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Kulkarni AV, Avadhanam M, Karandikar P, Rakam K, Gupta A, Simhadri V, Premkumar M, Zuberi AA, Gujjarlapudi D, Narendran R, Shaik S, Sharma M, Iyengar S, Alla M, Venishetty S, Reddy DN, Rao PN. Antibiotics With or Without Rifaximin for Acute Hepatic Encephalopathy in Critically Ill Patients With Cirrhosis: A Double-Blind, Randomized Controlled (ARiE) Trial. Am J Gastroenterol 2024; 119:864-874. [PMID: 37942950 DOI: 10.14309/ajg.0000000000002575] [Citation(s) in RCA: 13] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 10/10/2023] [Indexed: 11/10/2023]
Abstract
INTRODUCTION Critically ill patients with cirrhosis admitted to the intensive care unit (ICU) are usually on broad-spectrum antibiotics because of suspected infection or as a hospital protocol. It is unclear if additional rifaximin has any synergistic effect with broad-spectrum antibiotics in ICU patients with acute overt hepatic encephalopathy (HE). METHODS In this double-blind trial, patients with overt HE admitted to ICU were randomized to receive antibiotics (ab) alone or antibiotics with rifaximin (ab + r). Resolution (or 2 grade reduction) of HE, time to resolution of HE, in-hospital mortality, nosocomial infection, and changes in endotoxin levels were compared between the 2 groups. A subgroup analysis of patients with decompensated cirrhosis and acute-on-chronic liver failure was performed. RESULTS Baseline characteristics and severity scores were similar among both groups (92 in each group). Carbapenems and cephalosporin with beta-lactamase inhibitors were the most commonly used ab. On Kaplan-Meier analysis, 44.6% (41/92; 95% confidence interval [CI], 32-70.5) in ab-only arm and 46.7% (43/92; 95% CI, 33.8-63) in ab + r arm achieved the primary objective ( P = 0.84).Time to achieve the primary objective (3.65 ± 1.82 days and 4.11 ± 2.01 days; P = 0.27) and in-hospital mortality were similar among both groups (62% vs 50%; P = 0.13). Seven percent and 13% in the ab and ab + r groups developed nosocomial infections ( P = 0.21). Endotoxin levels were unaffected by rifaximin. Rifaximin led to lower in-hospital mortality (hazard ratio: 0.39 [95% CI, 0.2-0.76]) in patients with decompensated cirrhosis but not in patients with acute-on-chronic liver failure (hazard ratio: 0.99 [95% CI, 0.6-1.63]) because of reduced nosocomial infections. DISCUSSION Reversal of overt HE in those on ab was comparable with those on ab + r.
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Affiliation(s)
| | | | | | - Kalyan Rakam
- Department of Critical Care Medicine, AIG Hospitals, Hyderabad, India
| | - Anand Gupta
- Department of Critical Care Medicine, AIG Hospitals, Hyderabad, India
| | - Venu Simhadri
- Department of Basic Sciences, Asian Healthcare Foundation, Hyderabad, India
| | | | | | | | | | - Sameer Shaik
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Mithun Sharma
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Sowmya Iyengar
- Department of Hepatology, AIG Hospitals, Hyderabad, India
| | - Manasa Alla
- Department of Hepatology, AIG Hospitals, Hyderabad, India
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Zaman T, Ahmed Attari MB, Ahmad A, Butt MA, Fayyaz K, Zubair SA. Comparison of Rifaximin Alone and With Quinolones in the Primary Prevention of Spontaneous Bacterial Peritonitis in Patients With Decompensated Chronic Liver Disease. Cureus 2024; 16:e55251. [PMID: 38558603 PMCID: PMC10981471 DOI: 10.7759/cureus.55251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/29/2024] [Indexed: 04/04/2024] Open
Abstract
Background In cirrhotic patients with ascites, primary prevention of spontaneous bacterial peritonitis (SBP) is a key strategy to lower morbidity and death. Rifaximin and fluoroquinolone used alternately as main prophylaxis are as effective as reported. This study aimed to compare the frequency of occurrence of SBP in patients with decompensated chronic liver disease treated with rifaximin alone and in combination with fluoroquinolone. Methodology A total of 76 patients with hepatitis C virus-related decompensated chronic liver disease and ascites were divided into two groups based on matching age, sex, and Child-Pugh class. Group A (38 patients) received rifaximin 1,100 mg/day in two divided doses with daily fluoroquinolone 400 mg/day, whereas group B (38 patients) received rifaximin 1,100 mg/day alone as a two dosage. The patients were monitored for up to three months. The study's endpoints were SBP, hepatocellular carcinoma, compliance failure, death, or liver transplantation. Results In this comparative study involving 76 patients, the demographic and clinical characteristics were assessed across two treatment groups: rifaximin alone (n = 38) and rifaximin with fluoroquinolone (n = 38). The combination therapy demonstrated a statistically significant reduction in SBP compared to rifaximin alone. Additionally, the overall survival rate was higher in the combination group. These findings suggest potential benefits of the combined approach in managing hepatic encephalopathy-related complications. Conclusions When compared to rifaximin alone for primary SBP prophylaxis, the combination of rifaximin with fluoroquinolone exhibited greater effectiveness with the same safety profile.
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Affiliation(s)
- Tahir Zaman
- Department of Medicine, Lahore General Hospital, Lahore, PAK
| | | | - Adeel Ahmad
- Medicine, Chelsea and Westminster Hospital NHS Foundation Trust, Chelsea, GBR
| | | | - Khurram Fayyaz
- Department of Medicine, Azra Naheed Medical College, Lahore, PAK
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Mendez-Sanchez N, Coronel-Castillo CE, Cordova-Gallardo J, Qi X. Antibiotics in Chronic Liver Disease and Their Effects on Gut Microbiota. Antibiotics (Basel) 2023; 12:1475. [PMID: 37887176 PMCID: PMC10603944 DOI: 10.3390/antibiotics12101475] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/18/2023] [Accepted: 09/21/2023] [Indexed: 10/28/2023] Open
Abstract
Impairments in liver function lead to different complications. As chronic liver disease progresses (CLD), hypoalbuminemia and alterations in bile acid compositions lead to changes in gut microbiota and, therefore, in the host-microbiome interaction, leading to a proinflammatory state. Alterations in gut microbiota composition and permeability, known as gut dysbiosis, have important implications in CLD; alterations in the gut-liver axis are a consequence of liver disease, but also a cause of CLD. Furthermore, gut dysbiosis plays an important role in the progression of liver cirrhosis and decompensation, particularly with complications such as hepatic encephalopathy and spontaneous bacterial peritonitis. In relation to this, antibiotics play an important role in treating CLD. While certain antibiotics have specific indications, others have been subjected to continued study to determine whether or not they have a modulatory effect on gut microbiota. In contrast, the rational use of antibiotics is important, not only because of their disrupting effects on gut microbiota, but also in the context of multidrug-resistant organisms. The aim of this review is to illustrate the role of gut microbiota alterations in CLD, the use and impact of antibiotics in liver cirrhosis, and their harmful and beneficial effects.
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Affiliation(s)
- Nahum Mendez-Sanchez
- Unit Liver Research, Medica Sur Clinic & Foundation, Mexico City 14050, Mexico
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City 04510, Mexico
| | | | - Jacqueline Cordova-Gallardo
- Department of Hepatology, Service of Surgery and Obesity Clinic, General Hospital “Dr. Manuel Gea González”, Mexico City 14080, Mexico
| | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, China
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Crocombe D, O’Brien A. Antimicrobial prophylaxis in decompensated cirrhosis: friend or foe? Hepatol Commun 2023; 7:e0228. [PMID: 37655979 PMCID: PMC10476838 DOI: 10.1097/hc9.0000000000000228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 06/21/2023] [Indexed: 09/02/2023] Open
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Mandorfer M, Aigner E, Cejna M, Ferlitsch A, Datz C, Gräter T, Graziadei I, Gschwantler M, Hametner-Schreil S, Hofer H, Jachs M, Loizides A, Maieron A, Peck-Radosavljevic M, Rainer F, Scheiner B, Semmler G, Reider L, Reiter S, Schoder M, Schöfl R, Schwabl P, Stadlbauer V, Stauber R, Tatscher E, Trauner M, Ziachehabi A, Zoller H, Fickert P, Reiberger T. Austrian consensus on the diagnosis and management of portal hypertension in advanced chronic liver disease (Billroth IV). Wien Klin Wochenschr 2023:10.1007/s00508-023-02229-w. [PMID: 37358642 DOI: 10.1007/s00508-023-02229-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 05/15/2023] [Indexed: 06/27/2023]
Abstract
The Billroth IV consensus was developed during a consensus meeting of the Austrian Society of Gastroenterology and Hepatology (ÖGGH) and the Austrian Society of Interventional Radiology (ÖGIR) held on the 26th of November 2022 in Vienna.Based on international recommendations and considering recent landmark studies, the Billroth IV consensus provides guidance regarding the diagnosis and management of portal hypertension in advanced chronic liver disease.
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Affiliation(s)
- Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
| | - Elmar Aigner
- First Department of Medicine, Paracelsus Medical University, Salzburg, Austria
| | - Manfred Cejna
- Department of Radiology, LKH Feldkirch, Feldkirch, Austria
| | - Arnulf Ferlitsch
- Department of Internal Medicine I, KH Barmherzige Brüder Wien, Vienna, Austria
| | - Christian Datz
- Department of Internal Medicine, General Hospital Oberndorf, Teaching Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria
| | - Tilmann Gräter
- Department of Radiology, Medical University of Graz, Graz, Austria
| | - Ivo Graziadei
- Department of Internal Medicine, KH Hall in Tirol, Hall, Austria
| | - Michael Gschwantler
- Division of Gastroenterology and Hepatology, Department of Medicine IV, Klinik Ottakring, Vienna, Austria
| | - Stephanie Hametner-Schreil
- Department of Gastroenterology and Hepatology, Ordensklinikum Linz Barmherzige Schwestern, Linz, Austria
| | - Harald Hofer
- Department of Internal Medicine I, Klinikum Wels-Grieskirchen, Wels, Austria
| | - Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Alexander Loizides
- Department of Radiology, Medical University of Innbsruck, Innsbruck, Austria
| | - Andreas Maieron
- Department of Internal Medicine II, University Hospital St. Pölten, St. Pölten, Austria
| | - Markus Peck-Radosavljevic
- Department of Internal Medicine and Gastroenterology, Hepatology, Endocrinology, Rheumatology and Nephrology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria
| | - Florian Rainer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Georg Semmler
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lukas Reider
- Department of Interventional Radiology, Medical University of Vienna, Vienna, Austria
| | - Silvia Reiter
- Department of Internal Medicine and Gastroenterology and Hepatology, Kepler Universitätsklinikum, Linz, Austria
| | - Maria Schoder
- Department of Interventional Radiology, Medical University of Vienna, Vienna, Austria
| | - Rainer Schöfl
- Department of Gastroenterology and Hepatology, Ordensklinikum Linz Barmherzige Schwestern, Linz, Austria
| | - Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Vanessa Stadlbauer
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Rudolf Stauber
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Elisabeth Tatscher
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria
| | - Alexander Ziachehabi
- Department of Internal Medicine and Gastroenterology and Hepatology, Kepler Universitätsklinikum, Linz, Austria
| | - Heinz Zoller
- Department of Internal Medicine I, Medical University of Innsbruck, Innsbruck, Austria
| | - Peter Fickert
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
- Vienna Hepatic Hemodynamic Laboratory, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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Bitto N, Ghigliazza G, Lavorato S, Caputo C, La Mura V. Improving Management of Portal Hypertension: The Potential Benefit of Non-Etiological Therapies in Cirrhosis. J Clin Med 2023; 12:934. [PMID: 36769582 PMCID: PMC9917703 DOI: 10.3390/jcm12030934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/17/2023] [Accepted: 01/20/2023] [Indexed: 01/27/2023] Open
Abstract
Portal hypertension is the consequence of cirrhosis and results from increased sinusoidal vascular resistance and hepatic blood inflow. Etiological therapies represent the first intervention to prevent a significant increase in portal pressure due to chronic liver damage. However, other superimposed pathophysiological drivers may worsen liver disease, including inflammation, bacterial translocation, endothelial dysfunction, and hyperactivation of hemostasis. These mechanisms can be targeted by a specific class of drugs already used in clinical practice. Albumin, rifaximin, statins, aspirin, and anticoagulants have been tested in cirrhosis and were a topic of discussion in the last Baveno consensus as non-etiological therapies. Based on the pathogenesis of portal hypertension in cirrhosis, our review summarizes the main mechanisms targeted by these drugs as well as the clinical evidence that considers them a valid complementary option to manage patients with cirrhosis and portal hypertension.
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Affiliation(s)
- Niccolò Bitto
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
| | - Gabriele Ghigliazza
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Division of Sub-Intensive Care Medicine, 20122 Milan, Italy
| | - Stanislao Lavorato
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
| | - Camilla Caputo
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
| | - Vincenzo La Mura
- Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Angelo Bianchi Bonomi Hemophilia and Thrombosis Center, 20122 Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
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Evaluating the Role of Antibiotics in Patients Admitted to Hospital With Decompensated Cirrhosis: Lessons From the ATTIRE Trial. Am J Gastroenterol 2023; 118:105-113. [PMID: 35970815 PMCID: PMC9810015 DOI: 10.14309/ajg.0000000000001937] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 06/08/2022] [Indexed: 02/04/2023]
Abstract
INTRODUCTION Hospital-acquired infections (HAI) are common in cirrhosis with antibiotics frequently used to prevent infections, but their efficacy for this role is unknown. To investigate this, we used Albumin to Prevent Infection in Chronic Liver Failure (ATTIRE) data to evaluate whether antibiotic use in patients without infection prevented HAI. METHODS In ATTIRE patients without infection at baseline grouped by antibiotic prescription or not, we studied HAI during trial treatment period and mortality, with propensity score matching to account for differences in disease severity. RESULTS Two hundred three of 408 patients prescribed antibiotics at enrollment did not have infection and they were more unwell than noninfected patients not given antibiotics. There were no differences in subsequent HAI comparing antibiotic treated (39/203, 19.2%) to nonantibiotic treated (73/360, 20.3%; P = 0.83). Twenty-eight-day mortality was higher in antibiotic-treated patients ( P = 0.004) likely reflecting increased disease severity. Matching groups using propensity scoring revealed no differences in HAI or mortality. In noninfected patients at enrollment treated with/without rifaximin, there were no differences in HAI ( P = 0.16) or mortality, confirmed with propensity matching. Patients given long-term antibiotic prophylaxis at discharge had no differences in 6-month mortality compared with nonantibiotic patients, although antibiotic-treated patients had more infections at trial entry, with numbers too small for matching. DISCUSSION Half of antibiotics at study entry were given to patients without an infection diagnosis which did not reduce the overall risk of HAI or improve mortality. This supports prompt de-escalation or discontinuation of antibiotics guided by culture sensitivities at 24-48 hours after commencement if no infection and the patient is improving.
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Li YG, Yu ZJ, Li A, Ren ZG. Gut microbiota alteration and modulation in hepatitis B virus-related fibrosis and complications: Molecular mechanisms and therapeutic inventions. World J Gastroenterol 2022; 28:3555-3572. [PMID: 36161048 PMCID: PMC9372803 DOI: 10.3748/wjg.v28.i28.3555] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 06/06/2022] [Accepted: 06/24/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) has posed a threat to public health, mainly resulting in liver damage. With long-term accumulation of extracellular matrix, patients with chronic hepatitis B are at high risk of developing into liver fibrosis and cirrhosis and even life-threatening hepatic carcinoma. The occurrence of complications such as spontaneous bacterial peritonitis and hepatic encephalopathy greatly increases disability and mortality. With deeper understanding of the bidirectional interaction between the liver and the gut (gut-liver axis), there is a growing consensus that the human health closely relates to the gut microbiota. Supported by animal and human studies, the gut microbiota alters as the HBV-related liver fibrosis initials and progresses, characterized as the decrease of the ratio between "good" and "potentially pathogenic" microbes. When the primary disease is controlled via antiviral treatment, the gut microbiota dysfunction tends to be improved. Conversely, the recovery of gut microbiota can promote the regression of liver fibrosis. Therapeutic strategies targeted on gut microbiota (rifaximin, probiotics, engineered probiotics and fecal microbiota transplantation) have been applied to animal models and patients, obtaining satisfactory results.
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Affiliation(s)
- Yao-Guang Li
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zu-Jiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Ang Li
- Gene Hospital of Henan Province, Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
| | - Zhi-Gang Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan Province, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan 250000, Shandong Province, China
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Abstract
The World Health Organization describes antimicrobial resistance as one of the biggest threats to global health, food security, and development with indiscriminate use of antimicrobials globally driving the emergence of multidrug-resistant bacteria, resistant to 60% of antimicrobials in some countries. Infections with multidrug-resistant organisms (MDROs) have increased in recent decades in patients with cirrhosis, who are frequently prescribed antibiotics, regularly undergo invasive procedures such as large volume paracentesis, and have recurrent hospitalizations, posing a particular risk in this already immunocompromised cohort of patients. In this review, we explore mechanisms underlying this vulnerability to MDRO infection; the effect of bacterial infections on disease course in cirrhosis; prevalence of MDROs in patients with cirrhosis; outcomes following MDRO infection; fungal infections; antibiotics and their efficacy; and management of MDRO infections in terms of detection, antimicrobial and nonantimicrobial treatments, prophylaxis, antibiotic stewardship, the gut microbiome, and technological interventions.
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Affiliation(s)
- Charles E Gallaher
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom
| | - Debbie L Shawcross
- Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, United Kingdom.,Institute of Liver Studies, School of Immunology and Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, London, United Kingdom
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Samonakis DN, Gatselis N, Bellou A, Sifaki-Pistolla D, Mela M, Demetriou G, Thalassinos E, Rigopoulou EI, Kevrekidou P, Tziortziotis I, Azariadi K, Kavousanaki M, Digenakis E, Vassiliadis T, Kouroumalis EA, Dalekos GN. Spontaneous bacterial peritonitis: a prospective Greek multicenter study of its epidemiology, microbiology, and outcomes. Ann Gastroenterol 2022; 35:80-87. [PMID: 34987293 PMCID: PMC8713337 DOI: 10.20524/aog.2021.0674] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2020] [Accepted: 07/20/2021] [Indexed: 11/11/2022] Open
Abstract
Background Spontaneous bacterial peritonitis (SBP) is an ominous complication of decompensated cirrhosis. This study aimed to assess several epidemiological, clinical, microbiological and outcome characteristics in Greek patients with SBP, as no solid representative nationwide data of this type was available. Methods During a 3-year period, 77 consecutive patients with SBP (61 male; median age: 67 years; model for end-stage liver disease [MELD] score: 20), diagnosed and followed in 5 tertiary liver units, were prospectively recruited and studied. Various prognostic factors for disease outcome were studied. Results Thirty-eight patients had alcohol-related cirrhosis, 17 viral hepatitis, 6 non-alcoholic steatohepatitis, 6 autoimmune liver diseases, and 10 cryptogenic cirrhosis. Hepatocellular carcinoma (HCC) was present in 23 (29.9%), whereas 10 (13%) had portal vein thrombosis. The first SBP episode at baseline was community-acquired in 53 (68.8%), while in 24 (31.1%) was hospital-acquired, with predominant symptoms abdominal pain and encephalopathy. A positive ascitic culture was documented in 36% of patients in the initial episode, with almost equal gram (+) and gram (-) pathogens, including 3 multidrug-resistant pathogens. Significant factors for 6-month survival were: higher MELD score, previous b-blocker use, lower serum albumin, higher lactate on admission and need for vasopressors, while factors for 12-month survival were MELD score and lactate. For overall survival, higher MELD score and lactate along with HCC presence were negative predictive factors. Conclusions MELD score, lactate, albumin, HCC and treatment with vasopressors were predictive of survival in SBP patients. In hospital-acquired SBP the prevalence of difficult-to-treat pathogens was higher.
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Affiliation(s)
- Dimitrios N Samonakis
- Department of Gastroenterology and Hepatology, University Hospital of Heraklion Crete, Greece (Dimitrios N. Samonakis, George Demetriou, Emmanuel Digenakis, Elias A. Kouroumalis)
| | - Nikolaos Gatselis
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece (Nikolaos Gatselis, Aristea Bellou, Eirini I. Rigopoulou, Kalliopi Azariadi, George N. Dalekos)
| | - Aristea Bellou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece (Nikolaos Gatselis, Aristea Bellou, Eirini I. Rigopoulou, Kalliopi Azariadi, George N. Dalekos).,3 Department of Internal Medicine, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Greece (Aristea Bellou, Polyxeni Kevrekidou, Themistoklis Vassiliadis)
| | - Dimitra Sifaki-Pistolla
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, Heraklion, Crete, Greece (Dimitra Sifaki-Pistolla, Ioannis Tziortziotis)
| | - Maria Mela
- Department of Gastroenterology, Evangelismos Hospital, Athens, Greece (Maria Mela)
| | - George Demetriou
- Department of Gastroenterology and Hepatology, University Hospital of Heraklion Crete, Greece (Dimitrios N. Samonakis, George Demetriou, Emmanuel Digenakis, Elias A. Kouroumalis)
| | - Evangelos Thalassinos
- Department of Internal Medicine, Venizeleion Hospital, Heraklion, Crete, Greece (Evangelos Thalassinos, Melina Kavousanaki)
| | - Eirini I Rigopoulou
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece (Nikolaos Gatselis, Aristea Bellou, Eirini I. Rigopoulou, Kalliopi Azariadi, George N. Dalekos)
| | - Polyxeni Kevrekidou
- 3 Department of Internal Medicine, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Greece (Aristea Bellou, Polyxeni Kevrekidou, Themistoklis Vassiliadis)
| | - Ioannis Tziortziotis
- Clinic of Social and Family Medicine, School of Medicine, University of Crete, Heraklion, Crete, Greece (Dimitra Sifaki-Pistolla, Ioannis Tziortziotis)
| | - Kalliopi Azariadi
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece (Nikolaos Gatselis, Aristea Bellou, Eirini I. Rigopoulou, Kalliopi Azariadi, George N. Dalekos)
| | - Melina Kavousanaki
- Department of Internal Medicine, Venizeleion Hospital, Heraklion, Crete, Greece (Evangelos Thalassinos, Melina Kavousanaki)
| | - Emmanuel Digenakis
- Department of Gastroenterology and Hepatology, University Hospital of Heraklion Crete, Greece (Dimitrios N. Samonakis, George Demetriou, Emmanuel Digenakis, Elias A. Kouroumalis)
| | - Themistoklis Vassiliadis
- 3 Department of Internal Medicine, Papageorgiou General Hospital, Aristotle University of Thessaloniki, Greece (Aristea Bellou, Polyxeni Kevrekidou, Themistoklis Vassiliadis)
| | - Elias A Kouroumalis
- Department of Gastroenterology and Hepatology, University Hospital of Heraklion Crete, Greece (Dimitrios N. Samonakis, George Demetriou, Emmanuel Digenakis, Elias A. Kouroumalis)
| | - George N Dalekos
- Department of Medicine and Research Laboratory of Internal Medicine, National Expertise Center of Greece in Autoimmune Liver Diseases, General University Hospital of Larissa, Greece (Nikolaos Gatselis, Aristea Bellou, Eirini I. Rigopoulou, Kalliopi Azariadi, George N. Dalekos)
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11
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Nathwani R, Mullish B, Kockerling D, Cole A, Selvapatt N, Dhar A. Review of Rifaximin: A Summary of the Current Evidence and Benefits Beyond Licensed Use. EUROPEAN MEDICAL JOURNAL 2021. [DOI: 10.33590/emj/21-00026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
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.
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Affiliation(s)
- Rooshi Nathwani
- Liver Unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, UK
| | - Benjamin Mullish
- Liver Unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, UK
| | - David Kockerling
- Liver Unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, UK
| | - Alexander Cole
- Liver Unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, UK
| | - Nowlan Selvapatt
- Liver Unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, UK
| | - Ameet Dhar
- Liver Unit/Division of Digestive Diseases, Department of Metabolism, Digestion and Reproduction, Imperial College London, UK
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12
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Caraceni P, Vargas V, Solà E, Alessandria C, de Wit K, Trebicka J, Angeli P, Mookerjee RP, Durand F, Pose E, Krag A, Bajaj JS, Beuers U, Ginès P, for the Liverhope Consortium JuanolaAdriàNapoleoneLauraCarolMartaAvitabileEmmaThuAnn MaCerveraMartaPérezMartinaBelén Rubio‐GarciaAnaArdiacaAliciaVivesAdrianaPichJuditFabrellasNúriaZaccheriniGiacomoChiappaMaria TeresaJiménezCésarPalacioEsterCampionDanielaLanzillottiTommasoPianoSalvatoreNicolaoGeaUschnerFrankGraf_DirmeierSabineFrancozClaireRouxOlivierEsnaultVanessaHelderJeltjeAbanMaritesKazankovKonstantinKorenjakMarkoKamathPatrickAbraldesJuan G.WatsonHugh, Napoleone L, Carol M, Avitabile E, Thu AM, Cervera M, Pérez M, Belén Rubio‐Garcia A, Ardiaca A, Vives A, Pich J, Fabrellas N, Zaccherini G, Chiappa MT, Jiménez C, Palacio E, Campion D, Lanzillotti T, Piano S, Nicolao G, Uschner F, Graf_Dirmeier S, Francoz C, Roux O, Esnault V, Helder J, Aban M, Kazankov K, Korenjak M, Kamath P, Abraldes JG, Watson H. The Use of Rifaximin in Patients With Cirrhosis. Hepatology 2021; 74:1660-1673. [PMID: 33421158 PMCID: PMC8518409 DOI: 10.1002/hep.31708] [Citation(s) in RCA: 76] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/10/2020] [Accepted: 12/02/2020] [Indexed: 12/12/2022]
Abstract
Rifaximin is an oral nonsystemic antibiotic with minimal gastrointestinal absorption and broad-spectrum antibacterial activity covering both gram-positive and gram-negative organisms. Rifaximin is currently used worldwide in patients with cirrhosis for preventing recurrent HE because its efficacy and safety have been proven by large randomized clinical trials. In the last decade, experimental and clinical evidence suggest that rifaximin could have other beneficial effects on the course of cirrhosis by modulating the gut microbiome and affecting the gut-liver axis, which in turn can interfere with major events of the pathophysiological cascade underlying decompensated cirrhosis, such as systemic inflammatory syndrome, portal hypertension, and bacterial infections. However, the use of rifaximin for prevention or treatment of other complications, including spontaneous bacterial peritonitis or other bacterial infections, is not accepted because evidence by clinical trials is still very weak. The present review deals in the first part with the potential impact of rifaximin on pathogenic mechanisms in liver diseases, whereas in the second part, its clinical effects are critically discussed. It clearly emerges that, because of its potential activity on multiple pathogenic events, the efficacy of rifaximin in the prevention or management of complications other than HE deserves to be investigated extensively. The results of double-blinded, adequately powered randomized clinical trials assessing the effect of rifaximin, alone or in combination with other drugs, on hard clinical endpoints, such as decompensation of cirrhosis, acute-on-chronic liver failure, and mortality, are therefore eagerly awaited.
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Affiliation(s)
- Paolo Caraceni
- University of BolognaUniversity Hospital S. Orsola‐Malpighi di BolognaBolognaItaly
| | - Victor Vargas
- Hospital Vall d’HebronUniversitat Autònoma de BarcelonaCIEREHDBarcelonaCataloniaSpain
| | - Elsa Solà
- Hospital Clinic of BarcelonaUniversity of BarcelonaIDIBAPSCIBEReHDBarcelonaCataloniaSpain
| | - Carlo Alessandria
- Division of Gastroenterology and HepatologyCittà della Salute e della Scienza HospitalUniversity of TorinoTurinItaly
| | - Koos de Wit
- Amsterdam University Medical CentersAmsterdamthe Netherlands
| | - Jonel Trebicka
- Goethe‐University ‐ Frankfurt am MainFrankfurt am MainGermany,EF‐CLIFBarcelonaCataloniaSpain
| | | | | | | | - Elisa Pose
- Hospital Clinic of BarcelonaUniversity of BarcelonaIDIBAPSCIBEReHDBarcelonaCataloniaSpain
| | - Aleksander Krag
- Department of Gastroenterology and HepatologyOdense University HospitalOdenseDenmark,Institute of Clinical ResearchUniversity of Southern DenmarkOdenseDenmark
| | | | - Ulrich Beuers
- Amsterdam University Medical CentersAmsterdamthe Netherlands
| | - Pere Ginès
- Hospital Clinic of BarcelonaUniversity of BarcelonaIDIBAPSCIBEReHDBarcelonaCataloniaSpain
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13
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Pörner D, Von Vietinghoff S, Nattermann J, Strassburg CP, Lutz P. Advances in the pharmacological management of bacterial peritonitis. Expert Opin Pharmacother 2021; 22:1567-1578. [PMID: 33878993 DOI: 10.1080/14656566.2021.1915288] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Introduction: Bacterial peritonitis is an infection with high mortality if not treated immediately. In the absence of an intraabdominal source of infection, bacterial peritonitis may arise in patients with liver cirrhosis, in patients on peritoneal dialysis (PD) for end-stage renal disease or in patients with tuberculosis. In patients with cirrhosis, bacterial peritonitis may trigger acute on chronic liver failure with substantial mortality despite optimal treatment. In patients on PD, peritonitis may make continuation of PD impossible, necessitating the switch to hemodialysis.Areas covered: Recovery from peritonitis and prevention of complications depend on timely pharmacological management. Challenges are the broad microbiological spectrum with growing rates of antimicrobial resistance, the underlying chronic liver or kidney failure and high rates of relapse. The authors provide a review of predisposing conditions, diagnosis, and prevention of bacterial peritonitis with a particular focus on the pharmacological management.Expert opinion: Diagnosis of the type of bacterial peritonitis is essential to pharmacological management. In patients with spontaneous bacterial peritonitis, broad-spectrum antibiotics should be given intravenously in conjunction with albumin. In patients on PD, antibiotic therapy should be preferably applied intraperitoneally with empirical coverage of gram-positive and gram-negative bacteria. Secondary peritonitis usually requires surgical or interventional treatment.
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Affiliation(s)
- Daniel Pörner
- Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
| | - Sibylle Von Vietinghoff
- Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
- German Center for Infection Research (DZIF), University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
| | - Christian P Strassburg
- Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
- German Center for Infection Research (DZIF), University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
| | - Philipp Lutz
- Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
- German Center for Infection Research (DZIF), University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
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14
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Fernández J, Piano S, Bartoletti M, Wey EQ. Management of bacterial and fungal infections in cirrhosis: The MDRO challenge. J Hepatol 2021; 75 Suppl 1:S101-S117. [PMID: 34039482 DOI: 10.1016/j.jhep.2020.11.010] [Citation(s) in RCA: 91] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 12/12/2022]
Abstract
Bacterial infections are frequent in cirrhotic patients with acute decompensation or acute-on-chronic liver failure and can complicate the clinical course. Delayed diagnosis and inappropriate empirical treatments are associated with poor prognosis and increased mortality. Fungal infections are much less frequent, usually nosocomial and associated with extremely high short-term mortality. Early diagnosis and adequate empirical treatment of infections is therefore key in the management of these patients. In recent decades, antibiotic resistance has become a major worldwide problem in patients with cirrhosis, warranting a more complex approach to antibiotic treatment that includes the use of broad-spectrum antibiotics, new administration strategies, novel drugs and de-escalation policies. Herein, we review epidemiological changes, the main types of multidrug-resistant organisms, mechanisms of resistance, new rapid diagnostic tools and currently available therapeutic options for bacterial and fungal infections in cirrhosis.
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Affiliation(s)
- Javier Fernández
- Liver ICU, Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain; European Foundation of Chronic Liver Failure (EF-Clif), Barcelona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHED), ISCIII, Spain.
| | - Salvatore Piano
- Unit of Internal Medicine and Hepatology, Department of Medicine - DIMED, University of Padova, Padova, Italy
| | - Michele Bartoletti
- Infectious Disease Unit- Department of Medical and Surgical Sciences, Alma Mater Studiorum, University of Bologna, Bologna, Italy
| | - Emmanuel Q Wey
- ILDH, Division of Medicine, University College London Medical School, London, United Kingdom; Centre for Clinical Microbiology, Division of Infection & Immunity, UCL, London, United Kingdom; Department of Infection, Royal Free London NHS Trust London, United Kingdom
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15
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Moreno-Gonzalez M, Beraza N. The Role of the Microbiome in Liver Cancer. Cancers (Basel) 2021; 13:2330. [PMID: 34066064 PMCID: PMC8150469 DOI: 10.3390/cancers13102330] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 04/30/2021] [Accepted: 05/03/2021] [Indexed: 12/11/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common malignancy occuring in the context of chronic liver disease and is one of the main causes of cancer-derived death worldwide. The lack of effective treatments, together with the poor prognosis, underlines the urge to develop novel and multidisciplinary therapeutics. An increasing body of evidence shows that HCC associates with changes in intestinal microbiota abundance and composition as well as with impaired barrier function, leading to the release of bacteria and their metabolites to the liver. These factors trigger a cascade of inflammatory responses contributing to liver cirrhosis and constituting an ideal environment for the progression of HCC. Interestingly, the use of bacteriotherapy in human and preclinical studies of chronic liver disease and HCC has been shown to successfully modify the microbiota composition, reducing overall inflammation and fibrosis. In this review, we explore the existing knowledge on the characterisation of the intestinal microbial composition in humans and experimental murine chronic liver disease and HCC, as well as the use of antibiotics and bacteriotherapy as therapeutic options.
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Affiliation(s)
- Mar Moreno-Gonzalez
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK;
| | - Naiara Beraza
- Gut Microbes and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK;
- Food Innovation and Health Institute Strategic Programme, Quadram Institute Bioscience, Norwich Research Park, Norwich NR4 7UQ, UK
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16
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Trebicka J, Bork P, Krag A, Arumugam M. Utilizing the gut microbiome in decompensated cirrhosis and acute-on-chronic liver failure. Nat Rev Gastroenterol Hepatol 2021; 18:167-180. [PMID: 33257833 DOI: 10.1038/s41575-020-00376-3] [Citation(s) in RCA: 110] [Impact Index Per Article: 27.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/07/2020] [Indexed: 12/12/2022]
Abstract
The human gut microbiome has emerged as a major player in human health and disease. The liver, as the first organ to encounter microbial products that cross the gut epithelial barrier, is affected by the gut microbiome in many ways. Thus, the gut microbiome might play a major part in the development of liver diseases. The common end stage of liver disease is decompensated cirrhosis and the further development towards acute-on-chronic liver failure (ACLF). These conditions have high short-term mortality. There is evidence that translocation of components of the gut microbiota, facilitated by different pathogenic mechanisms such as increased gut epithelial permeability and portal hypertension, is an important driver of decompensation by induction of systemic inflammation, and thereby also ACLF. Elucidating the role of the gut microbiome in the aetiology of decompensated cirrhosis and ACLF deserves further investigation and improvement; and might be the basis for development of diagnostic and therapeutic strategies. In this Review, we focus on the possible pathogenic, diagnostic and therapeutic role of the gut microbiome in decompensation of cirrhosis and progression to ACLF.
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Affiliation(s)
- Jonel Trebicka
- Translational Hepatology, Department of Internal Medicine I, Goethe University Clinic Frankfurt, Frankfurt, Germany. .,European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain. .,Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark. .,Institute for Bioengineering of Catalonia, Barcelona, Spain.
| | - Peer Bork
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Aleksander Krag
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark
| | - Manimozhiyan Arumugam
- Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark. .,Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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17
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Shamseya MM, Madkour MA. Rifaximin: A reasonable alternative for norfloxacin in the prevention of spontaneous bacterial peritonitis in patients with HCV-related liver cirrhosis. ALEXANDRIA JOURNAL OF MEDICINE 2019. [DOI: 10.1016/j.ajme.2015.09.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Affiliation(s)
- Mohammed M. Shamseya
- Department of Clinical and Experimental Internal Medicine, Medical Research Institute, University of Alexandria, EgyptDepartment of Clinical and Experimental Internal Medicine, Medical Research Institute, University of Alexandria, Egypt
| | - Marwa A. Madkour
- Department of Clinical and Experimental Internal Medicine, Medical Research Institute, University of Alexandria, EgyptDepartment of Clinical and Experimental Internal Medicine, Medical Research Institute, University of Alexandria, Egypt
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18
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Nonalcoholic Fatty Liver Disease: Basic Pathogenetic Mechanisms in the Progression From NAFLD to NASH. Transplantation 2019; 103:e1-e13. [DOI: 10.1097/tp.0000000000002480] [Citation(s) in RCA: 326] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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19
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Dirchwolf M, Marciano S, Martínez J, Ruf AE. Unresolved issues in the prophylaxis of bacterial infections in patients with cirrhosis. World J Hepatol 2018; 10:892-897. [PMID: 30631393 PMCID: PMC6323518 DOI: 10.4254/wjh.v10.i12.892] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Revised: 09/05/2018] [Accepted: 10/11/2018] [Indexed: 02/06/2023] Open
Abstract
Bacterial infections are highly prevalent and a frequent cause of hospitalization and short-term mortality in patients with cirrhosis. Due to their negative impact on survival, antibiotic prophylaxis for bacterial infections in high-risk subgroups of patients with cirrhosis has been the standard of care for decades. Patients with prophylaxis indications include those at risk for a first episode of spontaneous bacterial peritonitis (SBP) due to a low ascitic fluid protein count and impaired liver and kidney function, patients with a prior episode of SBP and those with an episode of gastrointestinal bleeding. Only prophylaxis due to gastrointestinal bleeding has a known and short-time duration. All other indications imply long-lasting exposure to antibiotics - once the threshold requirement for initiating prophylaxis is met - without standardized criteria for re-assessing antibiotic interruption. Despite the fact that the benefit of antibiotic prophylaxis in reducing bacterial infections episodes and mortality has been thoroughly reported, the extended use of antibiotics in patients with cirrhosis has also had negative consequences, including the emergence of multi-drug resistant bacteria. Currently, it is not clear whether restricting the use of broad and fixed antibiotic regimens, tailoring the choice of antibiotics to local bacterial epidemiology or selecting non-antibiotic strategies will be the preferred antibiotic prophylaxis strategy for patients with cirrhosis in the future.
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Affiliation(s)
- Melisa Dirchwolf
- Unidad de Hígado, Hospital Privado de Rosario, Rosario 2000, Argentina
| | - Sebastián Marciano
- Unidad de Hígado, and Departamento de Investigación del Hospital Italiano de Buenos Aires, Buenos Aires 1424, Argentina
| | - José Martínez
- Unidad de Hígado, Hospital Privado de Rosario, Rosario 2000, Argentina
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20
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Flamm SL, Mullen KD, Heimanson Z, Sanyal AJ. Rifaximin has the potential to prevent complications of cirrhosis. Therap Adv Gastroenterol 2018; 11:1756284818800307. [PMID: 30283499 PMCID: PMC6166307 DOI: 10.1177/1756284818800307] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 08/09/2018] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Cirrhosis-related complications are associated with poor prognosis. With our analyses, we examined the potential benefit of rifaximin in reducing the risk of developing cirrhosis-related complications. METHODS Adults with cirrhosis and hepatic encephalopathy (HE) in remission were randomly assigned to receive rifaximin 550 mg twice daily or placebo for 6 months with concomitant lactulose permitted. Post hoc analyses examined time to cirrhosis-related complications (HE, spontaneous bacterial peritonitis (SBP), variceal bleeding, acute kidney injury/hepatorenal syndrome). Subgroup analyses evaluated efficacy for select baseline disease characteristics. RESULTS Of patients receiving rifaximin (n = 140) and placebo (n = 159), 53.6% and 49.1%, respectively, had baseline Model for End-Stage Liver Disease (MELD) score ⩾ 12 and international normalized ratio (INR) ⩾ 1.2. Baseline ascites was observed in 36.4% (rifaximin) and 34.6% (placebo) of patients. In patients with MELD score ⩾ 12 and INR ⩾ 1.2, rifaximin reduced the relative risk (RR) of any first complication experienced during trial by 59% [hazard ratio (HR) = 0.41, 95% confidence interval (CI): 0.25-0.67; p < 0.001] versus placebo. For patients with baseline ascites, rifaximin reduced the RR of any first complication experienced during trial by 42% versus placebo (HR = 0.58, 95% CI: 0.34-1.0; p = 0.045). For some subgroups, there was a decrease in RR of complications of SBP, variceal bleeding, and acute kidney injury/hepatorenal syndrome with rifaximin versus placebo, although there were few events reported in the study. CONCLUSION Rifaximin may reduce the incidence of cirrhosis-related complications and the recurrence of overt HE.[ClinicalTrials.gov identifier: NCT00298038.].
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21
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KASL clinical practice guidelines for liver cirrhosis: Ascites and related complications. Clin Mol Hepatol 2018; 24:230-277. [PMID: 29991196 PMCID: PMC6166105 DOI: 10.3350/cmh.2018.1005] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Accepted: 04/06/2018] [Indexed: 02/07/2023] Open
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Engelmann C, Berg T. Management of Infectious Complications Associated with Acute-on-Chronic Liver Failure. Visc Med 2018; 34:261-268. [PMID: 30345283 DOI: 10.1159/000491107] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Introduction Acute-on-chronic liver failure (ACLF) is associated with a high susceptibility to infections leading to complications and poor prognosis. The sensitized immune system overwhelmingly responds to invading bacteria leading to organ damage. After resolution of infection or prolonged disease duration, the phagocytic system becomes irresponsive with a reduced bacterial clearance capacity promoting secondary infection. Methods This review focuses on the best management strategies for patients with ACLF and infections. Using the following terms, an extensive literature research on the Medline database was performed: 'acute-on-chronic liver failure', 'infection', 'ACLF', 'bacteria', 'multi-resistance'. Results Analysis of the literature confirmed that delayed diagnosis and treatment of infections in patients with ACLF results in a poor prognosis. Patients with ACLF should be considered as having a potential infection and should undergo a complete screening for sepsis. Once biochemical analysis indicates a potential infection, such as abnormal levels of C-reactive protein and procalcitonin, antibiotic treatment should be initiated immediately without microbiological culture results. For community-acquired infections third-generation cephalosporins are still the first choice, whereas in the nosocomial setting antibiotics with broader spectrum, such as piperacillin/combactam or carbapenems ± glycopeptides, are preferred. The patient should be re-assessed 48 h after treatment initiation in order to tailor the treatment. Non-response is suspicious, likely due to bacterial resistance or fungal infection, which should be considered when choosing further treatment strategies. Albumin substitution to prevent hepatorenal syndrome and to improve patients' outcome is mandatory in patients with spontaneous bacterial peritonitis. Prophylactic antibiotic therapy is suitable to prevent infections in high-risk patients. Conclusion The screening for infections and its treatment is an essential part of managing patients with ACLF. In order to improve patients' prognosis, antibiotic treatment should be initiated once an infection is suspected. However, preventive strategies are already established and should be applied according to the guidelines.
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Affiliation(s)
- Cornelius Engelmann
- Section Hepatology, Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
| | - Thomas Berg
- Section Hepatology, Department of Gastroenterology and Rheumatology, University Hospital Leipzig, Leipzig, Germany
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23
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Suzuki K, Endo R, Takikawa Y, Moriyasu F, Aoyagi Y, Moriwaki H, Terai S, Sakaida I, Sakai Y, Nishiguchi S, Ishikawa T, Takagi H, Naganuma A, Genda T, Ichida T, Takaguchi K, Miyazawa K, Okita K. Efficacy and safety of rifaximin in Japanese patients with hepatic encephalopathy: A phase II/III, multicenter, randomized, evaluator-blinded, active-controlled trial and a phase III, multicenter, open trial. Hepatol Res 2018; 48:411-423. [PMID: 29235218 DOI: 10.1111/hepr.13045] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2017] [Revised: 12/06/2017] [Accepted: 12/08/2017] [Indexed: 02/06/2023]
Abstract
AIM The efficacy and safety of rifaximin in the treatment of hepatic encephalopathy (HE) are widely known, but they have not been confirmed in Japanese patients with HE. Thus, two prospective, randomized studies (a phase II/III study and a phase III study) were carried out. METHODS Subjects with grade I or II HE and hyperammonemia were enrolled. The phase II/III study, which was a randomized, evaluator-blinded, active-comparator, parallel-group study, was undertaken at 37 institutions in Japan. Treatment periods were 14 days. Eligible patients were randomized to the rifaximin group (1200 mg/day) or the lactitol group (18-36 g/day). The phase III study was carried out in the same patients previously enrolled in the phase II/III study, and they were all treated with rifaximin (1200 mg/day) for 10 weeks. RESULTS In the phase II/III study, 172 patients were enrolled. Blood ammonia (B-NH3 ) concentration was significantly improved in the rifaximin group, but the difference between the two groups was not significant. The portal systemic encephalopathy index (PSE index), including HE grade, was significantly improved in both groups. In the phase III study, 87.3% of enrolled patients completed the treatment. The improved B-NH3 concentration and PSE index were well maintained from the phase II/III study during the treatment period of the phase III study. Adverse drug reactions (ADRs) were seen in 13.4% of patients who received rifaximin, but there were no severe ADRs leading to death. CONCLUSION The efficacy of rifaximin is sufficient and treatment is well tolerated in Japanese patients with HE and hyperammonemia.
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Affiliation(s)
- Kazuyuki Suzuki
- Department of Nutritional Science, Morioka University, Iwate, Japan
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Ryujin Endo
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Yasuhiro Takikawa
- Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan
| | - Fuminori Moriyasu
- Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan
| | - Yutaka Aoyagi
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
| | - Hisataka Moriwaki
- Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Shuji Terai
- Division of Gastroenterology and Hepatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Isao Sakaida
- Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Yoshiyuki Sakai
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Shuhei Nishiguchi
- Division of Hepatobiliary and Pancreatic Disease, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan
| | - Toru Ishikawa
- Department of Gastroenterology, Saiseikai Niigata Daini Hospital, Niigata, Japan
| | - Hitoshi Takagi
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Atsushi Naganuma
- Department of Gastroenterology, National Hospital Organization Takasaki General Medical Center, Takasaki, Japan
| | - Takuya Genda
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Takafumi Ichida
- Department of Gastroenterology and Hepatology, Juntendo University Shizuoka Hospital, Shizuoka, Japan
| | - Koichi Takaguchi
- Department of Internal Medicine, Kagawa Prefectural Central Hospital, Takamatsu, Japan
| | - Katsuhiko Miyazawa
- Clinical Development Department, ASKA Pharmaceutical Co., Ltd, Tokyo, Japan
| | - Kiwamu Okita
- Shunan Memorial Hospital/Yamaguchi University, Yamaguchi, Japan
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Zhao J, Zhang Y, Tian H, Sun H, Liang C. Letter: the efficacy and safety of rifaximin for the prophylaxis of spontaneous bacterial peritonitis in cirrhotic patients. Aliment Pharmacol Ther 2018; 47:697-698. [PMID: 29417632 DOI: 10.1111/apt.14496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- J Zhao
- Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Y Zhang
- Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - H Tian
- Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - H Sun
- Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - C Liang
- Changzheng Hospital, Second Military Medical University, Shanghai, China
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Sinkala E, Zyambo K, Besa E, Kaonga P, Nsokolo B, Kayamba V, Vinikoor M, Zulu R, Bwalya M, Foster GR, Kelly P. Rifaximin Reduces Markers of Inflammation and Bacterial 16S rRNA in Zambian Adults with Hepatosplenic Schistosomiasis: A Randomized Control Trial. Am J Trop Med Hyg 2018; 98:1152-1158. [PMID: 29436337 PMCID: PMC5928821 DOI: 10.4269/ajtmh.17-0637] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Cirrhosis is the dominant cause of portal hypertension globally but may be overshadowed by hepatosplenic schistosomiasis (HSS) in the tropics. In Zambia, schistosomiasis seroprevalence can reach 88% in endemic areas. Bacterial translocation (BT) drives portal hypertension in cirrhosis contributing to mortality but remains unexplored in HSS. Rifaximin, a non-absorbable antibiotic may reduce BT. We aimed to explore the influence of rifaximin on BT, inflammation, and fibrosis in HSS. In this phase II open-label trial (ISRCTN67590499), 186 patients with HSS in Zambia were evaluated and 85 were randomized to standard care with or without rifaximin for 42 days. Changes in markers of inflammation, BT, and fibrosis were the primary outcomes. BT was measured using plasma 16S rRNA, lipopolysaccharide-binding protein, and lipopolysaccharide, whereas hyaluronan was used to measure fibrosis. Tumor necrosis factor receptor 1 (TNFR1) and soluble cluster of differentiation 14 (sCD14) assessed inflammation. 16S rRNA reduced from baseline (median 146 copies/µL, interquartile range [IQR] 9, 537) to day 42 in the rifaximin group (median 63 copies/µL, IQR 12, 196), P < 0.01. The rise in sCD14 was lower (P < 0.01) in the rifaximin group (median rise 122 ng/mL, IQR-184, 783) than in the non-rifaximin group (median rise 832 ng/mL, IQR 530, 967). TNFR1 decreased (P < 0.01) in the rifaximin group (median -39 ng/mL IQR-306, 563) but increased in the non-rifaximin group (median 166 ng/mL, IQR 3, 337). Other markers remained unaffected. Rifaximin led to a reduction of inflammatory markers and bacterial 16S rRNA which may implicate BT in the inflammation in HSS.
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Affiliation(s)
- Edford Sinkala
- Department of Internal Medicine, Tropical Gastroenterology & Nutritional Group, University of Zambia, Lusaka, Zambia.,Department of Internal Medicine, University Teaching Hospital, Lusaka, Zambia
| | - Kanekwa Zyambo
- Department of Internal Medicine, Tropical Gastroenterology & Nutritional Group, University of Zambia, Lusaka, Zambia
| | - Ellen Besa
- Department of Internal Medicine, Tropical Gastroenterology & Nutritional Group, University of Zambia, Lusaka, Zambia
| | - Patrick Kaonga
- Department of Internal Medicine, Tropical Gastroenterology & Nutritional Group, University of Zambia, Lusaka, Zambia.,Department of Internal Medicine, University Teaching Hospital, Lusaka, Zambia
| | - Bright Nsokolo
- Department of Internal Medicine, Tropical Gastroenterology & Nutritional Group, University of Zambia, Lusaka, Zambia.,Department of Internal Medicine, University Teaching Hospital, Lusaka, Zambia
| | - Violet Kayamba
- Department of Internal Medicine, Tropical Gastroenterology & Nutritional Group, University of Zambia, Lusaka, Zambia.,Department of Internal Medicine, University Teaching Hospital, Lusaka, Zambia
| | - Michael Vinikoor
- Centre for Infectious Disease Research in Zambia, Lusaka, Zambia.,Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - Rabison Zulu
- Paediatric Centre of Excellence Laboratory, University Teaching Hospital, Lusaka, Zambia
| | - Martin Bwalya
- Paediatric Centre of Excellence Laboratory, University Teaching Hospital, Lusaka, Zambia
| | - Graham R Foster
- Blizard Institute, Barts & The London School of Medicine, Queen Mary University of London, London, United Kingdom
| | - Paul Kelly
- Paediatric Centre of Excellence Laboratory, University Teaching Hospital, Lusaka, Zambia.,Department of Internal Medicine, Tropical Gastroenterology & Nutritional Group, University of Zambia, Lusaka, Zambia.,Department of Internal Medicine, University Teaching Hospital, Lusaka, Zambia
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Gómez-Hurtado I, Gimenez P, García I, Zapater P, Francés R, González-Navajas JM, Manichanh C, Ramos JM, Bellot P, Guarner F, Such J. Norfloxacin is more effective than Rifaximin in avoiding bacterial translocation in an animal model of cirrhosis. Liver Int 2018; 38:295-302. [PMID: 28834270 DOI: 10.1111/liv.13551] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2017] [Accepted: 08/09/2017] [Indexed: 02/13/2023]
Abstract
BACKGROUND & AIMS Norfloxacin administration is useful in preventing bacterial infections in cirrhosis but associated to the generation of resistant species. Rifaximin is known to reach high concentrations in the intestinal lumen without generating relevant resistance in the intestinal flora. Our aim was to compare the effect of Norfloxacin and Rifaximin on intestinal flora composition, bacterial translocation and survival in cirrhotic rats. METHODS Cirrhosis was induced in rats by oral administration of CCl4 . Animals were divided into three groups: only CCl4 (group I, n = 10); CCl4 + Norfloxacin (group II, n = 17) and CCl4 + Rifaximin (group III, n = 14). Gut bacterial composition, bacterial translocation and cytokine levels were measured. RESULTS Forty-one rats were finally included. The incidence of viable and non-viable bacterial translocation was significantly reduced in animals receiving Norfloxacin; Rifaximin also decreased the incidence of viable and non-viable bacterial translocation, but did not reach statistical significance. Serum TNF-α levels were significantly lower in antibiotic groups. Norfloxacin modified intestinal microbiota, depleting significantly more pathobionts than Rifaximin. CONCLUSION Norfloxacin is more effective than Rifaximin in preventing bacterial translocation in rats with cirrhosis probably because of its capacity to reduce pathobionts from intestinal microbiota.
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Affiliation(s)
- Isabel Gómez-Hurtado
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
| | - Paula Gimenez
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
| | - Irma García
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
| | - Pedro Zapater
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
- Departamento Farmacología Clínica, UMH, Alicante, Spain
| | - Rubén Francés
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
- Departamento Medicina Clínica, UMH, Alicante, Spain
| | - José M González-Navajas
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
| | - Chaysavanh Manichanh
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Departamento Gastroenterología, VHIR, Barcelona, Spain
| | - José M Ramos
- Departamento Medicina Interna, HGUA, Alicante, Spain
| | - Pablo Bellot
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL-FISABIO), Alicante, Spain
| | - Francisco Guarner
- CIBERehd, Instituto Salud Carlos III, Madrid, Spain
- Departamento Gastroenterología, VHIR, Barcelona, Spain
| | - José Such
- Cleveland Clinic, Digestive Disease institute, Abu Dhabi, UAE
- Lerner School of Medicine, Case Western Reserve University, Cleveland, OH, USA
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Goel A, Nguyen MH. Editorial: rifaximin-a kick in the gut for spontaneous bacterial peritonitis? Authors' reply. Aliment Pharmacol Ther 2018; 47:303. [PMID: 29265465 DOI: 10.1111/apt.14450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- A Goel
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
| | - M H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
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Goel A, Rahim U, Nguyen LH, Stave C, Nguyen MH. Systematic review with meta-analysis: rifaximin for the prophylaxis of spontaneous bacterial peritonitis. Aliment Pharmacol Ther 2017; 46:1029-1036. [PMID: 28994123 DOI: 10.1111/apt.14361] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Revised: 06/12/2017] [Accepted: 09/14/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND The primary and secondary prevention of spontaneous bacterial peritonitis (SBP) is recommended in high-risk patients with cirrhosis. Several studies evaluating the efficacy of rifaximin for SBP prophylaxis have yielded conflicting results. Rifaximin has the potential advantage of preventing bacterial overgrowth and translocation without the systemic side effects of broad-spectrum antibiotics. AIM To evaluate the efficacy of rifaximin in the primary and secondary prevention of SBP. METHODS A literature search using five databases was performed to identify studies on the association between rifaximin and SBP. We performed two meta-analyses: (1) rifaximin compared to systemic antibiotics and (2) rifaximin compared to no antibiotics. Random-effect modelling was conducted to determine overall pooled estimates and 95% confidence intervals (CIs). RESULTS Five studies with 555 patients (295 rifaximin, 260 systemic antibiotics) compared rifaximin with systemic antibiotics. The pooled odds ratio (OR) for SBP was 0.45 (95% CI 0.16-1.27; P = .13) in patients receiving rifaximin and strengthened on sensitivity analysis (OR 0.38, 95% CI 0.19-0.76, P = .01). In the analysis comparing rifaximin with no antibiotics, there were five studies with 784 patients (186 rifaximin, 598 no antibiotics). The OR for SBP was 0.34 (95% CI 0.11-0.99; P < .05) in patients receiving rifaximin. In subgroup analysis, rifaximin reduced the risk of SBP by 47% compared to no antibiotics for primary prophylaxis and by 74% compared to systemic antibiotics for secondary prophylaxis. CONCLUSION Rifaximin may be effective in preventing SBP in patients with cirrhosis and ascites compared to systemically absorbed antibiotics and compared to placebo.
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Affiliation(s)
- A Goel
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
| | - U Rahim
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
| | - L H Nguyen
- Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA, USA
| | - C Stave
- Lane Medical Library, Stanford University School of Medicine, Stanford, CA, USA
| | - M H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, CA, USA
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Ibrahim ES, Alsebaey A, Zaghla H, Moawad Abdelmageed S, Gameel K, Abdelsameea E. Long-term rifaximin therapy as a primary prevention of hepatorenal syndrome. Eur J Gastroenterol Hepatol 2017; 29:1247-1250. [PMID: 28902040 DOI: 10.1097/meg.0000000000000967] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Hepatorenal syndrome (HRS) is a severe complication of liver cirrhosis, with poor survival. Rifaximin is a gut-selective broad-spectrum antibiotic. AIM The aim of this study was to evaluate the role of rifaximin as a primary prevention of HRS. PATIENTS AND METHODS Eighty patients with liver cirrhosis and ascites were enrolled. They were randomized into two groups: control (n=40) and rifaximin group (n=40). Baseline liver function tests, renal function tests, complete blood count, international normalized ratio, urine analysis, and abdominal ultrasonography were carried out. Rifaximin 550 mg was administered twice daily for 12 weeks. Renal functions were measured every 4 weeks with monitoring of HRS occurrence and possible precipitating factor. RESULTS Both groups were matched for age, sex, virology, serum bilirubin, serum albumin, aspartate aminotransferase, alanine aminotransferase, hemoglobin, white blood cells, platelets, international normalized ratio, potassium, and Child-Pugh score. In contrast to the rifaximin group, the control group showed statistically significant serial blood urea nitrogen (18.84±7.17, 19.85±6.10, 21.54±4.79, and 22.96±5.82 mg/dl; P=0.001) and serum creatinine (0.94±0.25, 1.02±0.24, 1.12±0.16, and 1.21±0.17 mg/dl; P=0.001) levels. The overall blood urea nitrogen and serum creatinine change was statistically higher in the control group than the rifaximin group (20.8 vs. 18.24 mg/dl and 1.07 vs. 0.99 mg/dl, respectively). HRS developed more in the control group than the rifaximin group [9 (22.5%) vs. 2 (5%); P=0.048]. In both groups, HRS was precipitated by spontaneous bacterial peritonitis mainly and large volume paracentesis. The Child-Pugh score, control group, baseline serum sodium, and creatinine were predictors of HRS. CONCLUSION Rifaximin may be useful as a primary prevention of HRS.
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Affiliation(s)
- El-Sayed Ibrahim
- Departments of aHepatology and Gastroenterology bClinical Biochemistry, National Liver Institute, Menoufia University, Shebeen El-Kom, Menoufia Governorate, Egypt
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Austrian consensus guidelines on the management and treatment of portal hypertension (Billroth III). Wien Klin Wochenschr 2017; 129:135-158. [PMID: 29063233 PMCID: PMC5674135 DOI: 10.1007/s00508-017-1262-3] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 08/22/2017] [Indexed: 12/14/2022]
Abstract
The Billroth III guidelines were developed during a consensus meeting of the Austrian Society of Gastroenterology and Hepatology (ÖGGH) and the Austrian Society of Interventional Radiology (ÖGIR) held on 18 February 2017 in Vienna. Based on international guidelines and considering recent landmark studies, the Billroth III recommendations aim to help physicians in guiding diagnostic and therapeutic strategies in patients with portal hypertension.
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31
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Kamal F, Khan MA, Khan Z, Cholankeril G, Hammad TA, Lee WM, Ahmed A, Waters B, Howden CW, Nair S, Satapathy SK. Rifaximin for the prevention of spontaneous bacterial peritonitis and hepatorenal syndrome in cirrhosis: a systematic review and meta-analysis. Eur J Gastroenterol Hepatol 2017; 29:1109-1117. [PMID: 28763340 DOI: 10.1097/meg.0000000000000940] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Prophylactic antibiotics have been recommended in patients with a previous history of spontaneous bacterial peritonitis (SBP). Recently, there has been interest in the use of rifaximin for the prevention of SBP and hepatorenal syndrome (HRS). We conducted a meta-analysis to evaluate this association of rifaximin. We searched several databases from inception through 24 January 2017, to identify comparative studies evaluating the effect of rifaximin on the occurrence of SBP and HRS. We performed predetermined subgroup analyses based on the type of control group, design of the study, and type of prophylaxis. Pooled odds ratios (ORs) were calculated using a random effects model. We included 13 studies with 1703 patients in the meta-analysis of SBP prevention. Pooled OR [95% confidence interval (CI)] was 0.40 (95% CI: 0.22-0.73) (I=58%). On sensitivity analysis, adjusted OR was 0.29 (95% CI: 0.20-0.44) (I=0%). The results of the subgroup analysis based on type of control was as follows: in the quinolone group, pooled OR was 0.42 (95% CI: 0.14-1.25) (I=55%), and in the no antibiotic group, pooled OR was 0.40 (95% CI: 0.18-0.86) (I=64%). However, with sensitivity analysis, benefit of rifaximin was demonstrable; pooled ORs were 0.32 (95% CI: 0.17-0.63) (I=0%) and 0.28 (95% CI: 0.17-0.45) (I=0%) for the comparison with quinolones and no antibiotics, respectively. Pooled OR based on randomized controlled trials was 0.41 (95% CI: 0.22-0.75) (I=13%). For the prevention of HRS, the pooled OR was 0.25 (95% CI: 0.13-0.50) (I=0%). Rifaximin has a protective effect against the development of SBP in cirrhosis. However, the quality of the evidence as per the GRADE framework was very low. Rifaximin appeared effective for the prevention of HRS.
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Affiliation(s)
- Faisal Kamal
- aDivision of Gastroenterology and Hepatology bMethodist University Hospital Transplant Institute, University of Tennessee Health Science Center, Memphis, Tennessee cDivision of Gastroenterology and Hepatology dCarlson and Mulford Libraries, University of Toledo, Toledo, Ohio eDivision of Gastroenterology and Hepatology, Stanford University, Stanford, California, USA
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Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of worldwide cancer mortality. HCC almost exclusively develops in patients with chronic liver disease, driven by a vicious cycle of liver injury, inflammation and regeneration that typically spans decades. Increasing evidence points towards a key role of the bacterial microbiome in promoting the progression of liver disease and the development of HCC. Here, we will review mechanisms by which the gut microbiota promotes hepatocarcinogenesis, focusing on the leaky gut, bacterial dysbiosis, microbe-associated molecular patterns and bacterial metabolites as key pathways that drive cancer-promoting liver inflammation, fibrosis and genotoxicity. On the basis of accumulating evidence from preclinical studies, we propose the intestinal-microbiota-liver axis as a promising target for the simultaneous prevention of chronic liver disease progression and HCC development in patients with advanced liver disease. We will review in detail therapeutic modalities and discuss clinical settings in which targeting the gut-microbiota-liver axis for the prevention of disease progression and HCC development seems promising.
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Affiliation(s)
- Le-Xing Yu
- Department of Medicine, Columbia University, 1130 St. Nicholas Avenue, Room 926, New York, New York 10032, USA
| | - Robert F Schwabe
- Department of Medicine, Columbia University, 1130 St. Nicholas Avenue, Room 926, New York, New York 10032, USA
- Institute of Human Nutrition, 1130 St. Nicholas Avenue, Room 926, New York, New York 10032, USA
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Sidhu GS, Go A, Attar BM, Mutneja HR, Arora S, Patel SA. Rifaximin versus norfloxacin for prevention of spontaneous bacterial peritonitis: a systematic review. BMJ Open Gastroenterol 2017; 4:e000154. [PMID: 28944070 PMCID: PMC5606119 DOI: 10.1136/bmjgast-2017-000154] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2017] [Revised: 06/26/2017] [Accepted: 06/30/2017] [Indexed: 02/07/2023] Open
Abstract
Aim The aim of this systematic review is to evaluate the efficacy and safety of rifaximin in the prophylaxis of spontaneous bacterial peritonitis (SBP) as compared with norfloxacin. Methods We searched MEDLINE, CINAHL, Google Scholar and Cochrane databases from inception to January 2017. Reference lists of articles as well as conference proceedings were manually screened. We included studies that recruited patients with cirrhosis and ascites who met the criteria for primary or secondary SBP prophylaxis as defined by the European Association for the Study of the Liver and American Association for the Study of Liver Diseases. Two independent investigators reviewed the studies for eligibility, extracted the data and assessed study quality using the Cochrane risk of bias tool. The primary outcome was occurrence of SBP. Secondary outcomes included mortality and adverse events with therapy. Results Of the 435 studies identified, a total of five were included for full-text review. Four studies were eligible for the systematic review, three of which were randomised controlled trials and one was a prospective observational study. The population examined in majority of studies was primarily hepatitis C cirrhosis. The results of individual studies indicated either superior efficacy of rifaximin or no statistical difference between rifaximin and norfloxacin for SBP prophylaxis. Conclusions Moderate-quality evidence shows that long-term use of rifaximin appears to be a reasonable alternative to norfloxacin for SBP prevention in hepatitis C cirrhosis.
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Affiliation(s)
| | - Andrew Go
- University of Illinois at Chicago, Chicago, IL, USA
| | - Bashar M Attar
- Cook County Health and Hospitals System, Chicago, IL, USA
| | | | - Shilpa Arora
- Cook County Health and Hospitals System, Chicago, IL, USA
| | - Sanjay A Patel
- Cook County Health and Hospitals System, Chicago, IL, USA
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A Real-World Evaluation of Repeat Paracentesis-guided Management of Spontaneous Bacterial Peritonitis. J Clin Gastroenterol 2017; 51:278-284. [PMID: 27661968 DOI: 10.1097/mcg.0000000000000704] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND Spontaneous bacterial peritonitis (SBP) is a common infection in cirrhosis associated with high mortality. More than 20% of patients with SBP do not respond to initial antibiotics. Guidelines differ in recommendations to repeat paracentesis (retap) to confirm antibiotic efficacy. We aim to evaluate the effect of retap-guided management of SBP on antibiotic escalation and 30-day transplant-free survival. MATERIALS AND METHODS Retrospective cohort study of cirrhotic patients with SBP admitted to a single transplant center from 2010 to 2014. Patients were divided into 2 groups: retap-guided management versus no retap. Prevalence of initial antibiotic treatment failure, defined as <25% decrease in ascitic polymorphonuclear cells, and factors associated with treatment failure, antibiotic escalation and 30-day transplant-free survival were evaluated. RESULTS Out of 210 patients, 146 (age 58, 74% male, mean model for end-stage liver disease score, 25) had retap and treatment failure was noted in 28 (22%). Gram-positive bacteria accounted for 44% of all positive cultures and third-generation cepahalosporin resistance was noted in 23%. Thirty-day transplant-free survival was 72% and 62% in retap and control groups, respectively (P=0.07). Treatment failure independently doubled the 30-day mortality rate (hazard ratio: 2.15, 1.03 to 4.50, P=0.04). After adjusting for age, model for end-stage liver disease and nosocomial infection, retap-guided management was not associated with improved survival (P=0.34). CONCLUSIONS The prevalence of initial treatment failure is high (22%) in patients with SBP and doubles the 30-day mortality risk, supporting recommendations to retap all patients with SBP.
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Fernández J, Bert F, Nicolas-Chanoine MH. The challenges of multi-drug-resistance in hepatology. J Hepatol 2016; 65:1043-1054. [PMID: 27544545 DOI: 10.1016/j.jhep.2016.08.006] [Citation(s) in RCA: 101] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Revised: 08/05/2016] [Accepted: 08/10/2016] [Indexed: 02/08/2023]
Abstract
Antimicrobial resistance has become a major global public health security problem that needs coordinated approaches at regional, national and international levels. Antibiotic overuse and the failure of control measures to prevent the spread of resistant bacteria in the healthcare environment have led to an alarming increase in the number of infections caused by resistant bacteria, organisms that resist many (multi-drug and extensively drug-resistant strains), if not all (pan-drug-resistant bacteria) currently available antibiotics. While Gram-positive cocci resistance (methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci) shows a heterogeneous geographical distribution, extended-spectrum β-lactamase-producing Enterobacteriaceae and carbapenem-resistant Enterobacteriaceae have become pandemic worldwide and endemic in some parts of the world, respectively. Moreover, currently available therapeutic options for resistant bacteria are very limited, with very few new agents in development. Antimicrobial resistance is especially relevant in decompensated cirrhosis. Firstly, cirrhotic patients are highly susceptible to develop infections caused by resistant bacteria as risk factors of multiresistance concentrate in this population (mainly repeated hospitalizations and antibiotic exposure). Secondly, inappropriate empirical antibiotic schedules easily translate into increased morbidity (acute kidney injury, acute-on-chronic liver failure, septic shock) and hospital mortality in advanced cirrhosis. Therefore, hepatologists must face nowadays a complex clinical scenario that requires new empirical antibiotic strategies that may further spread resistance. Global, regional and local preventive measures should therefore be implemented to combat antimicrobial resistance in cirrhosis including the restriction of antibiotic prophylaxis to high-risk populations, investigation on non-antibiotic prophylaxis, stewardship programs on adequate antibiotic prescription and on increasing awareness of the problem among health professionals, and well-defined early de-escalation policies based on rapid microbiological diagnostic tests. Other infection control practices such as hand hygiene and barrier precautions are also important. Clinical impact and cost-effectiveness of epidemiological surveillance programs (periodic rectal and nasal swabs) should also be explored.
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Affiliation(s)
- Javier Fernández
- Liver Unit, Hospital Clínic Barcelona, University of Barcelona, Spain; Institut d'Investigacions Biomèdiques August-Pi-Sunyer (IDIBAPS), Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHED), Spain.
| | - Frédéric Bert
- Service de Microbiologie, Hôpital Beaujon, AP-HP, Clichy, France; INSERM UMR 1149, Université Paris 7, Paris, France
| | - Marie-Hélène Nicolas-Chanoine
- Service de Microbiologie, Hôpital Beaujon, AP-HP, Clichy, France; INSERM UMR 1149, Université Paris 7, Paris, France; Faculté de Médecine Paris Diderot, Paris, France
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Shayto RH, Abou Mrad R, Sharara AI. Use of rifaximin in gastrointestinal and liver diseases. World J Gastroenterol 2016; 22:6638-6651. [PMID: 27547007 PMCID: PMC4970477 DOI: 10.3748/wjg.v22.i29.6638] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2016] [Revised: 06/17/2016] [Accepted: 07/06/2016] [Indexed: 02/06/2023] Open
Abstract
Rifaximin is a broad spectrum oral antibiotic with antimicrobial activity against Gram-positive and Gram-negative aerobic and anaerobic bacteria. It is poorly absorbed and thus has a highly favorable safety profile. Rifaximin has been shown to be effective in the treatment of traveler's diarrhea, functional bloating and irritable bowel syndrome, small bowel bacterial overgrowth and in the prevention of recurrent overt hepatic encephalopathy. In addition, there is emerging evidence for a possible beneficial effect of rifaximin in the treatment of uncomplicated diverticular disease and in the prevention of recurrent diverticulitis. The use of rifaximin is associated with a low incidence of development, or persistence of spontaneous bacterial mutants. Moreover, the development of important drug resistance among extra-intestinal flora during rifaximin therapy is unlikely because of minimal systemic absorption and limited cross-resistance of rifaximin with other antimicrobials. This review addresses the current and emerging role of rifaximin in the treatment of gastrointestinal and liver disorders.
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Fernández J, Tandon P, Mensa J, Garcia-Tsao G. Antibiotic prophylaxis in cirrhosis: Good and bad. Hepatology 2016; 63:2019-31. [PMID: 26528864 DOI: 10.1002/hep.28330] [Citation(s) in RCA: 131] [Impact Index Per Article: 14.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2015] [Accepted: 11/02/2015] [Indexed: 12/13/2022]
Abstract
UNLABELLED Patients with cirrhosis, particularly those with decompensated cirrhosis, are at increased risk of bacterial infections that may further precipitate other liver decompensations including acute-on-chronic liver failure. Infections constitute the main cause of death in patients with advanced cirrhosis, and strategies to prevent them are essential. The main current strategy is the use of prophylactic antibiotics targeted at specific subpopulations at high risk of infection: prior episode of spontaneous bacterial peritonitis, upper gastrointestinal bleeding, and low-protein ascites with associated poor liver function. Antibiotic prophylaxis effectively prevents not only the development of bacterial infections in all these indications but also further decompensation (variceal bleeding, hepatorenal syndrome) and improves survival. However, antibiotic prophylaxis is also associated with a clinically relevant and increasing drawback, the development of infections due to multidrug-resistant organisms. Several strategies have been suggested to balance the risks and benefits of antibiotic prophylaxis. CONCLUSION Antibiotic stewardship principles such as the restriction of antibiotic prophylaxis to subpopulations at a very high risk for infection, the avoidance of antibiotic overuse, and early deescalation policies are key to achieve this balance; nonantibiotic prophylactic measures such as probiotics, prokinetics, bile acids, statins, and hematopoietic growth factors could also contribute to ameliorate the development and spread of multidrug-resistant bacteria in cirrhosis. (Hepatology 2016;63:2019-2031).
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Affiliation(s)
- Javier Fernández
- Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain.,Institut d'Investigacions Biomèdiques August-Pi-Sunyer (IDIBAPS), Barcelona, Spain.,Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHED), Barcelona, Spain
| | - Puneeta Tandon
- Cirrhosis Care Clinic, Cirrhosis Care, Liver Unit, Division of Gastroenterology, University of Alberta, Edmonton, Canada
| | - Jose Mensa
- Infectious Disease Department, Hospital Clínic, University of Barcelona, Barcelona, Spain
| | - Guadalupe Garcia-Tsao
- Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT.,Section of Digestive Diseases, VA-CT Healthcare System, West Haven, CT
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Abstract
INTRODUCTION Bacterial infections are a serious complication of cirrhosis, as they can lead to decompensation, multiple organ failure, and/or death. Preventing infections is therefore very relevant. Because gut bacterial translocation is their main pathogenic mechanism, prevention of infections is mostly based on the use of orally administered poorly absorbed antibiotics such as norfloxacin (selective intestinal decontamination). However, antibiotic prophylaxis leads to antibiotic resistance, limiting therapy and increasing morbidity and mortality. Prevention of bacterial infections in cirrhosis should therefore move away from antibiotics. AREAS COVERED This review focuses on various potentially novel methods to prevent infections in cirrhosis focusing on non-antibiotic strategies. The use of probiotics, nonselective intestinal decontamination with rifaximin, prokinetics and beta-blockers or fecal microbiota transplant as means of targeting altered gut microbiota, bile acids and FXR agonists are all potential alternatives to selective intestinal decontamination. Prokinetics and beta-blockers can improve intestinal motility, while bile acids and FXR agonists help by improving the intestinal barrier. Finally, granulocyte colony stimulating factor (G-CSF) and statins are emerging therapeutic strategies that may improve immune dysfunction in cirrhosis. EXPERT OPINION Evidence for these strategies has been restricted to animal studies and proof-of concept studies but we expect this to change in coming years.
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Ponziani FR, Gerardi V, Pecere S, D’Aversa F, Lopetuso L, Zocco MA, Pompili M, Gasbarrini A. Effect of rifaximin on gut microbiota composition in advanced liver disease and its complications. World J Gastroenterol 2015; 21:12322-12333. [PMID: 26604640 PMCID: PMC4649116 DOI: 10.3748/wjg.v21.i43.12322] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2015] [Revised: 09/03/2015] [Accepted: 10/17/2015] [Indexed: 02/06/2023] Open
Abstract
Liver cirrhosis is a paradigm of intestinal dysbiosis. The qualitative and quantitative derangement of intestinal microbial community reported in cirrhotic patients seems to be strictly related with the impairment of liver function. A kind of gut microbial "fingerprint", characterized by the reduced ratio of "good" to "potentially pathogenic" bacteria has recently been outlined, and is associated with the increase in Model for End-Stage Liver Disease and Child Pugh scores. Moreover, in patients presenting with cirrhosis complications such as spontaneous bacterial peritonitis (SBP), hepatic encephalopathy (HE), and, portal hypertension intestinal microbiota modifications or the isolation of bacteria deriving from the gut are commonly reported. Rifaximin is a non-absorbable antibiotic used in the management of several gastrointestinal diseases. Beyond bactericidal/bacteriostatic, immune-modulating and anti-inflammatory activity, a little is known about its interaction with gut microbial environment. Rifaximin has been demonstrated to exert beneficial effects on cognitive function in patients with HE, and also to prevent the development of SBP, to reduce endotoxemia and to improve hemodynamics in cirrhotics. These results are linked to a shift in gut microbes functionality, triggering the production of favorable metabolites. The low incidence of drug-related adverse events due to the small amount of circulating drug makes rifaximin a relatively safe antibiotic for the modulation of gut microbiota in advanced liver disease.
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Nousbaum JB. [Spontaneous bacterial peritonitis in patients with cirrhosis]. Presse Med 2015; 44:1235-42. [PMID: 26358667 DOI: 10.1016/j.lpm.2015.07.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 07/09/2015] [Indexed: 11/19/2022] Open
Abstract
Spontaneous bacterial peritonitis (SBP) is a severe complication occurring in patients with cirrhosis, and is associated with high mortality. Liver transplantation should be considered after a first episode of SBP. Gram-negative bacilli are the major cause of SBP, however there is an increasing trend of Gram-positive cocci related SBP. Management includes empirical antibiotic treatment and albumin infusion. The choice of antibiotics depends on the site of acquisition (community-acquired vs nosocomial or health-care associated infection) and local resistance profile, due to the emergence of drug-resistant bacteria. Secondary prophylaxis is recommended after resolution of SBP and reduces recurrence and mortality. Primary prophylaxis in patients with low protein ascites (<15 g/L) should be restricted to patients with severe cirrhosis awaiting for liver transplantation.
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Affiliation(s)
- Jean-Baptiste Nousbaum
- CHU La Cavale-Blanche, service d'hépato-gastroentérologie, boulevard Tanguy-Prigent, 29609 Brest cedex, France.
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Dever JB, Sheikh MY. Review article: spontaneous bacterial peritonitis--bacteriology, diagnosis, treatment, risk factors and prevention. Aliment Pharmacol Ther 2015; 41:1116-31. [PMID: 25819304 DOI: 10.1111/apt.13172] [Citation(s) in RCA: 121] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2015] [Revised: 02/02/2015] [Accepted: 03/03/2015] [Indexed: 02/06/2023]
Abstract
BACKGROUND Spontaneous bacterial peritonitis (SBP) is a severe and often fatal infection in patients with cirrhosis and ascites. AIM To review the known and changing bacteriology, risk factors, ascitic fluid interpretation, steps in performing paracentesis, treatment, prophylaxis and evolving perspectives related to SBP. METHODS Information was obtained from reviewing medical literature accessible on PubMed Central. The search term 'spontaneous bacterial peritonitis' was cross-referenced with 'bacteria', 'risk factors', 'ascites', 'paracentesis', 'ascitic fluid analysis', 'diagnosis', 'treatment', 'antibiotics', 'prophylaxis', 'liver transplantation' and 'nutrition'. RESULTS Gram-positive cocci (GPC) such as Staphylococcus, Enterococcus as well as multi-resistant bacteria have become common pathogens and have changed the conventional approach to treatment of SBP. Health care-associated and nosocomial SBP infections should prompt greater vigilance and consideration for alternative antibiotic coverage. Acid suppressive and beta-adrenergic antagonist therapies are strongly associated with SBP in at-risk individuals. CONCLUSIONS Third-generation, broad-spectrum cephalosporins remain a good initial choice for SBP treatment. Levofloxacin is an acceptable alternative for patients not receiving long-term flouroquinolone prophylaxis or for those with a penicillin allergy. For uncomplicated SBP, early oral switch therapy is reasonable. Alternative antibiotics such as pipercillin-tazobactam should be considered for patients with nosocomial SBP or for patients who fail to improve on traditional antibiotic regimens. Selective albumin supplementation remains an important adjunct in SBP treatment. Withholding acid suppressive medication deserves strong consideration, and discontinuing beta-adrenergic antagonist therapy in patients with end-stage liver disease and resistant ascites is standard care. Liver transplant evaluation should be undertaken for patients who develop SBP barring contraindications.
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Affiliation(s)
- J B Dever
- Department of Gastroenterology, VA San Diego Healthcare System, San Diego, CA, USA
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Lutz P, Nischalke HD, Strassburg CP, Spengler U. Spontaneous bacterial peritonitis: The clinical challenge of a leaky gut and a cirrhotic liver. World J Hepatol 2015; 7:304-314. [PMID: 25848460 PMCID: PMC4381159 DOI: 10.4254/wjh.v7.i3.304] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/28/2014] [Revised: 11/30/2014] [Accepted: 12/31/2014] [Indexed: 02/06/2023] Open
Abstract
Spontaneous bacterial peritonitis (SBP) is a frequent, life-threatening bacterial infection in patients with liver cirrhosis and ascites. Portal hypertension leads to increased bacterial translocation from the intestine. Failure to eliminate invading pathogens due to immune defects associated with advanced liver disease on the background of genetic predisposition may result in SBP. The efficacy of antibiotic treatment and prophylaxis has declined due to the spread of multi-resistant bacteria. Patients with nosocomial SBP and with prior antibiotic treatment are at a particularly high risk for infection with resistant bacteria. Therefore, it is important to adapt empirical treatment to these risk factors and to the local resistance profile. Rifaximin, an oral, non-absorbable antibiotic, has been proposed to prevent SBP, but may be useful only in a subset of patients. Since novel antibiotic classes are lacking, we have to develop prophylactic strategies which do not induce bacterial resistance. Farnesoid X receptor agonists may be a candidate, but so far, clinical studies are not available. New diagnostic tests which can be carried out quickly at the patient’s site and provide additional prognostic information would be helpful. Furthermore, we need tools to predict antibiotic resistance in order to tailor first-line antibiotic treatment of spontaneous bacterial peritonitis to the individual patient and to reduce mortality.
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Casper M, Mengel M, Fuhrmann C, Herrmann E, Appenrodt B, Schiedermaier P, Reichert M, Bruns T, Engelmann C, Grünhage F, Lammert F. The INCA trial (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites): study protocol for a randomized controlled trial. Trials 2015; 16:83. [PMID: 25887140 PMCID: PMC4359533 DOI: 10.1186/s13063-015-0594-4] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2014] [Accepted: 02/09/2015] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Patients with liver cirrhosis have a highly elevated risk of developing bacterial infections that significantly decrease survival rates. One of the most relevant infections is spontaneous bacterial peritonitis (SBP). Recently, NOD2 germline variants were found to be potential predictors of the development of infectious complications and mortality in patients with cirrhosis. The aim of the INCA (Impact of NOD2 genotype-guided antibiotic prevention on survival in patients with liver Cirrhosis and Ascites) trial is to investigate whether survival of this genetically defined high-risk group of patients with cirrhosis defined by the presence of NOD2 variants is improved by primary antibiotic prophylaxis of SBP. METHODS/DESIGN The INCA trial is a double-blind, placebo-controlled clinical trial with two parallel treatment arms (arm 1: norfloxacin 400 mg once daily; arm 2: placebo once daily; 12-month treatment and observational period). Balanced randomization of 186 eligible patients with stratification for the protein content of the ascites (<15 versus ≥ 15 g/L) and the study site is planned. In this multicenter national study, patients are recruited in at least 13 centers throughout Germany. The key inclusion criterion is the presence of a NOD2 risk variant in patients with decompensated liver cirrhosis. The most important exclusion criteria are current SBP or previous history of SBP and any long-term antibiotic prophylaxis. The primary endpoint is overall survival after 12 months of treatment. Secondary objectives are to evaluate whether the frequencies of SBP and other clinically relevant infections necessitating antibiotic treatment, as well as the total duration of unplanned hospitalization due to cirrhosis, differ in both study arms. Recruitment started in February 2014. DISCUSSION Preventive strategies are required to avoid life-threatening infections in patients with liver cirrhosis, but unselected use of antibiotics can trigger resistant bacteria and worsen outcome. Thus, individualized approaches that direct intervention only to patients with the highest risk are urgently needed. This trial meets this need by suggesting stratified prevention based on genetic risk assessment. To our knowledge, the INCA trial is first in the field of hepatology aimed at rapidly transferring and validating information on individual genetic risk into clinical decision algorithms. TRIAL REGISTRATIONS German Clinical Trials Register DRKS00005616 . Registered 22 January 2014. EU Clinical Trials Register EudraCT 2013-001626-26 . Registered 26 January 2015.
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Affiliation(s)
- Markus Casper
- Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, 66421, Homburg, Germany.
| | - Martin Mengel
- Study Center Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Sigmund-Freud-Straße 25, 53125, Bonn, Germany.
| | - Christine Fuhrmann
- Study Center Bonn, Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, Sigmund-Freud-Straße 25, 53125, Bonn, Germany.
| | - Eva Herrmann
- Institute for Biostatistics and Mathematical Modelling, Goethe University Hospital, Theodor-Stern-Kai 7, 60590, Frankfurt am Main, Germany.
| | - Beate Appenrodt
- Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, 66421, Homburg, Germany.
| | - Peter Schiedermaier
- Department of Medicine, Nardini Hospital, Kaiserstraße 14, 66482, Zweibrücken, Germany.
| | - Matthias Reichert
- Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, 66421, Homburg, Germany.
| | - Tony Bruns
- Department of Medicine IV, University Hospital Jena, Bachstraße 18, 07743, Jena, Germany.
| | - Cornelius Engelmann
- Department of Medicine II, University Hospital Leipzig, Liebigstraße 18, 04103, Leipzig, Germany.
| | - Frank Grünhage
- Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, 66421, Homburg, Germany.
| | - Frank Lammert
- Department of Medicine II, Saarland University Medical Center, Kirrberger Straße 100, 66421, Homburg, Germany.
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