Content uploaded by Angie Eaton
Author content
All content in this area was uploaded by Angie Eaton on Oct 08, 2014
Content may be subject to copyright.
A preview of the PDF is not available
Rifaximin for Treatment of Hepatic Encephalopathy
Abstract and Figures
To review the effectiveness and safety of rifaximin in the treatment of hepatic encephalopathy (HE).
MEDLINE (1990-October 2008) was searched using the terms rifaximin, rifamycins, hepatic encephalopathy, liver cirrhosis, and acute liver failure. Other sources included the bibliographies of pertinent articles as well as programs and abstracts from infectious diseases and gastrointestinal diseases meetings.
All English-language articles identified from the search were evaluated. All primary literature that addressed the efficacy and safety of rifaximin in the treatment of HE was included in this review.
HE is a complex neuropsychiatric syndrome seen in patients with liver failure. It is characterized by disturbances in consciousness and behavior, personality changes, fluctuating neurologic signs, asterixis, and electroencephalographic changes. Although the etiology of HE is unknown, the accumulation of several gut-derived toxins such as mercaptans, ammonia, and benzodiazepine has been implicated. Current treatment options for HE include agents that reduce the concentration of these toxins, such as nonabsorbable disaccharides and antibiotics. Several studies have evaluated the use of rifaximin in the treatment of HE. They include a dose-finding study, 9 open-label studies, and 4 double-blind studies comparing rifaximin with either nonabsorbable disaccharides or antibiotics. Commonly used outcomes in most of these studies were changes in portal systemic encephalopathy index and the improvement in HE grade. Despite various limitations of the studies, rifaximin showed superior efficacy compared with lactulose for the treatment of HE, similar efficacy to paromomycin, and similar or greater efficacy than neomycin. Rifaximin was found to be associated with fewer hospitalizations, fewer days of hospitalization, and lower hospitalization charges than were seen with lactulose. Rifaximin also had a better tolerance profile than the comparative agents.
Rifaximin appears to be an effective and safe treatment option for HE. Better-designed studies are needed to characterize its efficacy in the treatment of HE.
Figures - uploaded by Angie Eaton
Author content
All figure content in this area was uploaded by Angie Eaton
Content may be subject to copyright.
... Rifaximin is a non-absorbable, gut-specifi c antibiotic. Compared with lactulose or neomycin, rifaximin has shown a general trend toward better effi cacy and better tolerability in patients with OHE ( 30,31 ). Till date, rifaximin has not been tried for the treatment of MHE. ...
... We chose rifaximin as the study drug because it is relatively cheap, easily available, well tolerated, and eff ective in reducing blood ammonia ( 39 ). Compared with lactulose or neomycin, rifaximin has shown a general trend toward better effi cacy, better safety, better tolerability, and lower hospitalization rates in patients with OHE ( 30,31,39,40 ). Th e adverse eff ects noted with rifaximin were either absent or were only minor gastrointestinal complaints ( 30,31,40,41 ). ...
... Compared with lactulose or neomycin, rifaximin has shown a general trend toward better effi cacy, better safety, better tolerability, and lower hospitalization rates in patients with OHE ( 30,31,39,40 ). Th e adverse eff ects noted with rifaximin were either absent or were only minor gastrointestinal complaints ( 30,31,40,41 ). On the other hand, lactulose is associated with annoying side eff ects such as fl atulence, abdominal discomfort, and diarrhea, which leads to low ( < 80 % ) adherence ( 3,29 ). ...
... 8 In various randomized controlled studies, rifaximin has been proved more helpful than nonabsorbable lactulose and had effectiveness equal or more than other antibiotics which were used in the management of portosystemic encephalopathy. [9][10][11][12] The rifaximin add on therapy to lactulose is more promising in the management of HE. Not only there is difference in effectiveness rather dual therapy also reduces the length of hospitalization in contrast with lactulose monotherapy. ...
Objective: To compare the efficacy of dual therapy (rifaximin and lactulose) and lactulose monotherapy in the treatment of porto-systemic encephalopathy. Study Design: Randomized control trial. Place and Duration of Study: Department of Gastroenterology, PIMS Hospital, Islamabad from 1st July 2020 to 31st December 2020. Methodology: One hundred and fifty patients of both genders age ranges from 18-65 years with liver cirrhosis having hepatic encephalopathy grade II or above were included. They were divided in two groups; each group comprised 75 patients. Group A took lactulose and rifaximin, while lactulose alone was given to Group B. All patients were monitored for 5 days on the basis of Child Pugh Criteria. Results: The mean age was 40.02+24.4 years. One hundred twenty six (85.1%) of patients were above 50 years. Males were 60%, majority of patients were from the emergency department, while 17 were from OPD. HCV was identified as the major cause of cirrhosis (72.6%), while HBV (14.6%), alcohol (4%) and others (8.6%) contributed nominally. Constipation was major precipitating factor in 83 patients while sepsis and UGI Bleed was culprit in 31 and 19 patients respectively. Sixty patients (80%) of group A of both genders showed improvement in five days, while 42 patients (56%) of group B showed improvement in the same period of time (p=0.006). It was found more in males and elder patients. Practical implication: Dual therapy will reduce the morbidity, hospital stay and cost of treatment. It may also help in making local guidelines for treatment of hepatic encephalopathy. Conclusion: Rifaximin plus lactulose therapy was far superior to lactulose monotherapy in every age group and either gender. Keywords: Porto systemic encephalopathy, Decompensated chronic liver disease, Rifaximin lactulose therapy, Lactulose monotherapy
... Rifaximin was additional with neomycin among patients with PSE and was recruited to be at best as working or better than neomycin in dropping ammonia stages, bradyarthria (irregular gradualness or negotiation of speech), and flapping tremor, as well as in tests to evaluate reasoning and behavioural discrepancies [88][89][90]. ...
Hepatic encephalopathy (HE) is a common complication among patients with liver cirrhosis associated with a high mortality rate. It is marked by fluctuating neuropsychiatric and cognitive impairment, which can be severe and life threatening. Liver cirrhosis is a leading cause of morbidity and mortality worldwide but exact prevalence of cirrhosis is not known. Prevalence of HE, also known as portosystemic encephalopathy (PSE), is 24% in cirrhotic patients. The diagnosis remains largely clinical, with the exclusion of possible other causes for the altered mental status. Symptoms of HE include attention deficits, alterations of sleep patterns and muscular incoordination progressing to stupor and coma. The pathogenesis of HE is still unidentified, although ammonia-induced variations of cerebral neurotransmitter balance, particularly at the astrocyte-neurone edge, may play a major role. Treatment of HE is therefore focused at reducing the manufacture and absorption of gut-derived neurotoxic substances, especially ammonia. Current treatment strategies include antibiotics such as neomycin, rifaximin, metronidazole, vancomycin and probiotics. The present review focuses on the pathogenesis, pathophysiology, diagnosis and management of HE.
... However, all these agents are fraught with drug related side effects and/or therapeutic compliance. [8]Rifaximin is a derivative of rifamycin that acts by inhibiting bacterial RNA synthesis. Rifaximin is virtually unabsorbed after oral administration and exhibits broad spectrum antimicrobial activity against both aerobic and anaerobic gram-positive and gramnegative microorganisms within the gastrointestinal tract. ...
... Rifaximin is a non-absorbable, gut-specifi c antibiotic. Compared with lactulose or neomycin, rifaximin has shown a general trend toward better efficacy and better tolerability in patients with OHE [8]. ...
... In the United States, however, it was used for the treatment of non-dysenteric diarrhea, but not for HE [2]. During the past decade, numeric studies have identified that rifaximin was at least as safe and as effective as lactulose and other non-absorbable antibiotics, such as neomycin and paromomycin, for the treatment of HE [4][5][6][7][8][9][10][11]. ...
Hepatic encephalopathy (HE) refers to a complex and reversible neuro-psychiatric syndrome that results from complications of acute or chronic hepatic failure, particularly alcoholic cirrhosis. It will lead to frequent life disruptions, poor quality of life and extensive use of health care resources. We conducted the review of several agents based on randomized controlled trials (RCTs) of high-quality Jadad scores (≥3) to provide effective information for clinical practice. Rifaximin appears at least to be as effective as conventional treatments, but not superior to them. L-Ornithine-L-aspartate appears to be a safe and effective treatment of chronic HE when compared with a placebo regime. Other treatments include non-absorbable disaccharides (NAD) and benzodiazepine receptor antagonists. In spite of the variability in the improvement of HE, NAD and non-absorbed antibiotics such as rifaximin offer a favorable benefit–risk ratio in the improvement of HE. Further RCTs with power calculation and a multi-centre approach with adequate population number are needed to resolve the heterogeneous results
Acute or chronic liver disease‐caused liver failure is the cause of hepatic encephalopathy (HE), characterized by neuropsychiatric manifestations. Liver diseases potentially lead to peripheral iron metabolism dysfunction and surges of iron concentration in the brain, contributing to the pathophysiological process of degenerative disorders of the central nervous system. In this study, the mechanism of rifaximin treating hepatic encephalopathy was investigated. Ferric ammonium citrate (FAC)‐induced iron overload significantly reduced the proliferation and boosted the apoptosis in SH‐SY5Y cells through increasing reactive oxygen species (ROS) levels and inducing iron metabolism disorder. Rifaximin treatment could rectify the FAC‐induced iron overload and lipopolysaccharide (LPS)‐induced iron deposition, therefore effectively protecting SH‐SY5Y cells from ROS‐induced cell injury and apoptosis. Signal transducer and activator of transcription 3 (STAT3)/nuclear factor‐kappaB (NF‐κB) signaling is involved in the protective function of rifaximin against LPS‐induced iron deposition. The therapeutic effect of rifaximin on HE associated with acute hepatic failure in mouse model was ascertained. In conclusion, Rifaximin could effectively protect SH‐SY5Y cells against injury caused by iron overload through the rectification of the iron metabolism disorder via the STAT3/NF‐κB signaling pathway. This article is protected by copyright. All rights reserved.
Antibiotic resistance in patients with cirrhosis continues to draw significant attention. With a propensity to frequent hospitalisations, patients with cirrhosis are subject to frequent antibiotic prescription. This increases their risk of developing resistance to one or more antimicrobial agents, making management of their condition particularly challenging. Despite advancements being made in the management of liver disease, mortality rates continue to rise: almost 5-fold in those <65 years of age while remaining the leading cause of death in those 35-49 years of age. Alternative therapeutic options to prevent disease progression and cirrhosis-associated complications are urgently required; rifaximin is one such example. The medication use in patients with cirrhosis demonstrates additional benefits beyond current licensed use in the UK, that being for the prevention of hepatic encephalopathy and traveller's diarrhoea; rifaximin has especially been explored beyond current licensed use in the context of enteric-driven pathologies. Through the therapy's key central action as a broad-spectrum antimicrobial, rifaximin has the ability to modulate the gut-liver axis via removal of gut microbial products associated with the progression of cirrhosis and its sequalae. The benefits of rifaximin use continues to gather momentum, given its non-absorbable nature and well-tolerated side-effect profile, and these require consideration. With broad-spectrum antimicrobial properties, its use may assist in overcoming the conundrum posed of antibiotic resistance amongst patients with cirrhosis. This literature review discusses the chemical and antimicrobial properties of rifaximin, its licenced indication for use, and its reported benefits beyond this, as well as concerns regarding rifaximin resistance.
Thirty-two patients suffering from post-cirrhotic portal systemic encephalopathy (PSE) and presenting high blood ammonia levels were treated, following a simple randomization list, either with the new rifamycin derivative (L 105) or with paromomycin sulphate. The two non-absorbable antibiotics proved highly effective, with significant changes in PSE signs and symptoms and in blood ammonia levels. The effectiveness and tolerance of the new compound seemed higher than those of the control drug.
Hepatic encephalopathy (HE) is a metabolic-neurophysiologic syndrome that occurs in patients with liver disease. One of the main pathogenic mechanisms is represented by circulating toxins produced from the intestinal metabolism of nitrogenous compounds. The therapeutic approach to HE includes drugs that eliminate ammoniaproducing bacteria. The aim of this study was to evaluate the efficacy and safety of rifaximin, a nonabsorbable antibacterial agent, in the treatment of chronic HE in a large population of cirrhotic patients. One hundred thirty-six cirrhotic patients (100 men, 36 women; mean age, 59.5 years) with clinical and biochemical signs of mild HE were studied under three different treatment protocols: one open study in which rifaximin (1200 mg/day) was administered for 21 days to 80 patients; and two randomized controlled studies, one in which rifaximin (1200 mg/day, 20 patients) and neomycin (3000 mg/day, 15 patients) were administered for 21 days and one in which rifaximin (1200 mg/day, 9 patients) and lactulose (40 gm/day, 12 patients) were administered for 21 days. In the open study, after 5 days of treatment, ammonia reached normal values in each patient; after 7 days, electroencephalographic abnormalities were present only in a few cases; and after 15 days, no patients showed neurologic signs of HE. In the rifaximin versus neomycin study, blood ammonia levels and neurologic signs significantly decreased during both treatments, but rifaximin induced an earlier disappearance of clinical and biochemical signs of HE. In the rifaximin versus lactulose study, both drugs were efficacious in reducing the neurologic signs of HE, but some patients treated with lactulose presented mild side effects at the beginning of the therapy, which disappeared in the course of treatment. This study confirms the usefulness of rifaximin in the management of cirrhotic patients with mild HE; the absence of significant side effects suggests its use even in more severe cases of HE, either alone or in association with other drugs.
Portal-systemic encephalopathy, a condition caused by liver failure, often complicates hepatic cirrhosis. Its pathogenesis is unknown, although hyperammonemia is thought to play an important role. Non-absorbable antibiotics have been used to treat hepatic encephalopathy because of their ability to reduce intestinal flora and thereby decrease the intestinal production of ammonia. We compared the effectiveness of rifaximin, a new non-absorbable antibiotic, with that of paromomycin. Thirty cirrhotic patients (20 men and 10 women, aged 39 to 75 years) suffering from portal-systemic encephalopathy with hyperammonemia were selected by Conn's grading. Fifteen patients were randomly assigned to treatment with paromomycin (1,500 mg/day), and the other 15 received rifaximin (1,200 mg/day) for 10 days. Before, after 5 days, and after 10 days of treatment, we evaluated blood ammonia levels and each patient's signs and symptoms according to Conn's grading. Baseline ammonia levels and the degree of hepatic encephalopathy were positively correlated (r = .65; P < 0.001). A significant decrease in blood ammonia levels (P < 0.001) and in the signs and symptoms of hepatic encephalopathy (P < 0.05) was observed in both groups after 5 and 10 days of therapy. The highly significant positive correlation between ammonia levels and degree of hepatic encephalopathy suggests the usefulness of non-absorbable antibiotic therapy in lowering blood ammonia levels. Rifaximin proved to be as effective as paromomycin even though baseline ammonia levels were higher in the rifaximin group. Because of its minimal absorption and a wide antibacterial activity, rifaximin should be considered the non-absorbable antibiotic of choice in the treatment of portal-systemic encephalopathy.
A randomized double blind clinical comparison of neomycin and lactulose was performed in 33 cirrhotic patients with chronic portal-systemic encephalopathy (PSE) at seven cooperating hospitals. In order to maintain double blindness, sorbitol syrup was used as a control solution along with neomycin and was compared with lactulose syrup and placebo tablets in a double drug protocol. Twenty-nine patients were studied in a crossover investigation in which each received both therapeutic regimens preceded and followed by control periods. Four additional patients received one or the other agent, but did not receive both. Serial, semiquantitative assessments were made in all patients of mental status, asterixis, and the trailmaking test (TMT) and electroencephalograms (EEG) and arterial ammonia levels. Both neomycin-sorbitol and lactulose were effective in the majority of patients (83 and 90%, respectively). Each of these parameters (mental state, asterixis, TMT, EEG, and NH3) was improved significantly by neomycin-sorbitol and lactulose. The post-treatment levels for each of these measures were similar in the neomycin and lactulose-treated groups. Mean stool pH was reduced by neomycinsorbitol to 6.1 and by lactulose to 5.5. This difference was highly significant statistically. Bowel activity was similar in the two groups. Both drugs were free of toxicity. These investigations demonstrate that both lactulose and neomycin-sorbitol are effective in the treatment of chronic portal-systemic encephalopathy.
In 14 patients with cirrhosis and chronic portosystemic encephalopathy, the effectiveness of treatment with a new non-assorbable antibiotic (rifaximine) was compared to neomycin. The parameters evaluated were: bradylalia, flapping tremor, performance, visual evoked potentials and the trial making test. Both treatments were combined with lactulose. The analysis of results showed a rate of positive results in the patients treated with rifaximine greater than that with neomycin. Differences, however, were not significant.
Preliminary data suggest that rifaximin a new non-absorbable rifamycin-derivate, has beneficial effects on chronic portal systemic encephalopathy (PSE). To compare the efficacy and safety of rifaximin vs neomycin in the treatment of the hyperammoniemic state of PSE, 30 cirrhotic patients with grade I to III of PSE were randomly allocated to one of two groups: group A (15 patients) receiving rifaximin (400 mg/8h) and group B (15 patients) neomycin (1gr/8h). The duration of treatment was 21 consecutive days. Age, sex, hepatic and renal function, level of PSE, EEG and number connection test were similar in both groups. A significant decrease in blood ammonia levels was observed at the end of the treatment period in both groups; moreover rifaximin produced an earlier reduction of blood ammonia levels. The neuropsychic syndrome related to the PSE improved in both groups without significant difference. No side effects attributable to therapy were observed in the rifaximin group. These results indicate that, rifaximin is at least as effective as neomycin in the achievement and maintenance of low blood ammonia levels in cirrhotics with chronic PSE.
Ammonia (NH3) plays a role in hepatic encephalopathy (HE). Agents affecting colonic ammonia production, such as non-absorbable antibiotics, decrease plasma levels of NH3 and findings of HE. The short-term efficacy of a non-absorbable rifamycin, rifaximin, was studied in comparison with paramomycin in 20 cirrhotic patients with high levels of NH3 and impaired number connection test (NCT). Both antibiotics significantly decreased ammonia-producing colonic bacteria. Rifaximin proved to be active on both aerobic and anaerobic bacteria and is thus effective, even at the dosage used, in the treatment of HE.
A study was performed to assess the efficacy and tolerability of rifaximin in the treatment of encephalopathy during cirrhosis of the liver. Fifty-five patients suffering from grade 1, 2 and 3 portosystemic encephalopathy, with a mean age of 58.9 years (range 30 to 86 years) were evaluated. The patients were treated for 15 consecutive days with rifaximin, an antibiotic which is not absorbed by the intestinal wall, at a dosage of 1200 mg/day in association with sufficient lactulose to induce 2 or 3 evacuations per day. Combined use of the 2 drugs proved an efficient means of controlling the majority of signs and symptoms. After just a few days, an improvement in the signs of encephalopathy was noted in all patients. The treatment was well tolerated and the patients completed the trial without any drug-related side-effects. The results of our trial, although in the context of an open assessment, confirm the clinical efficacy of rifaximin in association with a non-absorbable disaccharide such as lactulose. The 2 compounds have a synergetic effect in reducing ammonia-producing flora. Its efficacy and good tolerability make rifaximin a valid alternative to the use of aminoglycoside antibiotics associated with disaccharides in the treatment of patients with liver disease, particularly in the case of prolonged therapy.