Letter: the effects of rifaximin in hepatic encephalopathy.

Abstract

We read with interest the article by Kimer et al. reporting to perform a meta-analysis of randomised controlled trials (RCTs) on rifaximin for hepatic encephalopathy (HE).1 The authors concluded that rifaximin has a beneficial effect on HE and may be considered in the evidence-based management of HE. There are, however, aspects of this study that warrant further discussion. Rifaximin has been proved to be safe in healthy subjects. However, liver cirrhosis significantly affects the pharmacokinetics of this drug, with systemic absorption markedly increased in these patients compared to controls. Indeed, plasma concentrations as high as 10 ng/mL have been observed in cirrhotics, with levels being even higher in those patients with Child–Pugh C disease, compared to only 1 ng/mL in controls.2 This could be a cause for concern, particularly when a daily, long-life therapy is proposed for chronic disorders, such as HE prevention. Therefore, a note for caution should be considered before suggesting long-term therapy with rifaximin for the prevention of HE in cirrhotics, and further studies are warranted to assess its actual safety. Of note, a significant increase in serum potassium and sodium concentrations has been reported during rifaximin therapy.3 This could be a matter for concern in cirrhotic patients with these electrolyte disturbances also being involved in the development of HE. At the same time, some concerns with both possible infection and bacterial resistance induction during rifaximin therapy should be also considered, particularly when long-term treatment is suggested. Following 6 months of rifaximin therapy, two cases of Clostridium difficile infection were found in the rifaximin group, despite this antibiotic being active against such a bacterium, while no case occurred in the placebo group.4 Therefore, a note of caution should be considered, particularly when long-term antibiotic therapy is suggested. Rifaximin markedly reduced faecal bacterial counts during oral intake, but the effect was short-lasting since the bacterial population recovered within 1–2 week after the end of treatment. Therefore, a rapid disappearance of resistant bacteria was observed after stopping a short course rifaximin treatment but no data are available for long-term therapy. Of note, anaerobic bacteria, especially the Gram-negative rods, regained sensitivity to rifaximin more slowly than aerobic species. Finally, Candida albicans, which has been implicated in the pathogenesis of antibiotic-associated diarrhoea, was isolated from the faecal samples of 20% of patients given 1200 mg of rifaximin daily. Therefore, it has been suggested that rifaximin therapy could be used as a rescue therapy in addition to disaccharides in those cirrhotics who experienced HE during disaccharides therapy. While waiting for further safety data, caution should be used in adding rifaximin therapy in the very short term, disclosing to the patients both the benefit and potential risks. Declaration of personal and funding interests: None.