficacy were measured by occurrence of diarrhea in the challenged mice together with stability of the microbiota composition. The results were analyzed and compared by SAS statistical software. All mice treated with only C. difficile developed diarrhea within 72 h. Mice treated with frozen (n = 5/group), lyophilized (n = 5/group) products stored for ≤ 7-month or fresh FMT product (n = 22) were protected from post C. difficile challenge diarrhea. There was no difference between frozen and lyophilized products (n = 5/group) stored for ≤ 7 months 95% CI 1.00 (0.38-2.64) and 1.00 (0.38-2.64), respectively. Prevention if CDI by frozen and lyophilized product was not different for storage of 9-, 11- and 15-months. qPCR results demonstrated there were no significant quantitative change in Bacteroides and Clostridium species during any of the storage times (P > 0.05). In the present study, frozen and lyophilized FMT products were stored up to 7 months without losing microbiota composition and therapeutic efficacy. The animal model described may be useful to study stability of human microbiota designed for FMT.

ACG Clinical Guideline: Diagnosis, Treatment, and Prevention of Acute Diarrheal Infections in Adults.

Acute diarrheal infections are a common health problem globally and among both individuals in the United States and traveling to developing world countries. Multiple modalities including antibiotic and non-antibiotic therapies have been used to address these common infections. Information on treatment, prevention, diagnostics, and the consequences of acute diarrhea infection has emerged and helps to inform clinical management. In this ACG Clinical Guideline, the authors present an evidence-based approach to diagnosis, prevention, and treatment of acute diarrhea infection in both US-based and travel settings.

Development and Validation of a Clostridium difficile Health-related Quality-of-Life Questionnaire.

GOALS AND BACKGROUND: Patients with Clostridium difficile infection (CDI) can experience long-term symptoms and poor quality of life due to the disease. Despite this, a health-related quality of life (HRQOL) instrument specific for patients with CDI does not exist. The aim of this study was to develop and validate a disease-specific instrument to assess HRQOL in patients with CDI. STUDY: A systematic literature review was conducted to identify HRQOL instruments and questions related to general health (n=3) or gastrointestinal disease (n=12) potentially related to CDI HRQOL. Removing duplicate questions and using direct patient or clinician interviews, a 36-item survey was developed. The survey was then tested using 98 patients with CDI and compared with the RAND Short-Form 36 (SF-36) Health Survey. Psychometric analysis techniques were used to identify domains and remove redundant items. RESULTS: Exploratory factor analysis identified 3 major domains (physical, mental, and social) with 4 associated subdomains. Survey overall and domain scores displayed good internal consistency (Cronbach α coefficient >0.87) and concurrent validity evidenced by significant correlation with SF-36 scores. The C. difficile survey scores were better able than the SF-36 to discriminate quality-of-life score differences in patients with primary versus recurrent CDI and increasing time since last episode of CDI. The final version contained 32 items related to the physical, mental, and social health of CDI patients. CONCLUSION: The properties of the newly developed Cdiff32 should make it appropriate to assess changes over time in HRQOL in patients with CDI.

Persistent Diarrhea: A Clinical Review.

IMPORTANCE: Diarrheal disease is commonly encountered in clinical practice. Persistent diarrhea (≥14 days) can be caused by pathogens that differ from those commonly seen in acute illness; proper etiologic diagnosis is important for appropriate therapeutic management. This review provides an overview of the epidemiology, etiology, diagnosis, and management of persistent diarrhea caused by infectious agents in immunocompetent individuals worldwide. OBSERVATIONS: Much of the data on persistent diarrhea comes from studies of residents in or expatriates of developing countries and travelers to these regions where follow-up studies have been performed. Persistent diarrhea occurs in approximately 3% of individuals traveling to developing countries. Schistosoma mansoni (and rarely Schistosoma haematobium) intestinal infection is also not very common and is found only in endemic areas. The microbiologic causes of protracted diarrhea include detectable parasitic (eg, Giardia, Cryptosporidium) and bacterial (eg, enteroaggregative Escherichia coli, Shigella) pathogens. Available diagnostic tests include culture-dependent for bacterial pathogens and culture-independent methods for bacterial, viral, and protozoal infections (eg, polymerase chain reaction [PCR]), including multiplex PCR, as well as and microscopy for protozoal infections. Antimicrobial therapy can be given empirically to patients returning from the undeveloped to the developed world. Otherwise, antibiotics should be given based on the results of laboratory testing. CONCLUSIONS AND RELEVANCE: Persistent diarrhea is a poorly recognized syndrome in all populations that requires proper assessment and diagnosis to ensure that affected individuals receive the treatment needed to experience improvement of clinical symptoms.

New approaches for bacteriotherapy: prebiotics, new-generation probiotics, and synbiotics.

The gut microbiota has a significant role in human health and disease. Dysbiosis of the intestinal ecosystem contributes to the development of certain illnesses that can be reversed by favorable alterations by probiotics. The published literature was reviewed to identify scientific data showing a relationship between imbalance of gut bacteria and development of diseases that can be improved by biologic products. The medical conditions vary from infectious and antibiotic-associated diarrhea to obesity to chronic neurologic disorders. A number of controlled clinical trials have been performed to show important biologic effects in a number of these conditions through administration of prebiotics, probiotics, and synbiotics. Controlled clinical trials have identified a limited number of prebiotics, probiotic strains, and synbiotics that favorably prevent or improve the symptoms of various disorders including inflammatory bowel disease, irritable bowel syndrome, infectious and antibiotic-associated diarrhea, diabetes, nonalcoholic fatty liver disease, necrotizing enterocolitis in very low birth weight infants, and hepatic encephalopathy. Studies have shown that probiotics alter gut flora and lead to elaboration of flora metabolites that influence health through 1 of 3 general mechanisms: direct antimicrobial effects, enhancement of mucosal barrier integrity, and immune modulation. Restoring the balance of intestinal flora by introducing probiotics for disease prevention and treatment could be beneficial to human health. It is also clear that significant differences exist between different probiotic species. Metagenomics and metatranscriptomics together with bioinformatics have allowed us to study the cross-talk between the gut microbiota and the host, furthering insight into the next generation of biologic products.

Traveler's diarrhea: a clinical review.

IMPORTANCE: Acute diarrhea is the most common illness that affects travelers to low-income regions of the world. Although improved hygiene has reduced the risk of traveler's diarrhea in many destinations, the risk remains high in others. OBJECTIVE: To review the current state of knowledge on the etiology, risk factors, prevention, and management of traveler's diarrhea. EVIDENCE REVIEW: A search of the PubMed, Google Scholar, and Cochrane Library databases for the period 2012-April 2014 was performed for articles on traveler's diarrhea. The database search yielded 2976 articles, of which 37 were included in this review. These were added to 85 articles previously identified by the authors. FINDINGS: Improved hygiene has reduced the risk of traveler's diarrhea from 20% or more (for a 2-week stay) to between 8% and 20% in some parts of the world. Acquiring traveler's diarrhea causes 12% to 46% of travelers to change their travel plans. Returning travelers seeking medical care have a diagnosis of gastrointestinal disturbance in approximately one-third of all cases. Postinfectious irritable bowel syndrome may occur in 3% to 17% of patients who have had traveler's diarrhea. Prevention of traveler's diarrhea by dietary avoidance measures is often not successful. Chemoprophylaxis should be restricted to travelers who are at risk of severe complications of diarrhea. Ciprofloxacin is the standard treatment in self-therapy of traveler's diarrhea except when patients are in South or Southeast Asia, where azithromycin is preferred. CONCLUSIONS AND RELEVANCE: Diarrhea remains a common problem for international travelers. Persons intending to travel to at-risk countries should be counseled regarding prevention measures and may be given a travel pack that includes medications for self-treatment should they become ill.

Motility abnormalities in irritable bowel syndrome.

BACKGROUND/AIMS: The intestinal pathophysiology in irritable bowel syndrome (IBS) is largely unknown. The lactulose breath test has been used to identify small bowel bacterial overgrowth in these patients. METHODS: We studied intestinal transit in patients with IBS using of the SmartPill® (SP) wireless pH/pressure recording capsule and performed lactulose breath tests to look for physiologic abnormalities. RESULTS: A total of 35/46 (76%) of the IBS patients had prolonged gastric emptying times. Constipation-predominant disease was associated with prolonged gut transit times. The mean hours ± SD for colonic transit time in the constipation group was 71.7 ± 61.1 (n = 13) compared with 22.5 ± 14.9 (n = 14) for diarrhea-predominant and 26.4 ± 21.5 (n = 20) for mixed clinical subtype (p = 0.0010). No correlation between small bowel transit time and abnormal breath hydrogen or methane excretion in the 46 combined patients with IBS was seen. CONCLUSIONS: Delayed gastric emptying was identified in IBS and in some patients may contribute to at least a component of their symptoms. Constipation-predominant IBS is associated with prolonged gut transit times. Otherwise, transit abnormalities do not appear to be important in IBS. Intestinal transit did not correlate with breath test results.

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.

Use of rifamycin drugs and development of infection by rifamycin-resistant strains of Clostridium difficile.

The relationship between rifamycin drug use and the development of resistant strains of Clostridium difficile was studied at a large university hospital in Houston, TX, between May 2007 and September 2011. In 49 of 283 (17.3%) patients with C. difficile infection (CDI), a rifamycin-resistant strain of C. difficile was identified that compares to a rate of 8% using the same definitions in 2006-2007 (P = 0.59). The 49 patients infected by a resistant organism were matched by date of admission to 98 control patients with CDI from whom a rifamycin-susceptible C. difficile strain was isolated. Cases and controls did not differ according to demographic and clinical characteristics and showed similar but low rates of prior rifamycin use. Similar rates of rifamycin resistance were seen in cases of hospital-acquired CDI (38/112 [34%]) versus community-acquired CDI (7/20 [35%]). At a university hospital in which rifaximin was commonly used, infection by rifamycin-resistant strains of C. difficile was not shown to relate to prior use of a rifamycin drug or to acquiring the infection in the hospital, although the rate of overall resistance appeared to be rising.