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A 52-year-old female with nonalcoholic steatohepatitis–related cirrhosis, Child-Turcotte-Pugh class C and MELD score 18, is hospitalized with stage 3 hepatic encephalopathy. There is no obvious precipitating factor to account for her recent worsening. Current infection has been ruled out and imaging carried out earlier has excluded a spontaneous portosystemic shunt. She has been compliant with instructions to take lactulose in a dose to produce 2-4 semiformed bowel movements per day. It is not likely that she will come to liver transplantation for at least another year based on her MELD score.
What is the role of rifaximin in this patient?
How should therapy be administered?
How will response to treatment be monitored?
FDA, U.S. Food and Drug Administration; HE, hepatic encephalopathy; MIC, minimum inhibitory concentration; PSE index, portosystemic encephalopathy index; RCT, randomized controlled trial; TIPS, transjugular intrahepatic portosystemic shunt.
Hepatic encephalopathy (HE) is characterized by a wide spectrum of neuropsychiatric changes and alterations in neuromuscular function which occurs as a consequence of severe liver insufficiency and/or portosystemic shunting.1
HE is the most common, but not the only, reason for change in mentation in patients with cirrhosis and is largely a diagnosis of exclusion.1 Cognitive dysfunction in patients with cirrhosis may also be related to intracranial events, metabolic abnormalities, and sepsis. The decision whether to hospitalize and whether to admit to the floor or the intensive care unit depends on the precipitating factor and ability to control the airway. There should be a low threshold for endotracheal intubation to prevent aspiration, especially in those patients with concurrent gastrointestinal bleeding.2 Once these decisions are taken, the next question to be answered is: what is the precipitating factor? Precipitating factors are identifiable in 97% of patients with episodic HE and in more than 70% with persistent HE; multiple factors may coexist. Although not specifically evaluated in trials, correction of precipitating factors is considered first-line therapy for HE. These include controlling bleeding and infections and correction of metabolic abnormalities. Prevention of falls or body injuries in disoriented patients and supportive care are essential. Maintenance of adequate nutrition with energy intake of 35-40 kcal/kg/day and protein intake of 1.2-1.5 g/kg/day are recommended, and protein should not be avoided.3
The specific pharmacological treatments are directed toward the reduction of ammonia production, and increase in fixation and/or excretion of ammonia.1 The majority of therapeutic options currently in use are directed toward reducing ammonia production from the gut, with lactulose and rifaximin being the most widely used agents. These drugs are associated with mental status improvement but as precipitating factors are simultaneously being corrected, it is difficult to pinpoint the true reason for improvement. Lactulose can be given as an enema in patients unable to take medications by mouth. Because patients with an episode of HE are at risk of developing subsequent episodes, prevention of recurrence of HE is essential. Recently the results of several randomized trials have became available. Patients enrolled had differing risk factors for HE such as TIPS or those who experienced a recent episodes of overt HE, and those with recurrent episodes.3-6 The prophylactic efficacy of lactitol, rifaximin, lactulose, and a low-protein diet have been tested.3-7 The multicenter study of rifaximin versus placebo in patients with at least two prior HE episodes demonstrated a significant reduction in HE episodes as well as hospitalizations in the rifaximin group.6 In patients randomized to either lactulose or placebo after their first episode of HE, lactulose significantly decreased the incidence of recurrence of HE.5 A multicenter Spanish study, still in abstract form, did not find any difference in recurrent HE episodes in patients randomized to either a long-term normal protein diet (although enhanced with branched-chain amino acids) or a low-protein diet. These trials represent a novel approach in testing the efficacy of drugs for HE. Patients enrolled did not have any current evidence of HE at inclusion. The main study outcomes were the occurrence of clear episodes of HE: a more objective endpoint than the amelioration of HE symptoms in patients already affected by HE at inclusion.
Rifaximin is a semisynthetic, gut-selective antibiotic whose mechanism of antimicrobial action depends on inhibition of RNA synthesis.8, 9 There are several lines of evidence that rifaximin has poor solubility and is poorly absorbed, which results in a gut-specific action. In healthy individuals, as much as 97% of radiolabeled rifaximin is recovered; 96% in the stool and only 0.32% in the urine.10 The systemic exposure to rifaximin in patients with Child A, B, and C cirrhosis compared to rifampin and neomycin is shown in Fig. 1.10
Dosing of rifaximin can be approached in two broad ways: cyclical or continuous. In Italy, cyclical dosing is preferred and several clinical trials have shown benefit with rifaximin treatment 2 weeks per month.8 The alternative is daily therapy with rifaximin that is currently being used in the United States. There are possible advantages and disadvantages to each approach; cyclical therapy reduces cost and exposure to antibiotic but adherence to the schedules may be difficult in patients who already have HE. Continuous therapy is more expensive and could have the potential to increase resistance to rifaximin. The daily dose most studied, regardless of cyclical or continuous, is 1200 mg whereas the most recent trial used 1100 mg/day.6 In some European countries, including Italy and Spain, rifaximin is available in packages containing only 12 tablets, which is the dosage needed for just 2 days of therapy, and this also may limit the availability of the drug for long term treatment. For example, in Italy, in order to obtain the drug by means of the public health care system, the patient should consult the prescribing practitioner every 4 days!
Mechanisms of Action.
Being a gut-selective antibiotic, the majority of the action of rifaximin is concentrated on the gut microflora. The antibacterial properties of rifaximin include bactericidal activity at rifaximin concentrations greater than or equal to the minimal inhibitory concentration (MIC); at sub-MIC concentrations, rifaximin can change functioning of epithelial cells as well as virulence of the gut bacteria.10
Studies Supporting Use of Rifaximin.
Several randomized, placebo-controlled trials have been performed with rifaximin, most of them in Europe.8, 10 These trials have studied short-term management of the acute episode, long-term therapy and prevention of recurrence.9 A summary of the trials with their key findings is shown in Table 1.
Table 1. Summary of Acute, Long-Term, and HE Recurrence Trials with Rifaximin
Type of Study
Number of Trials and Sample Size
Adapted from Alcorn et al.8 PSE index is a composite score for HE consisting of100 × [Mental status (Conn score) × 3 + asterixis grade × 1 + NCT grade × 1 + ammonia grade × 1 + EEG grade × 1 (if available)]; it is not widely used at this time.
Acute therapy studies (5-30 days)
Rifaximin vs. placebo
Asterixis improved only with rifaximin. PSE index, mental status, and intellectual function improved similarly in both groups.
Rifaximin 200 mg vs. 400 mg vs. 800 mg
PSE index improved only in 400-mg and 800-mg groups.
Rifaximin vs. other antibiotics
Ammonia improved more with rifaximin than neomycin (one RCT) or similarly in both (six RCTs). PSE index improved similarly in both groups (one RCT). Intellectual function or mental status improved similarly in both groups (five RCTs). Asterixis improved faster with rifaximin than with neomycin (one RCT).
Rifaximin vs. nonabsorbable disaccharides
Higher ammonia improvement was observed with rifaximin (three RCTs) or similar improvement in both groups (two RCTs). PSE or symptoms improved more with disaccharides.
Long-term studies (3-6 months cyclical)
Rifaximin vs. nonabsorbable disaccharides
Ammonia and mental status improved with both trials with all strategies compared to baseline. Higher improvement in PSE index, EEG, and mental status with rifaximin. In the second study, rifaximin ± lactitol did better than lactitol alone with mental status.
Rifaximin vs. neomycin
Improvement in psychometric/neurophysiologic tests, mental status, and ammonia were similar across both groups.
Prevention of recurrence
Rifaximin vs. placebo
Reduction in recurrent HE episodes and hospitalization in the rifaximin group with significantly higher improvement in neurophysiological, quality-of-life, and ammonia in the rifaximin group. A total of 91% of patients were on lactulose in both groups.
Rifaximin has been studied in the context of intestinal pathogens and the concentration needed to inhibit 50% (MIC50) and 90% of microorganism growth (MIC90) have been established for 1607 pathogens; the highest MIC reached was 1024 μg/mL.10 Because of its high concentration in the gut, the concentration of rifaximin in the feces was almost 8 times the MIC needed for inhibition of these intestinal pathogens.11 Comparable antimicrobial activity was seen between rifaximin and other antimicrobials for E. coli. In addition, activity against Clostridium difficile was comparable to metronidazole and vancomycin (MIC90 = 0.005 through 2 μg/mL).10, 12 Of importance, in studies on traveler's diarrhea, aerobic gut species return to baseline after the end of rifaximin therapy.10
Therapy with rifaximin can be associated with adverse effects that are relatively minor and rarely require reduction or discontinuation of therapy.
Patients who are allergic to not only rifaximin, but also rifabutin (Mycobutin), rifampin (Rifadin, Rifamate, Rifater, Rimactane), and rifapentine (Priftin) should avoid use of rifaximin.
Gastrointestinal Adverse Effects.
The main gastrointestinal adverse events are flatulence, nausea, vomiting, abdominal pain, and weight loss which have been reported in ranges from 5%-17%, no different from placebo.
Clostridium difficile in cirrhosis has a poor prognosis therefore the notion of long-term antibiotic therapy in this population does raise some concerns.13 In the Bass et al. trial, there were two cases of C. difficile in the rifaximin group but none in the placebo group. This is interesting because rifaximin is active against C. difficile.6, 12 It is a relevant concern, specifically because of depressed immunity, frequent hospitalization and other antibiotic use in these patients.13 Additionally, if patients are on lactulose concomitantly, C. difficile diarrhea may be mistakenly attributed to lactulose, further delaying the diagnosis. Clinicians should be vigilant against C. difficile in patients with cirrhosis and specifically those receiving long-term therapy such as rifaximin.
Development of drug resistance is discussed in the next section.
Areas of Uncertainty
Although rifaximin has been approved for therapy in several European countries and the experience in those countries has not raised any significant concerns, the U.S. experience remains limited. The specific areas of uncertainty involve the evolving role of rifaximin as a possible first or second-line therapy, emergence of resistant strains and the possibility of clinical drug interactions.
Rifaximin Instead of or in Addition to Lactulose?
Rifaximin is currently a second-line therapy for HE in part due to the extreme cost difference between rifaximin and lactulose and also because lactulose therapy alone can prevent recurrent HE in selected patients. Also, there are only short-term studies that use rifaximin as an initial therapy for HE.10 With U.S. Food and Drug Administration (FDA) approval for this in the United States for prevention of recurrence, the current role appears to be a second-line. The role of rifaximin is evolving and it is feasible that with longer-term and head-to-head studies and with reduction in cost, it may become first-line therapy for HE.
There are two possible choices regarding use of rifaximin in patients with inadequate response to lactulose: switch to rifaximin or add rifaximin to lactulose therapy. The first solution is preferable for a number of reasons. In fact, the concomitant use of two drugs increases costs and the possibility of side effects. At the present time, a direct comparison between lactulose and rifaximin in prevention of HE is available only for patients with cirrhosis submitted to TIPS; in this group both agents failed to prevent HE efficiently.4 However, these results may not be extendable to other categories of patients at risk of HE. The recent trial by Bass et al. was not designed to compare rifaximin to lactulose but included patients who had essentially failed lactulose.6 This is because all patients had to have at least 2 HE episodes in the 6 months while compliant on lactulose. In addition, during the study, lactulose was dispensed according to guidelines which ensured that they were taking it as prescribed. Because <10% of patients were not on lactulose, the confidence interval for rifaximin in this subgroup was wide and did not reach significance. On the other hand, break-through HE episodes occurred in 22.1% of patients in the rifaximin arm, and in 45.9% of the placebo group. Similarly, HE-related hospitalisation was reported in 13.6% of rifaximin compared to 22.6% of placebo group. Thus, the second choice, adding rifaximin to lactulose seems to maintain HE remission in a larger number of patients when compared to lactulose therapy alone.6 This approach could increase possible side effects and reduce adherence.
Use of Rifaximin in Patients with MELD Scores >19.
The Bass study did not show a significant effect of rifaximin (P = 0.21) in patients with MELD score >19, probably due to the low numbers of patients enrolled. Thus the question whether or not patients with a MELD score >19 will benefit from use of rifaximin remains undetermined.
Clinically significant drug interactions are not significant with rifaximin. Rifaximin undergoes efflux through P-glycoprotein and does not have significant interactions with other substrates for the P-glycoprotein such as digoxin. In addition no significant interactions with the bile-salt export pump were observed in vitro. Even at concentrations of 200 ng/mL, rifaximin did not inhibit the major cytochrome P450 and in vitro, the ability to induce cytochrome P450 3A4 was half that of rifampin. Clinically, the dose of 200 mg three times daily did not alter the pharmacokinetics of oral midazolam or oral Ortho-cyclen whereas the 550 mg three times daily dose for 7-14 days only slightly (10%) reduced midazolam exposure. In contrast previous exposure to midazolam reduced area under the curve of oral midazolam by 95%. Thus, based on in vitro and in vivo data, no dose adjustment is recommended when rifaximin is coadministered with other drugs.10
Potential for Developing Drug Resistance.
Selection of resistant mutants, especially when an antibiotic therapy is needed life-long, is a valid concern. This risk is probably low.14 Encouragingly, the resistant bacteria disappear after a 5 day course but there are no long-term data at this time. Sensitivity of anaerobes is regained comparatively slower than to aerobes. The mechanism of resistance to rifaximin is by chromosomal alteration in the DNA-dependent RNA polymerase which is in contrast to the clinically significant plasmid-mediated resistance that affects other antibiotics. Therefore, the resistance to rifaximin is not transmittable easily between bacteria.10, 14 However, the clinical relevance of this resistance, especially for long-term therapy, needs to be studied.
Because the patient under discussion will not come to liver transplantation for at least another year based on her MELD score, the challenge is how to maintain remission from HE until transplantation. The prevention of HE recurrence is important not only to reduce the risk for hospitalization and subsequent infections but also because increasing episodes of HE can adversely affect cognition before and after transplant.2, 15, 16 The patient developed HE despite being adherent on lactulose therapy and portosytemic shunts have been excluded by imaging. Based on these observations, the use of rifaximin as an additive therapy to lactulose is appropriate in this patient to prevent further recurrences. Before we can recommend use of rifaximin as the sole therapy, long-term head-to-head studies are needed demonstrating the superiority of rifaximin over lactulose. It is uncertain whether rifaximin will be useful or safe in her as the liver disease progresses; studies in patients with MELD scores >19 have been recommended by the FDA.17 The concerns about the long-term use of antibiotic treatment as well as resistance do remain, which is why the FDA label for rifaximin has postmarketing C. difficile surveillance and warning for rifaximin. Ultimately, the most reliable therapy for HE is liver transplantation, and maintaining functionality and health by avoiding subsequent episodes of HE is a key step toward achieving that goal.
Rifaximin is marketed for treatment of HE in the United States by Salix Pharmaceuticals as Xifaxan 550 (550 mg tablets). It is also available as 200 mg tablets. The cost for a 30-day supply of Xifaxan 550 mg twice daily is $1120, whereas the cost of a 30-day supply of Xifaxan 400 mg three times a day is $900. The cost of a 30-day supply of lactulose (60 mL/day) is $150.