Rifaximin on epigenetics and autophagy in animal model of hepatocellular carcinoma secondary to metabolic-dysfunction associated steatotic liver disease

BACKGROUND Prevalence of hepatocellular carcinoma(HCC)is increasing,especially in patients with metabolic dysfunctionassociated steatotic liver disease(MASLD).AIM To investigate rifaximin(RIF)effects on epigenetic/autophagy markers in animals.METHODS Adult Sprague-Dawley rats were randomly assigned(n=8,each)and treated from 5-16 wk:Control[standard diet,water plus gavage with vehicle(Veh)],HCC[high-fat choline deficient diet(HFCD),diethylnitrosamine(DEN)in drinking water and Veh gavage],and RIF[HFCD,DEN and RIF(50 mg/kg/d)gavage].Gene expression of epigenetic/autophagy markers and circulating miRNAs were obtained.RESULTS All HCC and RIF animals developed metabolic-dysfunction associated steatohepatitis fibrosis,and cirrhosis,but three RIF-group did not develop HCC.Comparing animals who developed HCC with those who did not,miR-122,miR-34a,tubulin alpha-1c(Tuba-1c),metalloproteinases-2(Mmp2),and metalloproteinases-9(Mmp9)were significantly higher in the HCC-group.The opposite occurred with Becn1,coactivator associated arginine methyltransferase-1(Carm1),enhancer of zeste homolog-2(Ezh2),autophagy-related factor LC3A/B(Map1 Lc3b),and p62/sequestosome-1(p62/SQSTM1)-protein.Comparing with controls,Map1 Lc3b,Becn1 and Ezh2 were lower in HCC and RIF-groups(P<0.05).Carm1 was lower in HCC compared to RIF(P<0.05).Hepatic expression of Mmp9 was higher in HCC in relation to the control;the opposite was observed for p62/Sqstm1(P<0.05).Expression of p62/SQSTM1 protein was lower in the RIF-group compared to the control(P=0.024).There was no difference among groups for Tuba-1c,Aldolase-B,alpha-fetoprotein,and Mmp2(P>0.05).miR-122 was higher in HCC,and miR-34a in RIF compared to controls(P<0.05).miR-26b was lower in HCC compared to RIF,and the inverse was observed for miR-224(P<0.05).There was no difference among groups regarding miR-33a,miR-143,miR-155,miR-375 and miR-21(P>0.05).CONCLUSION RIF might have a possible beneficial effect on preventing/delaying liver carcinogenesis through epigenetic modulation in a rat model of MASLD-HCC.

Can rifaximin for hepatic encephalopathy be discontinued during broad-spectrum antibiotic treatment?

Hepatic encephalopathy(HE)is a formidable complication in patients with decompensated cirrhosis,often necessitating the administration of rifaximin(RFX)for effective management.RFX,is a gut-restricted,poorly-absorbable oral rifamycin derived antibiotic that can be used in addition to lactulose for the secondary prophylaxis of HE.It has shown notable reductions in infection,hospital readmission,duration of hospital stay,and mortality.However,limited data exist about the concurrent use of RFX with broad-spectrum antibiotics,because the patients are typically excluded from studies assessing RFX efficacy in HE.A pharmacist-driven quasi-experimental pilot study was done to address this gap.They argue against the necessity of RFX in HE during broad-spectrum antibiotic treatment,particularly in critically ill patients in intensive care unit(ICU).The potential for safe RFX discontinuation without adverse effects is clearly illuminated and valuable insight into the optimization of therapeutic strategies is offered.The findings also indicate that RFX discontinuation during broadspectrum antibiotic therapy was not associated with higher rates of delirium or coma,and this result remained robust after adjustment in multivariate analysis.Furthermore,rates of other secondary clinical and safety outcomes,including ICU mortality and 48-hour changes in vasopressor requirements,were comparable.However,since the activity of RFX is mainly confined to the modulation of gut microbiota,its potential utility in patients undergoing extensive systemic antibiotic therapy is debatable,given the overlapping antibiotic activity.Further,this suggests that the action of RFX on HE is class-specific(related to its activity on gut microbiota),rather than drug-specific.A recent double-blind randomized controlled(ARiE)trial provided further evidence-based support for RFX withdrawal in critically ill cirrhotic ICU patients receiving broad-spectrum antibiotics.Both studies prompt further discussion about optimal therapeutic strategy for patients facing the dual challenge of HE and systemic infections.Despite these compelling results,both studies have limitations.A prospective,multi-center evaluation of a larger sample,with placebo control,and comprehensive neurologic evaluation of HE is warranted.It should include an exploration of longer-term outcome and the impact of this protocol in non-critically ill liver disease patients.

Evaluation of a protocol for rifaximin discontinuation in critically ill patients with liver disease receiving broad-spectrum antibiotic therapy

BACKGROUND Rifaximin is frequently administered to critically ill patients with liver disease and hepatic encephalopathy,but patients currently or recently treated with antibiotics were frequently excluded from studies of rifaximin efficacy.Due to overlapping spectrums of activity,combination therapy with broad-spectrum antibiotics and rifaximin may be unnecessary.A pharmacist-driven protocol was piloted to reduce potentially overlapping therapy in critically ill patients with liver disease.It was hypothesized that withholding rifaximin during broad-spectrum antibiotic therapy would be safe and reduce healthcare costs.AIM To determine the clinical,safety,and financial impact of discontinuing rifaximin during broad-spectrum antibiotic therapy in critically ill liver patients.METHODS This was a single-center,quasi-experimental,pre-post study based on a pilot pharmacist-driven protocol.Patients in the protocol group were prospectively identified via the medical intensive care unit(ICU)(MICU)protocol to have rifaximin withheld during broad-spectrum antibiotic treatment.These were compared to a historical cohort who received combination therapy with broadspectrum antibiotics and rifaximin.All data were collected retrospectively.The primary outcome was days alive and free of delirium and coma(DAFD)to 14 d.Safety outcomes included MICU length of stay,48-h change in vasopressor dose,and ICU mortality.Secondary outcomes characterized rifaximin cost savings and protocol adherence.Multivariable analysis was utilized to evaluate the association between group assignment and the primary outcome while controlling for potential confounding factors.RESULTS Each group included 32 patients.The median number of delirium-and coma-free days was similar in the control and protocol groups[3 interquartile range(IQR 0,8)vs 2(IQR 0,9.5),P=0.93].In multivariable analysis,group assignment was not associated with a reduced ratio of days alive and free of delirium or coma at 14 d.The protocol resulted in a reduced median duration of rifaximin use during broad-spectrum antibiotic therapy[6 d control(IQR 3,9.5)vs 1 d protocol(IQR 0,1);P<0.001].Rates of other secondary clinical and safety outcomes were similar including ICU mortality and 48-h change in vasopressor requirements.Overall adherence to the protocol was 91.4%.The median estimated total cost of rifaximin therapy per patient was reduced from$758.40(IQR$379.20,$1200.80)to$126.40(IQR$0,$126.40),P<0.01.CONCLUSION The novel pharmacist-driven protocol for rifaximin discontinuation was associated with significant cost savings and no differences in safety outcomes including DAFD.

Rifaximin Prevents Intestinal Barrier Dysfunction and Alleviates Liver Injury in MCT-induced HSOS Mice

Objective Rifaximin is an effective component of treatment strategies for liver and intestinal diseases.However,the efficacy of rifaximin in hepatic sinusoidal obstruction syndrome(HSOS)has not been explored.The present study aimed to investigate the efficacy and mechanism of rifaximin in HSOS.Methods An HSOS model was established in mice through the administration of monocrotaline(MCT,800 mg/kg),and part of the HSOS mice were intragastrically administered with rifaximin.Then,the efficacy of rifaximin in HSOS was evaluated based on the liver pathological findings,liver proinflammatory cytokines,and alanine aminotransferase and aspartate aminotransferase levels.The Ussing chamber was used to evaluate the intestinal permeability,and tight junction(TJ)proteins were measured by Western blotting and real-time polymerase chain reaction to evaluate the intestinal barrier integrity.Then,the serum proinflammatory cytokine levels were evaluated by enzyme-linked immunosorbent assay.Afterwards,an in vitro experiment was performed to determine the relationship between rifaximin and TJ proteins.Results Rifaximin effectively alleviated the MCT-induced HSOS liver injury,suppressed the expression of liver proinflammatory cytokines,and reduced the serum levels of tumor necrosis factor-alpha and interleukin-6.Furthermore,rifaximin reduced the intestinal permeability,improved the intestinal barrier integrity,and promoted the expression of TJ proteins.Conclusion The results revealed that the intestinal barrier integrity was destroyed in MCT-induced HSOS.The significant alleviation of MCT-induced HSOS induced by rifaximin might be correlated to the repairment of intestinal barrier integrity via the regulation of the TJ protein expression.

Rifaximin in the Treatment of Gastroesophageal Reflux Disease: A New Idea Based on the Relationship between Intestinal Microecology and Gastroesophageal Reflux Disease

Rifaximin in the Treatment of Gastroesophageal Reflux Disease (GERD) is a common clinical disorder, the most common symptom of which is a burning sensation behind the breastbone (heartburn) or reflux of stomach contents into the upper pharynx (acid reflux). The prevalence in China is increasing year by year, which can affect the quality of life of patients and also increase the economic burden on families and society. The pathogenesis of GERD is still unclear, and some studies suggest that intestinal microecology may be closely related to the development of GERD. Rifaximin is not readily absorbed orally and acts locally in the intestine, so it has mild adverse effects and good safety, and can be used to treat gastrointestinal diseases such as irritable bowel syndrome, traveler’s diarrhea, small intestinal bacterial overgrowth, diverticulosis, inflammatory bowel disease and hepatic encephalopathy. Therefore, this paper focuses on intestinal microecology as a possible pathogenesis of GERD and further explores the feasibility of rifaximin for the treatment of GERD.

Effect of rifaximin on gut microbiota composition in advanced liver disease and its complications

Liver cirrhosis is a paradigm of intestinal dysbiosis. The qualitative and quantitative derangement of intestinal microbial community reported in cirrhotic patients seems to be strictly related with the impairment of liver function. A kind of gut microbial "fingerprint",characterized by the reduced ratio of "good" to "potentially pathogenic" bacteria has recently been outlined,and is associated with the increase in Model for End-Stage Liver Disease and Child Pugh scores. Moreover,in patients presenting with cirrhosis complications such as spontaneous bacterial peritonitis(SBP),hepatic encephalopathy(HE),and,portal hypertension intestinal microbiota modifications or the isolation of bacteria deriving from the gut are commonly reported. Rifaximin is a non-absorbable antibiotic used in the management of several gastrointestinal diseases. Beyond bactericidal/bacteriostatic,immune-modulating and anti-inflammatory activity,a little is known about its interaction with gut microbial environment. Rifaximin has been demonstrated to exert beneficial effects on cognitive function in patients with HE,and also to prevent the development of SBP,to reduce endotoxemia and to improve hemodynamics in cirrhotics. These results are linked to a shift in gut microbes functionality,triggering the production of favorable metabolites. The low incidence of drug-related adverse events due to the small amount of circulating drug makes rifaximin a relatively safe antibiotic for the modulation of gut microbiota in advanced liver disease.

Eubiotic properties of rifaximin: Disruption of the traditional concepts in gut microbiota modulation

Antibiotics are usually prescribed to cure infections but they also have significant modulatory effects on the gut microbiota. Several alterations of the intestinal bacterial community have been reported during antibiotic treatment, including the reduction of beneficial bacteria as well as of microbial alpha-diversity. Although after the discontinuation of antibiotic therapies it has been observed a trend towards the restoration of the original condition, the new steady state is different from the previous one, as if antibiotics induced some kind of irreversible perturbation of the gut microbial community. The poorly absorbed antibiotic rifaximin seem to be different from the other antibiotics, because it exerts non-traditional effects additional to the bactericidal/bacteriostatic activity on the gut microbiota. Rifaximin is able to reduce bacterial virulence and translocation, has anti-inflammatory properties and has been demonstrated to positively modulate the gut microbial composition. Animal models, culture studies and metagenomic analyses have demonstrated an increase in Bifidobacterium, Faecalibacterium prausnitzii and Lactobacillus abundance after rifaximin treatment, probably consequent to the induction of bacterial resistance, with no major change in the overall gut microbiota composition. Antibiotics are therefore modulators of the symbiotic relationship between the host and the gut microbiota. Specific antibiotics, such as rifaximin, can also induce eubiotic changes in the intestinal ecosystem; this additional property may represent a therapeutic advantage in specific clinical settings.

Rifaximin ameliorates hepatic encephalopathy and endotoxemia without affecting the gut microbiome diversity

AIM To determine the efficacy of rifaximin for hepatic encephalopathy(HE) with the linkage of gut microbiome in decompensated cirrhotic patients.METHODS Twenty patients(12 men and 8 women; median age, 66.8 years; range, 46-81 years) with decompensated cirrhosis(Child-pugh score > 7) underwent cognitive neuropsychological testing, endotoxin analysis, and fecal microbiome assessment at baseline and after 4 wk of treatment with rifaximin 400 mg thrice a day. HE was determined by serum ammonia level and number connection test(NCT)-A. Changes in whole blood endotoxin activity(EA) was analyzed by endotoxinactivity assay. Fecal microbiome was assessed by 16 S ribosome RNA(rR NA) gene sequencing.RESULTS Treatment with rifaximin for 4 wk improved hyperammonemia(from 90.6 ± 23.9 μg/d L to 73.1 ± 33.1 μg/dL; P < 0.05) and time required for NCT(from 68.2 ± 17.4 s to 54.9 ± 20.3 s; P < 0.05) in patients who had higher levels at baseline. Endotoxin activity was reduced(from 0.43 ± 0.03 to 0.32 ± 0.09; P < 0.05) in direct correlation with decrease in serum ammonia levels(r = 0.5886, P < 0.05). No statistically significant differences were observed in the diversity estimator(Shannon diversity index) and major components of the gut microbiome between the baseline and after treatment groups(3.948 ± 0.548 at baseline vs 3.980 ± 0.968 after treatment; P = 0.544), but the relative abundances of genus Veillonella and Streptococcus were lowered.CONCLUSION Rifaximin significantly improved cognition and reduced endotoxin activity without significantly affecting the composition of the gut microbiome in patients with decompensated cirrhosis.

Rifaximin improves survival in cirrhotic patients with refractory ascites: A real-world study

BACKGROUND Rifaximin has been shown to reduce the incidence of hepatic encephalopathy and other complications in patients with cirrhosis.However,few studies have investigated the effect of rifaximin in cirrhotic patients with refractory ascites.AIM To evaluate the effects of rifaximin in the treatment of refractory ascites and to preliminarily explore its possible mechanism.METHODS A total of 75 cirrhotic patients with refractory ascites were enrolled in the study(50 in a rifaximin and 25 in a control group).Patients in the rifaximin group were divided into two subgroups according to the presence of spontaneous bacterial peritonitis and treatment with or without other antibiotics(19 patients treated with rifaximin and 31 patients treated with rifaximin plus intravenous antibiotics).All patients received conventional treatment for refractory ascites,while patients in the rifaximin group received oral rifaximin-α200 mg four times daily for at least 2 wk.The ascites grade,fasting weight,liver and kidney function,and inflammatory factors in the plasma were evaluated before and after treatment.In addition,the gut microbiota was determined by metagenomics sequencing to analyse the changes in the characteristics of the gut microbiota before and after rifaximin treatment.The patients were followed for 6 mo.RESULTS Compared with the control group,the fasting weight of patients significantly decreased and the ascites significantly subsided after treatment with rifaximin(P=0.011 and 0.009,respectively).The 6-mo survival rate of patients in the rifaximin group was significantly higher than that in the control group(P=0.048).The concentration of interferon-inducible protein 10 decreased significantly in the rifaximin group compared with that in the control group(P=0.024).The abundance of Roseburia,Haemophilus,and Prevotella was significantly reduced after rifaximin treatment,while the abundance of Lachnospiraceae_noname,Subdoligranulum,and Dorea decreased and the abundance of Coprobacillus increased after treatment with rifaximin plus intravenous antibiotics.The gene expression of virulence factors was significantly reduced after treatment in both subgroups treated with rifaximin or rifaximin plus intravenous antibiotics.CONCLUSION Rifaximin mitigates ascites and improves survival of cirrhotic patients with refractory ascites.A possible mechanism is that rifaximin regulates the structure and function of intestinal bacteria,thus improving the systemic inflammatory state.

Small intestine bacterial overgrowth and irritable bowel syndrome-related symptoms:Experience with Rifaximin

AIM： TO estimate the prevalence of small intestinal bacterial overgrowth （SIBO） in our geographical area （Western Sicily, Italy） by means of an observational study, and to gather information on the use of locally active, non-absorbable antibiotics for treatment of SIBO.METHODS： Our survey included 115 patients fulfilling the Rome II criteria for diagnosis of irritable bowel syndrome （IBS）; a total of 97 patients accepted to perform a breath test with lactulose （BTLact）, and those who had a positive test, received Rifaximin （Normix , Alfa Wassermann） 1200 mg/d for 7 d; 3 wk after the end of treatment, the BTLact was repeated.RESULTS： Based on the BTLact results, SIBO was present in about 56% of IBS patients, and it was responsible for some IBS-related symptoms, such as abdominal bloating and discomfort, and diarrhoea. 1-wk treatment with Rifaximin turned the BTLact to negative in about 50% of patients and significantly reduced the symptoms, especially in those patients with an alternated constipation/diarrhoea-variant IBS. CONCLUSION： SIBO should be always suspected in patients with IBS, and a differential diagnosis is done by means of a ＂breath test＂. Rifaximin may represent a valid approach to the treatment of SIBO.

Rifaximin vs conventional oral therapy for hepatic encephalopathy:A meta-analysis

AIM: To characterize the efficacy of rifaximin in the management of hepatic encephalopathy (HE) as several randomized controlled studies have shown contradictory results on its effectiveness in comparison to other oral agents. METHODS: We performed a systematic review and random effects meta-analysis of all eligible trials identifi ed through electronic and manual searches. Twelve randomized controlled trials met the inclusion criteria with a total of 565 patients. RESULTS: The clinical effectiveness of rifaximin was equivalent to disaccharides or other oral antibiotics[odds ratio (OR) 0.96; 95% CI: 0.94-4.08] but with a better safety profi le (OR 0.27; 95% CI: 0.12-0.59). At the completion of treatment protocols, patients receiving rifaximin showed lower serum ammonia levels [weighted mean difference (WMD) = -10.65; 95% CI: -23.4-2.1; P = 0.10], better mental status (WMD = -0.24; 95% CI: -0.57-0.08; P = 0.15) and less asterixis (WMD -0.1; 95% CI -0.26-0.07; P = 0.25) without reaching statistical signifi cance. On the other hand, other psychometric outcomes such as electroencephalographic response and grades of portosystemic encephalopathy were superior in patients treated with rifaximin in comparison to the control group (WMD = 0.21, 95% CI: -0.33-0.09, P = 0.0004; and WMD = -2.33, 95% CI: -2.68-1.98, P = 0.00001, respectively). Subgroup and sensitivity analysis did not show any signifi cant difference in the above fi ndings. CONCLUSION: Rifaximin appears to be at least as effective as other conventional oral agents for the treatment of HE with a better safety profi le.

Chronic bacterial prostatitis and irritable bowel syndrome： effectiveness of treatment with rifaximin followed by the probiotic VSL#3

This study was undertaken to evaluate the influence of treatment with rifaximin followed by the probiotic VSL#3 versus no treatment on the progression of chronic prostatitis toward chronic microbial prostate-vesiculitis （PV） or prostate-vesiculo-epididymitis （PVE）. A total of 106 selected infertile male patients with bacteriologically cured chronic bacterial prostatitis （CBP） and irritable bowel syndrome （IBS） were randomly prescribed rifaximin （200 mg, 2 tablets bid, for 7 days monthly for 12 months） and probiotic containing multiple strains VSL#3 （450 × 10^9 CFU per day） or no treatment. Ninety-five of them （89.6%） complied with the therapeutic plan and were included in this study. Group A = ＂6Tx/6-＂： treatment for the initial 6 and no treatment for the following 6 months （n = 26）; Group B = ＂12Tx＂： 12 months of treatment （n = 22）; Group C = ＂6-/6Tx＂： no treatment for the initial 6 months and treatment in the last 6 months （n = 23）; Group D = ＂12-＂： no treatment （n = 24）. The patients of Groups A = ＂6Tx/6-＂ and B = ＂12Tx＂ had the highest frequency of chronic prostatitis （88.5% and 86.4%, respectively）. In contrast, group ＂12-＂： patients had the lowest frequency of prostatitis （33.4%）. The progression of prostatitis into PV in groups ＂6Tx/6-＂ （15.5%） and ＂6-/6Tx＂ （13.6%） was lower than that found in the patients of group ＂12-＂ （45.8%）. Finally, no patient of groups ＂6Tx/6-＂ and ＂6-/6Tx＂ had PVE, whereas it was diagnosed in 20.8% of group ＂12-＂ patients. Long-term treatment with rifaximin and the probiotic VSL#3 is effective in lowering the progression of prostatitis into more complicated forms of male accessory gland infections in infertile patients with bacteriologically cured CBP plus IBS.

Efficacy of long-term rifaximin treatment for hepatic encephalopathy in the Japanese

BACKGROUND Hepatic encephalopathy(HE)is a complication of liver cirrhosis and can result in neuropsychological and neuromuscular dysfunctions in patients.Rifaximin,an antibiotic,has been reported to decrease the occurrence of overt HE and also improve cognitive function in studies from Europe and the United States of America.There is not enough evidence of the relationship between the long-term use of rifaximin and its clinical effects in the Japanese.AIM To determine the clinical effects of long-term rifaximin therapy in decompensated liver cirrhosis patients,with overt HE or hyperammonemia.METHODS In this single-center retrospective observational cohort study,we reviewed the data of 38 patients who had taken rifaximin at the dose of 1200 mg/d for more than 24 wk.The primary outcome measured was the efficacy of long-term rifaximin use,and secondary outcome measured was the safety of its long-term use as determined by its influence on portosystemic shunts as well as Escherichia coli-related infections.Moreover,we compared the prognosis between the rifaximin group and control cases,matched for hepatic elasticity assessed by magnetic resonance ela-stography,age,and Child-Pugh classification.RESULTS Of the 38 patients included in the study,12(31.6%)had overt HE,27(71.1%)had complications of esophageal varices,and 9(23.7%)had hepatocellular carcinoma(HCC).The control group was matched for age,Child-Pugh classification,liver stiffness,and presence of HCC.The median of serum ammonia level before treatment was 104μg/dL(59-297),and 2 wk after treatment,it significantly decreased to 85μg/dL(34-153)(P=0.002).A significantly low value of 80.5μg/dL(44-150)was maintained 24 wk after treatment.The long-term use of rifaximin did not cause a decline in liver function.Diarrhea occurred in 2 patients,who improved with the administration of probiotics,and there were no cases of aborted rifaximin therapy owing to adverse events.In patients with Child C,the survival was short,but there was no significant difference compared with that of the control group.CONCLUSION Rifaximin therapy improves overt HE.The long-term use of rifaximin in the Japanese is effective and safe.

Rifaximin in the treatment of inflammatory bowel disease

The gut microbiota plays a role in promoting and maintaining inflammation in inflammatory bowel diseases （IBD）, hence the rationale for the use of antibiotics in the treatment of those disorders. Antibiotics, however, may induce untoward effects, especially during longterm therapy. Rifaximin α polymer is an antibacterial agent that is virtually unabsorbed after oral administration and is devoid of systemic side effects. Rifaximin has provided promising results in inducing remission of Crohn＇s disease （up to 69% in open studies and significantly higher rates than placebo in double blind trials） and ulcerative colitis （76% in open studies and significantly higher rates than placebo in controlled studies） and might also have a role in maintaining remission of ulcerative colitis and pouchitis. The potential therapeutic activity of rifaximin in IBD deserves to be further investigated and confirmed in larger, controlled studies. The optimal dosage still needs to be better defined.

Lessons from “real life experience” of rifaximin use in the management of recurrent hepatic encephalopathy

BACKGROUND Hepatic encephalopathy(HE)is a major complication of cirrhosis with independent prognostic significance.The current management of HE is mainly based on lactulose.Rifaximin has been shown to decrease the risk of HE recurrence in patients with episodic forms.HE can also be persistent.However,there is no drug support recommendation for rifaximin use in this setting.AIM To assess the effectiveness of rifaximin in the management of recurrent episodes of HE and recurrent acute exacerbations on persistent HE,in“real life conditions”.METHODS In this retrospective study,using a within-subjects design,we collected data of patients treated with rifaximin for HE in two liver diseases centers,during the six-month period before and during the six-month period after the initiation of rifaximin.The primary effectiveness endpoint was the total number of HE events involving hospitalization.RESULTS Rifaximin was introduced for prevention of recurrent HE episodes in 29 out of 62 patients with normal mental status between episodes and for prevention of recurrent acute exacerbations on persistent HE in 33 out of 62 patients.In the“prevention of recurrent HE episodes”group,fewer HE events(0.79 vs 1.78;P=0.013)were reported during the period of time when rifaximin was used.In the“prevention of recurrent acute exacerbations on persistent HE”group,there was no significant difference in the number of HE-events(1.48 vs 1.77;P=0.582).CONCLUSION In this real-life experience,the effectiveness of rifaximin was confirmed in the prevention of HE episodes recurrence but was not proved in the prevention of acute exacerbations recurrence on persistent HE.

Rifaximin therapy and hepatic encephalopathy:Pros and cons

Hepatic encephalopathy(HE) is the second most common major complication in cirrhotics and it significantly impacts quality of life.Therapeutic approaches for HE treatment and prevention mainly continue to rely on ammonia-lowering strategies and non-absorbable disaccharides are currently considered the cornerstone therapy.Non-absorbable antibiotics,such as neomycin and paramomycin,are effective in treatment of acute HE episodes but their prolonged use for recurrence prevention is hampered by possible side-effects.To overcome these limitations,rifaximin use has been proposed.Rifaximin has been shown to be not superior to non-absorbable disaccharides for either HE treatment or prevention,with a similar incidence of side-effects.Cirrhosis significantly increases rifaximin absorption and this could be a cause for concern.Following long-term rifaximin therapy,Clostridium difficile colitis has been observed and Candida albicans has been isolated from 20% of patients.In addition,selection of resistant mutants of both Gram-negative and-positive bacteria in the gastrointestinal tract cannot be definitely ruled out.Electrolyte alterations(sodium and potassium) have been reported during rifaximin therapy,a warning for its long-term use in cirrhotics.Moreover,a potential interference with vitamin K production should be considered which could further impair the already altered clotting status of these patients.The therapeutic cost of rifaximin is markedly higher than non-absorbable disaccharides.While waiting for further safety data,caution should be used to limit the use of rifaximin therapy for a very short-term period in selected HE cirrhotics not responding to nonabsorbable disaccharides.

Rifaximin for the prevention of spontaneous bacterial peritonitis

According to a review article by Biecker et al published in a previous issue of World Journal of Gastroenterology in March 2011,intestinal decontamination with norfloxacin remains the mainstay of primary prophylaxis of spontaneous bacterial peritonitis(SBP) at the expense of development of quinolone-resistant bacteria after long-term use.In our research,the administration of a 4-wk regimen with rifaximin 1200 mg/d reduced significantly the ascitic neutrophil count in cirrhotic patients with sterile ascites in line with a significant decrease in plasma endotoxin levels.Our observations concur with recent findings,showing a significantly reduced 5-year probability of SBP in cirrhotic patients taking rifaximin.

Rifaximin and Crohn's disease

In a recent article,Longman and Swaminath analyzed our paper on the use of rifaximin in patients with moderately active Crohn’s disease(CD).Here we report some considerations concerning their article.The exploratory post-hoc subgroup analysis showed that early-stage disease and,differently from that written by Longman and Swaminath,also colonic involvement seemed to be associated with a significant higher efficacy of rifaximin-EIR 800 mg twice daily.Early-stage disease is generally considered as the more easily treatable phase of CD,and the better response to rifaximin in Crohn’s colitis is in accordance with the high concentration of bacteria in the colon.In addition,patients with C reactive protein level>5 mg/L achieved remission more significantly than patients with normal values,thus suggesting that the symptoms were probably caused by inflammation instead of by non-inflammatory causes.We also analyze the role of rifaximin against gut bacteria and the clinical situations that could obtain the best results from antibiotics.

Rifaximin,but not growth factor 1,reduces brain edema in cirrhotic rats

AIM:To compare rifaximin and insulin-like growth factor(IGF)-1 treatment of hyperammonemia and brain edema in cirrhotic rats with portal occlusion.METHODS:Rats with CCl4-induced cirrhosis with ascites plus portal vein occlusion and controls were randomized into six groups:Cirrhosis;Cirrhosis + IGF-1;Cirrhosis + rifaximin;Controls;Controls + IGF-1;and Controls + rifaximin.An oral glutamine-challenge test was performed,and plasma and cerebral ammonia,glucose,bilirubin,transaminases,endotoxemia,brain water content and ileocecal cultures were measured and liver histology was assessed.RESULTS:Rifaximin treatment significantly reduced bacterial overgrowth and endotoxemia compared with cirrhosis groups,and improved some liver function parameters(bilirubin,alanine aminotransferase and aspartate aminotransferase).These effects were associated with a significant reduction in cerebral water content.Blood and cerebral ammonia levels,and area-underthe-curve values for oral glutamine-challenge tests were similar in rifaximin-treated cirrhotic rats and control group animals.By contrast,IGF-1 administration failed to improve most alterations observed in cirrhosis.CONCLUSION:By reducing gut bacterial overgrowth,only rifaximin was capable of normalizing plasma and brain ammonia and thereby abolishing low-grade brain edema,alterations associated with hepatic encephalopathy.

Assessment of the Efficacy of Rifaximin in the Management of Irritable Bowel Syndrome (IBS)

The aim of our study was to assess in our context, the efficacy of Rifaxim in improving the symptoms of irritable bowel syndrome particularly in its diarrheal (IBS-D) or mixed (IBS-DC) component and therefore assess its impact on patients’ quality of life. Patients and methods: This was an uncontrolled, non-comparative prospective cohort study of a single group of patients. Patients recruitment was done in two University Hospitals for 6 months (September 2015-February 2016). Were included ambulatory patients, male or female, aged 18 - 75 years, with diarrheic IBS (IBS-D) or mixed IBS (IBS-DC) diagnosed according to Rome III criteria and who agreed to participate in the study. Each patient received 400mg Rifaximin × 2/d for 15 days. The overall assessment of the efficacy of treatment at D15 (end of treatment) and D30 (2 weeks post-treatment) was the primary criterion of judgment. The statistical tests used were the Chi-square test and Fisher’s exact test for the qualitative variables and Student’s test for the quantitative variables. Results: A total number of 30 patients (16 women) with an average age of 44.5 ± 13.9 years were included. The overall assessment of symptoms by the patient with the Likert scale found 28 (93.3%) patients, 12 (40%) patients and 10 patients (33.3%) for a scale ≥2 at D0, D15 and D30 respectively. The assessment of the intensity of pain or abdominal discomfort found at D0, D15 and D30 respectively: 27(90%), 13(43.4%) and 6(20.1%) patients who had an EVA score > 2. The mean score for Francis to assess the improved quality of life was 247.1 ± 97.4 at D0, 99.8 ± 63.1 at D15 and 128.8 ± 70.6 at D30. Conclusion: There is a good overall improvement of symptoms in our patients suffering from IBS-D or mixed (IBS-DC) on Rifaximin with improvement of the quality of life.