Hepatic encephalopathy rifaximin

Rifaximin Rifamycin Antibiotic Gut bacteria Enteric infection Diarrhea, infectious Hepatic encephalopathy Small intestine bacterial overgrowth Inflammatory bowel disease Colonic diverticular disease Irritable bowel syndrome Constipation Clostridium difficile infection Helicobacter pylori infection Colorectal surgery Bowel decontamination, selective Pancreatitis, acute Bacterial peritonitis, spontaneous Nonsteroidal anti-inflammatory drug enteropathy... 

A large number of human studies [71, 77-80] performed in patients with infectious diarrhea or other GI diseases (e.g. hepatic encephalopathy, small bowel bacterial overgrowth, IBD, colonic diverticular disease) have confirmed the antibacterial activity of rifaximin demonstrated in vitro and in laboratory animals. 

On the basis of log bacterial survival rates, the antibacterial activity of rifaximin was greater than that of paromomycin against Enterococcus spp., anaerobic cocci, Bac-terioides spp. and Clostridium spp. isolated in fecal samples from 20 patients with subclinical hepatic encephalopathy (fig. 4) [81]. On the other hand, E. coli dead Klebsiella spp. appeared more susceptible to paromomycin while both antibiotics showed equal potency against Proteus spp. [81]. Here again it should be pointed out that stool concentrations of rifaximin are 250-500 times higher than the MIC90 values [71], which makes the in vitro differences of activity between this and other antimicrobials meaningless from a clinical standpoint. 

Antimicrobial resistance to rifamycins develops rapidly both in vitro and in vivo [65,85,86], As a consequence, all the three members of the family (i.e. rifampicin, rifabutin and rifapentine) are used clinically as components of combination therapies [65,87], Being structurally related, rifaximin could share this potential. And indeed resistance rates, recorded in fecal strains of Enterobacteriaceae, Enterococcus, Bacteroides, Clostridium and anaerobic cocci, ranged between 30 and 90% after short-term (5 days) antibiotic (800 mg daily) treatment [82], A similar pattern was observed in 10 patients with hepatic encephalopathy after treatment with rifaximin 1,200 mg/day for 5 days [80]. 

Nevertheless, a rapid disappearance of resistant bacteria was observed after stopping the antibiotic treatment (fig. 5). Different kinetics of disappearance were, however, observed. The aerobic species showed a more rapid return to the baseline sensitive status whereas the anaerobic bacteria, especially the Gram-negative rods, regained sensitivity to rifaximin more slowly. In any case, 3 months after the end of treatment resistant strains were no longer detectable in the feces [82], These results support the cyclic use of rifaximin that has been adopted by the investigators in the treatment of hepatic encephalopathy [77] and colonic diverticular disease [79]. 

Although the pharmacokinetics of rifaximin in patients with renal insufficiency has not been specifically studied, its very low renal excretion makes any dose adjustment unnecessary. The same holds true for patients with hepatic insufficiency. In fact, the mean peak drug plasma concentrations (i.e. 13.5 ng/ml) detected in subjects with hepatic encephalopathy patients given rifaximin 800 mg 3 times daily for 7 days [34, 108] were not dissimilar to those found in healthy subjects [102] and patients with IBD [98], Indeed, in all the trials performed in this condition the drug has been well tolerated [33, 77],... 

Zeneroli ML, Avallone R, Corsi L, Venturini I, Baraldi C, Baraldi M Management of hepatic encephalopathy Role of rifaximin. Chemotherapy 2005 51(suppl 1) 90—95. 

Williams R, James OF, Warnes TW, Morgan MY Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy A double-blind, randomized, dosefinding multi-centre study. Eur J Gastroenterol Hepatol 2000 12 203-208. 

Rifaximin is available in Europe for the treatment of acute intestinal bacterial infections, hepatic encephalopathy, bacterial overgrowth syndrome, diverticular disease of the colon, and for the prevention of infections after colorectal surgery [3, 4]. Rifaximin is also licensed in Mexico, Asia and Northern Africa and has recently been approved in USA for the treatment of traveler s diarrhea. 

Rifaximin has been shown to possess good antibacterial activity against a variety of anaerobic bacteria (table 3) [24, 27, 28], Anaerobes have been shown to be capable of producing ammonia (especially Clostridia), which has been incriminated in the pathogenesis of hepatic encephalopathy [29], The authors suggested that since rifaximin is a nonabsorbable and effective antibiotic against anaerobic flora, it would be an ideal treatment for patients with compromised hepatic function. Eubacterium is inhibited by rifaximin with an MIC90 < 2 pg/ml [27]. 

As outlined in the excellent review by Gilles and Brogden [9], the current indications for rifaximin include surgical prophylaxis and the treatment of hepatic encephalopathy, infectious diarrhea and intestinal bacterial overgrowth syndromes. As such, rifaximin is aimed only at enteric flora. Owing to its lack of absorption, rifaximin will likely not be used for other conditions or indications. Such limited indications should help preserve the activity of the agent, since overuse for common conditions like urinary or respiratory tract infections will naturally not occur. Limited use should help retard the development of resistance among enteric flora. 

Massa MD, Vallerino MD, Dodero MD Treatment of hepatic encephalopathy with rifaximin Double blind, double dummy study versus lactulose. Eur J Clin Res 1993 4 7-18. 

FeraG, AgostinacchioF,NigroM, SchiraldiO, Ferrieri A Rifaximin in the treatment of hepatic encephalopathy. Eur J Clin Res 1993 4 57-66. 

Bucci L, Palmieri GC Double-blind, doubledummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy. Curr Med Res Opin 1993 13 109—118. 

Miglio F, Valpiani D, Rossellini SR, Ferrieri A Rifaximin, a non-absorbable rifamycin, for the treatment of hepatic encephalopathy. A double-blind, randomised trial. Curr Med Res Opin 1997 13 593-601. 

Loguercio C, Federico A, De Girolamo V, Ferrieri A, Del Vecchio Blanco C Cyclic treatment of chronic hepatic encephalopathy with rifaximin. Minerva Gastroenterol Dietol 2003 49 53-62... 

Mas A, Rodes J, Sunyer L, Rodrigo L, Planas R, Vargas V, Castells L, Rodriguez-Martinez D, Fernandez-Rodriguez C, Coll I, Pardo A Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy Results of a randomized, double-blind, doubledummy, controlled clinical trial. J Hepatol 2003 38 51-58. 

Rifaximin, a nonabsorbable derivative of rifamycin, has shown promising bactericidal action against both aerobes and anaerobes, such as bacterioides, lactobacilli and clostridia [33, 34], The development of resistance to this antibiotic can occur, but resistant strains rapidly disappear from the intestine thus allowing cyclic administration of rifaximin. Controlled clinical trials showed efficacy of rifaximin in adult and pediatric patients with infectious diarrhea [36,37], hepatic encephalopathy [38], post-surgical complications [39] and colonic diverticulosis [40], Only recently was the efficacy of rifaximin in the treatment of SIBO demonstrated [41-43]. 

Uses Rifaximin is a non-systemic, gut-selective antibiotic and has been approved in the USA for reducing the risk of recurrence of hepatic encephalopathy in adults. The effects of rifaximin 400-1200 mg/day have been assessed in a retrospective study after treatment with lactulose 20-120 g/day in improving hospitalization outcomes in 65 patients with hepatic encephalopathy [17 ]. Rifaximin reduced the risk, number, and duration of hospitalizations for hepatic encephalopathy compared with lactulose. Fewer patients had evidence of spontaneous bacterial peritonitis while taking rifaximin. Lactulose was associated with many adverse events, including abdominal cramps (n = 2l), bloating ( = 8), pain ( = 19), and excessive diarrhea ( = 54) in contrast, there was only one case of abdominal pain in those who took rifaximin. 

In a multicenter, double-blind, randomized, placebo-controlled study in the USA and Russia, 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease were randomized to either rifaximin 550 mg bd (n = 140) or placebo ( = 159) for 6 months [IS "]. Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy over 6 months (HR = 0.42 95% Cl = 0.28, 0.64). There were breakthrough episodes of hepatic encephalopathy in 22% of those who took rifaximin, compared with 46% of those who took placebo. In all, 14% of those who took rifaximin were hospitalized for encephalopathy compared with 23% of those who took placebo (HR=0.50 95% Cl = 0.29, 0.87). The incidence of adverse events reported during the study was similar in the two groups, as was the incidence of serious adverse events. 

Mantry PS, Munsaf S. Rifaximin for the treatment of hepatic encephalopathy. Transplant Proc 2010 42(10) 4543-7. 

Jalan R. Rifaximin in hepatic encephalopathy more than just a non-absorbable antibiotic J Hepatol 2010 53(3) 580-2. 

Sharma BC, Sharma P, Lunia MK, Srivastava S, Goyal R, Sarin SK. A randomized, double-blind, controlled trial comparing rifaximin plus lactulose with lactulose alone in treatment of overt hepatic encephalopathy. Am J Gastroenterol. 2013 108 1458-1463. 

Ammonia Bacterial flora Benzodiazepines, endogenous Encephalopathy, hepatic Liver cirrhosis Rifaximin... 

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