Rifaximin for the treatment of irritable bowel syndrome – a drug safety evaluation

ABSTRACT

Introduction: Irritable bowel syndrome is a functional gastrointestinal disorder with a multifactorial etiology. Alterations of intestinal motility and immunity, gut-brain interactions, as well as gut microbiota dysbiosis contribute to the development of irritable bowel syndrome. Therefore, gut microbiota modulation by non-absorbable antibiotics is a therapeutic option in patients with IBS.

Areas covered: Published articles including patients with irritable bowel syndrome reporting data about rifaximin activity and safety have been searched throughout the literature and selected.

Expert opinion: The optimal antibiotic molecule should be local-acting, long-acting and safe-acting. Rifaximin is a non-absorbable antibiotic with additional anti-inflammatory and gut microbiota-modulating activity. It is effective in inducing symptoms relief in patients with IBS, even after repeated treatment courses. Rifaximin-related side effects in patients with IBS are reported to be mild and infrequent; microbial resistance is rare and transient, due to the high local concentration of the drug and to the absence of horizontal transmission. Clostridium difficile infection is not usual in patients receiving rifaximin in absence of predisposing conditions such as hospitalization and immunosuppression, which are uncommon in patients affected by irritable bowel syndrome. Nevertheless rifaximin is an antibiotic active against Clostridium difficile infection. Rifaximin has limited metabolic interactions and is not expected to interfere with drug metabolism in patients with normal hepatic function. These properties make rifaximin a safe antibiotic for gut microbiota modulation in patients with IBS.     

Structure–Activity Relationship for the Picolinamide Antibacterials that Selectively Target Clostridioides difficile

Clostridioides difficile is a leading health threat. This pathogen initiates intestinal infections during gut microbiota dysbiosis caused by oral administration of antibiotics. C. difficile is difficult to eradicate due to its ability to form spores, which are not susceptible to antibiotics. To address the urgent need for treating recurrent C. difficile infection, antibiotics that selectively target C. difficile over common gut microbiota are needed. We herein describe the class of picolinamide antibacterials which show potent and selective activity against C. difficile. The structure–activity relationship of 108 analogues of isonicotinamide 4, a compound that is equally active against methicillin-resistant Staphylococcus aureus and C. difficile, was investigated. Introduction of the picolinamide core as exemplified by analogue 87 resulted in exquisite potency and selectivity against C. difficile. The ability of the picolinamide class to selectively target C. difficile and to prevent gut dysbiosis holds promise for the treatment of recurrent C. difficile infection.     

Increased health burden associated with Clostridium difficile diarrhoea in patients with inflammatory bowel disease

Background Clostridium difficile (C. difficile) infection in hospitals in developed countries continues to be a major public health hazard despite increased control measures including review of antibiotic policies and hygiene measures. Patients with colitis are thought to be particularly vulnerable to C. difficile associated diarrhoea (CDAD). Identifying the clinical burden among hospitalised patients admitted with inflammatory bowel disease is an essential first step towards identifying and treating severe C. difficile infection in such individuals. Aim To determine excess morbidity and in‐hospital mortality associated with hospital acquired CDAD in patients with inflammatory bowel disease (IBD‐CDAD‐HAI) admitted to NHS hospitals in England compared with those admitted for inflammatory bowel disease alone. Methods Time trends study of all admissions to NHS hospitals between 2002/03 and 2007/08. We developed case definitions for IBD‐CDAD‐HAI patients. The primary outcomes were in‐hospital mortality and length of stay. The secondary outcome was gastrointestinal surgery. Results Patients in the IBD‐CDAD‐HAI group were more likely to die in hospital (adjusted OR 6.32), had 27.9 days longer in‐patient stays and higher gastrointestinal surgery rates (adjusted OR 1.87) than patients admitted for inflammatory bowel disease alone. Conclusion Patients with inflammatory bowel disease admitted to NHS hospitals in England with co‐existent C. difficile infection are at risk of greater in‐hospital mortality and morbidity than patients admitted for inflammatory bowel disease alone.     

Gut Non-Bacterial Microbiota: Emerging Link to Irritable Bowel Syndrome

As a common functional gastrointestinal disorder, irritable bowel syndrome (IBS) significantly affects personal health and imposes a substantial economic burden on society, but the current understanding of its occurrence and treatment is still inadequate. Emerging evidence suggests that IBS is associated with gut microbial dysbiosis, but most studies focus on the bacteria and neglect other communities of the microbiota, including fungi, viruses, archaea, and other parasitic microorganisms. This review summarizes the latest findings that link the nonbacterial microbiota with IBS. IBS patients show less fungal and viral diversity but some alterations in mycobiome, virome, and archaeome, such as an increased abundance of Candida albicans. Moreover, fungi and methanogens can aid in diagnosis. Fungi are related to distinct IBS symptoms and induce immune responses, intestinal barrier disruption, and visceral hypersensitivity via specific receptors, cells, and metabolites. Novel therapeutic methods for IBS include fungicides, inhibitors targeting fungal pathogenic pathways, probiotic fungi, prebiotics, and fecal microbiota transplantation. Additionally, viruses, methanogens, and parasitic microorganisms are also involved in the pathophysiology and treatment. Therefore, the gut nonbacterial microbiota is involved in the pathogenesis of IBS, which provides a novel perspective on the noninvasive diagnosis and precise treatment of this disease.     

The antidepressant-like effect of probiotics and their faecal abundance may be modulated by the cohabiting gut microbiota in rats

Numerous studies have been published describing the effect of various probiotics (PRO) on behaviours related to psychiatric disease. We have previously shown a robust antidepressant-like effect of PRO in rats, but over time, the treatment effect seems to vary significantly between different sets of rats from the same commercial vendor. Therefore, we hypothesised that the antidepressant-like response may be modulated by the cohabiting gut microbiota.The aims of the present study were (1) to investigate any differences in the gut microbiota composition between responders (Resp) and non-responders (Non-resp) to PRO with regards to depressive-like behaviour, and (2) to evaluate the effects of PRO on the microbiota composition.Two sets of 20 male Sprague-Dawley rats each were treated with multi-species PRO (nine Bifidobacterium, Lactococcus and Lactobacillus species) for eight weeks and subjected to a behavioural assessment. Faecal samples were collected for 16?s rRNA (VR4) gene amplicon sequencing (Illumina MiSeq).As previously reported, PRO-treated Resp animals showed a marked decrease in depressive-like behaviour, whereas no such response was seen in Non-resp. We observed profound differences in the gut microbiota composition between the two sets of rats, and the relative faecal abundance of the genera that comprised PRO was higher in Resp than in Non-resp although treated with the same dose of PRO. Particularly, the relative abundance of the Lactobacillus genus was not increased in PRO-treated Non-resp animals.In conclusion, the cohabiting microbiota and the faecal abundance of PRO may modulate the antidepressant-like effect of PRO in rats.     

Randomised clinical trial: the effects of perioperative probiotic treatment on barrier function and post-operative infectious complications in colorectal cancer surgery - a double-blind study

Aliment Pharmacol Ther 2011; 33: 50–63

Summary

Background Infection following abdominal operation remains a major factor affecting the morbidity of patients after surgery. Aim To determine the effects of perioperative administration of probiotics on the gut barrier function and the surgical outcome in patients undergoing elective colorectal surgery. Methods One hundred patients with colorectal carcinoma were randomly divided into the control group (n = 50) and the probiotics group (n = 50). The probiotics were given orally for 6 days preoperatively and 10 days post‐operatively. Outcomes were measured by bacterial translocation, gut permeability, the effect on the faecal microbiota, and the clinical outcomes such as infectious‐related complications and gut defecation function. Results Compared with the control group, probiotics group had increased transepithelial resistance (P < 0.05), reduced transmucosal permeation of horseradish peroxidase and lactulose/mannitol ratio, reduced bacterial translocation (P < 0.05), decreased ileal‐bile acid binding protein (P < 0.05) and positive rate of blood bacterial DNA (P < 0.05) and an enhanced mucosal tight junction protein expression. They had decreased blood enteropathogenic bacteria and increased faecal bacterial variety. The post‐operative recovery of peristalsis, incidence of diarrhoea, and infectious‐related complications were also improved. Conclusion Probiotics can improve the integrity of gut mucosal barrier by benefiting the faecal microbiota, and decreasing infectious complications in patients with colorectal cancer undergoing colorectomy.     

Dysbiosis-Related Advanced Glycation Endproducts and Trimethylamine N-Oxide in Chronic Kidney Disease

Chronic kidney disease (CKD) is a public health concern that affects approximately 10% of the global population. CKD is associated with poor outcomes due to high frequencies of comorbidities such as heart failure and cardiovascular disease. Uremic toxins are compounds that are usually filtered and excreted by the kidneys. With the decline of renal function, uremic toxins are accumulated in the systemic circulation and tissues, which hastens the progression of CKD and concomitant comorbidities. Gut microbial dysbiosis, defined as an imbalance of the gut microbial community, is one of the comorbidities of CKD. Meanwhile, gut dysbiosis plays a pathological role in accelerating CKD progression through the production of further uremic toxins in the gastrointestinal tracts. Therefore, the gut-kidney axis has been attracting attention in recent years as a potential therapeutic target for stopping CKD. Trimethylamine N-oxide (TMAO) generated by gut microbiota is linked to the progression of cardiovascular disease and CKD. Also, advanced glycation endproducts (AGEs) not only promote CKD but also cause gut dysbiosis with disruption of the intestinal barrier. This review summarizes the underlying mechanism for how gut microbial dysbiosis promotes kidney injury and highlights the wide-ranging interventions to counter dysbiosis for CKD patients from the view of uremic toxins such as TMAO and AGEs.     

肠道菌群在中草药抗溃疡性结肠炎中的作用

溃疡性结肠炎(ulcerative colitis,UC)是一种慢性非特异性炎症性肠病,病情迁延难愈,且易反复发作,被世界卫生组织列为现代难治性疾病.UC的发病机制与肠道菌群失调密切相关.肠道菌群与胆汁酸、短链脂肪酸和色氨酸等代谢,与免疫系统以及肠黏膜屏障等的相互作用均影响UC的发生和发展.中草药活性成分、单味中草药及...     

Novel compound FLZ alleviates rotenone-induced PD mouse model by suppressing TLR4/MyD88/NF-κB pathway through microbiota–gut–brain axis

Parkinson's disease (PD) is the second most common neurodegenerative disease, but none of the current treatments for PD can halt the progress of the disease due to the limited understanding of the pathogenesis. In PD development, the communication between the brain and the gastrointestinal system influenced by gut microbiota is known as microbiota–gut–brain axis. However, the explicit mechanisms of microbiota dysbiosis in PD development have not been well elucidated yet. FLZ, a novel squamosamide derivative, has been proved to be effective in many PD models and is undergoing the phase I clinical trial to treat PD in China. Moreover, our previous pharmacokinetic study revealed that gut microbiota could regulate the absorption of FLZ in vivo. The aims of our study were to assess the protective effects of FLZ treatment on PD and to further explore the underlying microbiota-related mechanisms of PD by using FLZ as a tool. In the current study, chronic oral administration of rotenone was utilized to induce a mouse model to mimic the pathological process of PD. Here we revealed that FLZ treatment alleviated gastrointestinal dysfunctions, motor symptoms, and dopaminergic neuron death in rotenone-challenged mice. 16S rRNA sequencing found that PD-related microbiota alterations induced by rotenone were reversed by FLZ treatment. Remarkably, FLZ administration attenuated intestinal inflammation and gut barrier destruction, which subsequently inhibited systemic inflammation. Eventually, FLZ treatment restored blood–brain barrier structure and suppressed neuroinflammation by inhibiting the activation of astrocytes and microglia in the substantia nigra (SN). Further mechanistic research demonstrated that FLZ treatment suppressed the TLR4/MyD88/NF-κB pathway both in the SN and colon. Collectively, FLZ treatment ameliorates microbiota dysbiosis to protect the PD model via inhibiting TLR4 pathway, which contributes to one of the underlying mechanisms beneath its neuroprotective effects. Our research also supports the importance of microbiota–gut–brain axis in PD pathogenesis, suggesting its potential role as a novel therapeutic target for PD treatment.     

Extended spectrum beta‐lactamase‐producing bacteria and Clostridium difficile in patients with pouchitis

Aliment Pharmacol Ther 2010; 32: 664–669

Summary

Background Treatment with fluoroquinolones is associated with the development of Clostridium difficile and extended spectrum beta‐lactamase‐producing bacteria (ESBL). Clostridium difficile and ESBL are resistant to many antibiotics and each may cause pouchitis after restorative proctocolectomy (RPC) refractory to empirical antibiotic therapy. Aim To assess the prevalence and establish risk factors for the development of ESBL and Clostridium difficile toxins (CDT) in RPC patients with recurrent or refractory pouchitis under follow‐up at our institution over a 1‐year period. Method An enzyme‐linked immunosorbent assay was used to detect CDT and a culture technique was used to identity ESBL in faecal samples. All patients had previously received fluoroquinolone treatment. Results Forty‐eight patients (35 (74%) men; median age 42 years) underwent testing at a median interval from RPC of 8 (range 1–25) years. No patient had a positive CDT result, but ESBL bacteria were identified in 16 (33%) samples. ESBL positivity was significantly related to prepouch ileitis (P = 0.035) and maintenance antibiotic therapy (P = 0.039). Conclusions Extended spectrum beta‐lactamase, but not CDT, is a common finding in faecal samples from patients with recurrent or refractory pouchitis. Treatment with maintenance antibiotics and prepouch ileitis are risk factors for developing ESBL‐producing bacteria.     

Subchronic Oral Cylindrospermopsin Exposure Alters the Host Gut Microbiome and Is Associated with Progressive Hepatic Inflammation,Stellate Cell Activation,and Mild Fibrosis in a Preclinical Study

Epidemiological studies have reported a strong association between liver injury and incidences of hepatocellular carcinoma in sections of humans globally. Several preclinical studies have shown a strong link between cyanotoxin exposure and the development of nonalcoholic steatohepatitis, a precursor of hepatocellular carcinoma. Among the emerging threats from cyanotoxins, new evidence shows cylindrospermopsin release in freshwater lakes. A known hepatotoxin in higher concentrations, we examined the possible role of cylindrospermopsin in causing host gut dysbiosis and its association with liver pathology in a mouse model of toxico-pharmacokinetics and hepatic pathology. The results showed that oral exposure to cylindrospermopsin caused decreased diversity of gut bacteria phyla accompanied by an increased abundance of Clostridioides difficile and decreased abundance of probiotic flora such as Roseburia, Akkermanssia, and Bacteroides thetaiotamicron, a signature most often associated with intestinal and hepatic pathology and underlying gastrointestinal disease. The altered gut dysbiosis was also associated with increased Claudin2 protein in the intestinal lumen, a marker of gut leaching and endotoxemia. The study of liver pathology showed marked liver inflammation, the release of damage-associated molecular patterns, and activation of toll-like receptors, a hallmark of consistent and progressive liver damage. Hepatic pathology was also linked to increased Kupffer cell activation and stellate cell activation, markers of progressive liver damage often linked to the development of liver fibrosis and carcinoma. In conclusion, the present study provides additional evidence of cylindrospermopsin-linked progressive liver pathology that may be very well-linked to gut dysbiosis, though definitive evidence involving this link needs to be studied further.     

Current developments in lantibiotic discovery for treating Clostridium difficile infection

Introduction: Clostridium difficile is a major cause of healthcare-associated diarrhea linked to the misuse of antimicrobials and the corresponding deleterious impact they have on the protective microbiota of the gut. Resistance to agents used to treat C. difficile including metronizadole and vancomycin has been reported highlighting the need for novel agents. Lantibiotics represent a novel class of agents that many studies have highlighted as effective against C. difficile.

Areas covered: In this review lantibiotics including nisin, actagardine, mersacidin, NAI-107 and MU-1140 that exhibit good activity against C.difficile, all of which are currently in the preclinical phase of investigation are discussed. The lantibiotic NVB302, which has completed phase I clinical trials for the treatment of C. difficile, is also described.

Expert opinion: Lantibiotics represent promising candidates for the treatment of C. difficile infections due to their novel mode of action, which is thought to decrease the potential of resistance developing and the fact they often possess a less deleterious effect on the protective gut microbiota when compared to traditional agents. They are also extremely amenable to bioengineering approaches and the incorporation of synthetic biology to produce more potent variants.     

Faecal microbiota transplantation shortens the colonisation period and allows re-entry of patients carrying carbapenamase-producing bacteria into medical care facilities

Background

Colonisation with carbapenemase-producing Enterobacteriaceae or Acinetobacter (CPE/A) is associated with complex medical care requiring implementation of specific isolation policies and limitation of patient discharge to other medical facilities. Faecal microbiota transplantation (FMT) has been proposed in order to reduce the duration of gut colonisation.

胆汁酸-肠道菌群轴在2型糖尿病中的作用

目的 分析2型糖尿病(type 2 diabetes mellitus,T2DM)患者和正常人群胆汁酸与肠道菌群差异,探讨胆汁酸-肠道菌群轴在T2DM中的作用。方法 利用代谢组学、16S rRNA测序手段分别对T2DM患者中的血清胆汁酸含量及粪便肠道微生物进行检测及分析,结合斯皮尔曼相关性分析,明确胆汁酸-肠道菌群在T2DM中的代谢对话关系。结果 血清胆汁酸含量和肠道微生物的丰度在T2DM患者与正常人群中存在一定的差异。与正常人群相比,甘氨熊脱氧胆酸、牛磺鹅脱氧胆酸、甘氨鹅脱氧胆酸的含量在T2DM患者中显著降低;T2DM患者中肺炎克雷伯菌属、普拉梭菌属的相对丰度较正常人群明显升高,而狄氏副拟杆菌属、普雷沃菌属、艾克曼菌属、双歧杆菌属的相对丰度明显降低;斯皮尔曼相关性分析表明甘氨熊脱氧胆酸与狄氏副拟杆菌属、艾克曼菌属呈正相关,与克雷伯氏菌属呈负相关。结论 胆汁酸-肠道菌群轴是维持机体稳态的必要因素,在T2DM中发挥重要作用。     

Rifaximin for the treatment of diarrhoea-predominant irritable bowel syndrome

Introduction: Rifaximin is a non-absorbable, semisynthetic antibiotic that acts as an inhibitor of bacterial RNA synthesis, with a broad spectrum of antibacterial activity. Due to its poor absorption, rifaximin has an increased exposure to the intestine, thus it is suitable for the treatment of many gastrointestinal (GI) diseases. In irritable bowel syndrome (IBS) pathogenesis, gut microbiota impairment may play a major role. The possibility of modulating intestinal bacteria using antibiotics, in particular, rifaximin, has been demonstrated to improve IBS symptoms in non-constipation subtypes of IBS.

Areas covered: We reviewed the use of rifaximin in diarrhoea-predominant IBS, focusing on its pharmacokinetic characteristics, its absorption in GI disease, its lack of interaction with other drugs and its new extended release formulation.

Expert opinion: Rifaximin, with its low systemic absorption and no clinically significant interactions with other drugs, may represent a treatment of choice for IBS, mainly due to its ability to act on IBS pathogenesis, through the modulation of gut microbiota. Further studies to analyse the effect of rifaximin treatment on the composition of faecal microbiota are warranted. In particular, they need to evaluate whether resistant bacterial strains are selected and whether they are still present in the faecal sample even a long time after therapy.     

Novel therapeutic strategies for Clostridium difficile infections

Introduction: In recent years, Clostridium difficile has become the primary cause of antibiotic-associated diarrhea and pseudomembranous colitis, resulting in long and complicated hospital stays that represent a serious burden for patients as well as health care systems. Currently, conservative treatment of C. difficile infection (CDI) relies on the antibiotics vancomycin, metronidazole or fidaxomicin, or in case of multiple recurrences, fecal microbiota transplantation (FMT).

Areas covered: The fast-spreading, epidemic nature of this pathogen urgently necessitates the search for alternative treatment strategies as well as antibiotic targets. Accordingly, in this review, we highlight the recent findings regarding virulence associated traits of C. difficile, evaluate their potential as alternative drug targets, and present current efforts in designing inhibitory compounds, with the aim of pointing out possibilities for future treatment strategies.

Expert opinion: Increased attention on systematic analysis of the virulence mechanisms of C. difficile has already led to the identification of several alternative drug targets. In the future, applying state of the art ‘omics’ and the development of novel infection models that mimic the human gut, a highly complex ecological niche, will unveil the genomic and metabolic plasticity of this pathogen and will certainly help dealing with future challenges.     

Mesalazine (5-aminosalicylic acid) alters faecal bacterial profiles, but not mucosal proteolytic activity in diarrhoea-predominant irritable bowel syndrome

Aliment Pharmacol Ther 2011; 34: 374–383

Summary

Background Imbalances in gut luminal bacteria may contribute to the pathogenesis of irritable bowel syndrome (IBS). Aim To explore select bacteriological and anti‐inflammatory effects of mesalazine (mesalamine; 5‐aminosalicylic acid or 5ASA) and their relation to potential therapeutic effects in IBS. Methods Prospective pilot study of 12 women with diarrhoea‐predominant IBS. Patients received oral mesalazine (1.5 g b.d.) for 4 weeks followed by a 4‐week washout phase. Molecular profiling of stool bacterial communities and IBS symptoms were assessed before, during and after mesalazine treatment. Colonic mucosal biopsies were assessed for proteolytic activity. Qualitative and quantitative effects of mesalazine on stool microbiota, mucosal proteolytic activity and IBS symptoms were assessed. Results Faecal bacteria decreased by 46% on mesalazine treatment (P = 0.014), but returned to baseline during washout. Firmicutes and Bacteroidetes represented 95% of identified phylotypes, with a trend towards an increase in the proportion of Firmicutes at week 4 in symptomatic responders [median (IQR) 14% (49) increase] compared with nonresponders [median 5% (11) decrease, P = 0.088]. Rectosigmoid mucosal proteolytic activity did not change between baseline and treatment [median 23.2 (17.9) vs. 19.5 (46.7) mU activity/mg tissue, P = 0.433]. Eight of 12 (67%) patients responded favourably to mesalazine based on a global relief questionnaire, with significant decreases in days with discomfort and increases in bowel movement satisfaction. Conclusions Mesalazine treatment is associated with a decrease in faecal bacteria abundance and rebalancing of the major constituents of the microbiota. Further study of the bacteriological and anti‐inflammatory properties of mesalazine in IBS is warranted.     

肠道菌群失衡与肠易激综合征

肠易激综合征（irritable bowel syndrome, IBS）是一种常见的功能性胃肠道疾病,其发病机制目前尚不完全清楚,但有越来越多的证据表明IBS可能与肠道菌群谱的改变有关。本文就IBS患者存在的结肠菌群失衡、小肠细菌过度生长及它们可能的致病机制,以及干预肠道菌群失衡等的治疗手段作一综述。     

Treatments targeting the luminal gut microbiota in patients with irritable bowel syndrome

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction affecting 4% of the world's population. Patients with IBS experience chronic or recurrent abdominal pain in combination with altered bowel habits (diarrhea and/or constipation), and have reduced quality of life. Despite the high prevalence and substantial burden of IBS, its pathophysiology is incompletely understood and remains to be elucidated. The importance of the gut microenvironment has been highlighted in IBS, as there are signs that the gut microbiota of patients differs from healthy controls. Recent studies have aimed to alter the gut microbiota and thereby, attempted to alleviate gastrointestinal symptoms in IBS patients. We highlighted recent advances in common treatments that are targeting the luminal gut microbiota in IBS.     

Faecal transplantation for the treatment of Clostridium difficile infection: a review

Clostridium difficile infection (CDI) remains a major healthcare burden despite recent global falls in its prevalence. The risk of recurrence is high when using antibiotics such as vancomycin, particularly in already recurrent disease. In light of this, new therapy options are being perused, including novel antibiotics such as fidaxomicin, probiotics, intravenous immunoglobulin and faecal transplantation. Faecal transplantation, referred to here as human probiotic infusion (HPI), is attracting an increasing amount of interest from physicians and patients. Its use has been documented in ca. 500 cases for the treatment of CDI, with overall efficacy rates reported to be ca. 91%. The first randomised controlled trial (RCT) demonstrated that HPI was superior to a 14-day course of vancomycin (89% vs. 31%; P < 0.001) and reported no deaths or serious adverse events. Safety and patient acceptability are often cited as limitations to the widespread use of this technique. However, data suggest that the short-term safety profile is encouraging, and concerns over patient acceptability are not warranted in the majority of cases. It seems appropriate to treat an infection which is caused by a major disturbance in the gut microbiota with a treatment that reverses this disturbance, rather than antibiotics that may exacerbate the problem. However, to fully understand the role of HPI in the management of CDI, further RCTs are needed with comparator antibiotics such as fidaxomicin and to establish the most efficacious HPI protocol for administration and preparation.