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

Table 1 Major studies describing the changes in gut microbiota composition and the effects of rifaximin treatment in patients with advanced liver disease and hepatic encephalopathy

Study	Study design	No. patients	Disease severity	HE type	Treatment schedule	Results	Safety
Mas et al[56] 2003	Prospective randomized, double-blind, double-dummy, controlled trial	103	Not reported	Overt HE	50 pts rifaximin 1200 mg/d for 5-10 d	Improved neuropsychiatric and psychometric parameters in both groups	Abdominal pain: 4% rifaximin
					53 pts lactitol 60 g/d for 5-10 d	Reduced blood ammonia levels in both groups	Mild diarrhea: 2% lactitol
						No significant differences in efficacy (resolution/improvement 81.6% rifaximin vs 80.4% lactitol; unchanged/failure 18.4% rifaximin vs 19.6% lactitol)	Vomiting: 2% lactitol
						HE complete resolution: 53.1% rifaximin vs 37.2% lactitol
Paik et al[57] 2005	Prospective randomized		CTP:	Overt HE	32 pts rifaximin 400 mg TID for 7 d	Reduction in blood ammonia levels similar in both groups	Abdominal pain: 3% rifaximin
			rifaximin A: 0%, B: 50%, C: 50%		22 pts lactulose 90 mL/d for 7 d	Improvement in HE grade and index similar in both groups	Severe diarrhea: 4.5% lactulose
			lactulose A: 0%, B: 64%, C: 36%			Improvement in HE grade similar in both groups
Leevy et al[58] 2007	Retrospective	145	Not reported	Overt HE	Lactulose 30 cc BID for ≥ 6 mo followed by rifaximin 400 mg TID for ≥ 6 mo	HE grade III or IV: 6% after rifaximin 25% after lactulose (P < 0.001)	Hospitalizations (mean number): 0.5 rifaximin period vs 1.6 lactulose period (P = 0.001)
						Asterixis: 63% after rifaximin vs 93% after lactulose (P < 0.001)	Hospitalizations days (mean): 2.5 rifaximin period vs 7.3 lactulose period (P = 0.001)
							Diarrhea: 89% during lactulose, 99% during rifaximin
							Flatulence: 100% during lactulose, 100% during rifaximin
							Abdominal pain: 100% during lactulose, 100% during rifaximin
							Headache: 100% during lactulose, 99% during rifaximin
							However, severe adverse events were more common in the lactulose period (P < 0.001)
Bass et al[51] 2010	Prospective, randomized, double-blind, placebo-controlled	299	MELD score (%):	Overt HE	140 pts 550 mg BID for 6 mo	Rifaximin is more effective than placebo in maintaining HE remission (P < 0.001)	Incidence of adverse events was similar in the two groups; most frequently reported: nausea diarrhea, fatigue
			rifaximin		159 pts placebo	Breakthrough episodes rate: 22.1% rifaximin vs 45.9% placebo	Bacterial peritonitis: 1.4% rifaximin vs 2.5% placebo
			≤ 10: 24.3%		90% of pts also received lactulose	Risk of HE-related hospitalization: 13.6% rifaximin vs 22.6% placebo (P = 0.01)	Bacteremia: 0.7% rifaximin vs 1.3% placebo
			11-18: 67.1%				C. difficile infection: 1.4% rifaximin vs 0% placebo
			19-24: 8.6%				Sepsis: 0% rifaximin vs 1.3% placebo
			placebo:
			≤ 10: 30.2%
			11-18: 60.4%
			19-24: 8.8%
Bajaj et al[59] 2011	Prospective, randomized, double-blind, placebo-controlled	42	MELD score (mean)	Minimal HE	21 pts rifaximin 550 mg BID	Total driving errors improvement: 76% rifaximin vs 31% placebo (P = 0.013), with a significant reduction of speeding tickets (P = 0.005) and illegal turns on navigation (P = 0.01)	Infections rate: 0%
			rifaximin: 9		21 pts placebo for 8-wk		Hospitalization rate: 0%
			placebo: 9				Nausea: 14% rifaximin vs 14% placebo
						Cognitive performance improvement: 91% rifaximin vs 61% placebo (P = 0.01)	Self-limited vomiting: 5% rifaximin vs 5% placebo
						Improved psycho-social dimension (quality of life assessment by Sickness Impact Profile questionnaire) in the rifaximin group compared with the placebo group (P = 0.04)	Abdominal pain: 24% rifaximin vs 24% placebo
							Flatulence: 19% rifaximin vs 43% placebo
							Headache: 19% rifaximin vs 33% placebo
							Flu-like symptoms: 5% rifaximin
							Constipation: 5% rifaximin
							Self-limited diarrhea: 5% rifaximin vs 5% placebo
							Hitching: 5% placebo
							Anorexia and dry mouth: 5% placebo
Neff et al[52] 2012	Retrospective	203	MELD score (mean, range):	Overt HE	149 pts rifaximin monotherapy (400-1600 mg/d)	1-yr HE remission rate: 81% rifaximin vs 67% rifaximin + lactulose	Incidence of gastrointestinal bleeding, infection, hospitalization for dehydration/overt HE similar in both groups
			rifaximin 12 (8-27)		54 pts rifaximin (600-1200 mg/d) + lactulose (90 mL/d) dual therapy	Lower incidence of overt HE episodes in pts with mean MELD score ≤ 20
			rifaximin + lactulose 13 (11-26)
Bajaj et al[62] 2013	Prospective	20	MELD score (mean ± SD): 9.8 ± 3.3	Minimal HE	550 mg BID for 8 wk	Significant improvement in cognitive performance on all tests apart from the block design test	Not reported
						Significant improvement in serum bilirubin but not the other MELD score components
						No significant microbial change (modest reduction in Veillonellaceae and increase in Eubacteriaceae)
						Significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids, serum fructose, succinic acid and citramalic acid
						Change in correlation networks involving several bacteria (Enterobacteriaceae, Bacteroidaceae, Veillonellaceae, Porphyromonadaceae and Rikenellaceae) reflecting a functional shift in the gut microbiome
Sharma et al[53] 2013	Prospective, randomized, double-blind, placebo-controlled	120	CTP score (mean ± SD):	Overt HE	group A (63 pts): lactulose + rifaximin 1200 mg/d	HE remission rate: 76% group A vs 50.8% group B (P < 0.004)	Diarrhea: 13% group A vs 10% group B (P > 0.05)
			group A 9.9 ± 2.8		group B (57 pts): lactulose + placebo	Mortality: 23.8% group A vs 49.1% group B (P < 0.05). Death was mainly due to sepsis	Abdominal pain: 6% group A vs 7% group B (P > 0.05)
			group B 9.4 ± 2.5			Hospital stay (mean ± SD): 5.8 ± 3.4 in group A vs 8.2 ± 4.6 group B (P = 0.001)
			MELD score (mean ± SD):
			group A 24.9 ± 6.6
			group B 23.8 ± 5.18
Maharshi et al[54] 2014	Prospective, randomized, controlled	120 pts with acute variceal bleeding and no HE	CTP and MELD scores comparable between groups but not reported	Overt HE	60 pts lactulose 30 mL QID	Incidence of HE: 15% rifaximin vs 17% lactulose (P = 1)	Rifaximn group: 5% abdominal pain and nausea
					60 pts rifaximin 400 mg TID	Mortality: 17% rifaximin vs 13% lactulose (P = 1)	Lactulose group: 26.6% diarrhea, 15% abdominal bloating
					for 5 d	Hospital stay (mean ± SD): 10.6 ± 3.1 d rifaximin vs 12.4 ± 3.5 lactulose (pts with HE, P = 0.35); 6.3 ± 1.6 rifaximin vs 6.9 ± 1.9 lactulose (pts without HE, P = 0.18)
Sharma et al[55] 2014	Prospective, randomized, controlled	124	CTP	Minimal HE	31 pts LOLA 3 g TID for 2 mo	LOLA, rifaximin, and probiotics are superior to placebo in improving critical flicker frequency score	Not reported
			LOLA		31 pts rifaximin 400 mg TID for 2 mo	LOLA, rifaximin, and probiotics are superior to placebo in improving neuropsychometric tests
			A: 22.5%, B: 42%, C: 35.5%		32 pts probiotics BID for 2 mo
			rifaximn		30 pts placebo
			A: 39%, B: 32%, C: 29%
			probiotics
			A: 19%, B: 66%, C: 16%
			placebo
			A: 33%, B: 27%, C: 40%

MELD: Model for end stage liver disease; HE: Hepatic encephalopathy; CTP: Child turcotte pugh; LOLA: L-ornithine L-aspartate.

Table 2 Major studies describing the efficacy of rifaximin in preventing episodes of spontaneous bacterial peritonitis in patients with advanced liver disease

Study	Study design	No. patients	Disease severity	Disease complication	Treatment schedule	Results	Safety
Hanouneh et al[66] 2012	Retrospective	404	MELD score (mean ± SD):	SBP	49 pts received rifaximin	SBP incidence: 11% in pts on rifaximin vs 32% in controls (P = 0.002)	Not reported
			rifaximin: 17.6 ± 7.7		400 mg TID mainly for HE
			no rifaximin 17.7 ± 7.5		(recurrent HE or intolerance to lactulose)	72% SBP reduction rate in rifaximin group after adjusting for MELD score, CTP score, serum sodium, and ascitic fluid total proteins (P = 0.007)
			CTP score
			rifaximin B: 6.1%, C: 93.9%
			no rifaximin B: 33%, C: 67%
						72% transplant-free survival for pts on rifaximin vs 57% for controls (P = 0.045)
Lutz et al[69] 2014	Prospective, observational	152	CTP score:	SBP	Group 1 (108 pts): no prophylaxis	SBP occurrence rate: 32/152 (21%) overall, 22.2% group 1, 29.6% group 2 and 0% group 3 (P = 0.02 group 2 vs group 3 and P = 0.04 group 1 vs group 3)	Data available for SBP pts only
			no prophylaxis:				Nosocomial infections: 38% rifaximin vs 54% no rifaximin (P = 0.690)
			A: 1%, B: 57%, C: 43%		Group 2 (27 pts): rifaximin 400 mg TID
			rifaximin:				Isolation of bacteria resistant to III generation cephalosporin: 25% rifaximin vs 46% no rifaximin
			A: 0%, B: 33%, C: 67%		Group 3 (17 pts): systemically absorbed antibiotic prophylaxis
			systemically absorbed antibiotics:
			A:12%, B: 47%, C: 41%				Isolation of multidrug resistant bacteria: 25% rifaximin vs 9% no rifaximin

SBP: Spontaneous bacterial peritonitis; CTP: Child turcotte pugh.

Table 3 Available studies describing the effects of rifaximin on endotoxemia in patients with advanced liver disease

Study	Study design	No. patients	Disease severity	Treatment schedule	Results	Safety
Vlachogiannakos et al[71] 2009	Prospective	30	welve patients (40%) were Child-Pugh B and 18 (60%) Child-Pugh C	Rifaximin 1200 mg/d for 28 d	Median (range) plasma endotoxin levels decreased significantly after rifaximin administration both in systemic [1.45 (0-3.1) vs 0.7 (0-2.7), P < 0.0001] and splanchnic circulation [1.8 (0-3.4) vs 0.8 (0-2.1), P < 0.0001]. Meanwhile, the difference seen in endotoxin levels between the splanchnic and systemic circulation at day 0 (P = 0.001) was not noted at day 29 (P = 0.137)	Abdominal pain: 3%
			CTP score: A: 0%, B: 40%, C: 60%			Self-limited diarrhea: 3%
			MELD score (mean, range): 17 (11-27)		Reduction in endotoxin levels in both systemic and splanchnic circulation compared to baseline (P < 0.0001)
			B: 40%, C: 60%		Reduction in HVPG compared to baseline (P < 0.0001)
					Reduction in HVPG correlated with hepatic vein endotoxin values (P = 0.023)
Kalambokis et al[73] 2012	Prospective	9	CTP score: B: 56%, C: 44%	8-wk course of rifaximin (1200 mg/d)	Rifaximin significantly reduced plasma endotoxin levels	Not reported
				Rifaximin 1200 mg/d for 8 wk	Reduction in plasma endotoxin levels compared to baseline (P < 0.01)
Vlachogiannakos et al[72] 2012	Prospective	69	welve patients (40%) were Child-Pugh B and 18 (60%) Child-Pugh C	23 pts who achieved a decrease in HVPG after 28-d rifaximin treatment[71]	Median (range) plasma endotoxin levels decreased significantly after rifaximin administration both in systemic [1.45 (0-3.1) vs 0.7 (0-2.7), P < 0.0001] and splanchnic circulation [1.8 (0-3.4) vs 0.8 (0-2.1), P < 0.0001]. Meanwhile, the difference seen in endotoxin levels between the splanchnic and systemic circulation at day 0 (P = 0.001) was not noted at day 29 (P = 0.137)	Nausea: 9%
						Self-limited rash in the extremities: 4%
						Persistent diarrhea: 4%
			CTP score	46 cirrhotic controls
			rifaximin		Reduction in plasma endotoxin levels in both systemic and splanchnic circulation compared to baseline (P < 0.0001)
			A: 0%, B: 48%, C: 52%
			controls:		Risk of developing variceal bleeding: 35% rifaximin vs 59.5% controls (P = 0.011)
			A: 0%, B: 48%, C: 52%		Incidence of HE: 31.5% rifaximin vs 47% controls (P = 0.034)
			MELD score (mean ± SD)		Incidence of SBP: 4.5% rifaximin vs 46% controls (P = 0.027)
			rifaximin: 17.2 ± 3.6		Incidence of HRS: 4.5% rifaximin vs 51% controls (P = 0.037)
			controls: 16.6 ± 3.5
Kalambokis et al[75] 2012	Prospective, randomized, placebo-controlled	23	CTP score	13 pts: rifaximin 1200 mg/d for 4 wk	Reduction in endotoxin levels compared to control group (P = 0.005)	Not reported
			rifaximin:		Increase in mean platelets count in rifaximin group compared to controls (P = 0.006)
			A: 0%, B: 46%, C: 54%
			placebo:	10 cirrhotic pts: placebo
			A: 0%, B: 40%, C: 60%
Bajaj et al[62] 2013	Prospective	20	MELD score (mean ± SD): 9.8 ± 3.3	Rifaximin 550 mg BID for 8 wk	Reduction in plasma endotoxin levels compared to baseline (P = 0.02)	Not reported

MELD: Model for end stage liver disease; CTP: Child turcotte pugh; HVPG: Hepatic venous pressure gradient.