Advertisement

Metabolic Brain Disease

, Volume 28, Issue 2, pp 307–312 | Cite as

Antibiotics for the treatment of hepatic encephalopathy

  • Kavish R. Patidar
  • Jasmohan S. Bajaj
Original Paper

Abstract

The treatment of hepatic encephalopathy (HE) is complex and therapeutic regimens vary according to the acuity of presentation and the goals of therapy. Most treatments for HE rely on manipulating the intestinal milieu and therefore antibiotics that act on the gut form a key treatment strategy. Prominent antibiotics studied in HE are neomycin, metronidazole, vancomycin and rifaximin. For the management of the acute episode, all antibiotics have been tested. However the limited numbers studied, adverse effects (neomycin oto- and nephrotoxicity, metronidazole neurotoxicity) and potential for resistance emergence (vancomycin-resistant enterococcus) has limited the use of most antibiotics, apart from rifaximin which has the greatest evidence base. Rifaximin has also demonstrated, in conjunction with lactulose, to prevent overt HE recurrence in a multi-center, randomized trial. Despite its cost in the US, rifaximin may prove cost-saving by preventing hospitalizations for overt HE. In minimal/covert HE, rifaximin is the only systematically studied antibiotic. Rifaximin showed improvement in cognition, inflammation, quality-of-life and driving simulator performance but cost-analysis does not favor its use at the current time. Antibiotics, especially rifaximin, have a definite role in the management across the spectrum of HE.

Keywords

Rifaximin Neomycin Covert hepatic encephalopathy Metronidazole Vancomycin Economics 

References

  1. Alcorn J (2008) Review: rifaximin is equally or more effective than other antibiotics and lactulose for hepatic encephalopathy. ACP J Club 149(5):11PubMedGoogle Scholar
  2. Atterbury CE, Maddrey WC, Conn HO (1978) Neomycin-sorbitol and lactulose in the treatment of acute portal-systemic encephalopathy: a controlled, double-blind clinical trial. Am J Dig Dis 23:398–406PubMedCrossRefGoogle Scholar
  3. Bajaj JS (2010) Review article: the modern management of hepatic encephalopathy. Aliment Pharmacol Ther 31(5):537–547PubMedCrossRefGoogle Scholar
  4. Bajaj JS, Riggio O (2010) Drug therapy: rifaximin. Hepatology 52(4):1484–1488PubMedCrossRefGoogle Scholar
  5. Bajaj JS, Heuman DM, Wade JB, Gibson DP, Saeian K, Wegelin JA, Hafeezullah M, Bell DE, Sterling RK, Stravitz RT, Fuchs M, Luketic V, Sanyal AJ (2011) Rifaximin improves driving simulator performance in a randomized trial of patients with minimal hepatic encephalopathy. Gastroenterology 140(2):478–487PubMedCrossRefGoogle Scholar
  6. Bajaj JS, Hylemon PB, Ridlon JM, Heuman DM, Daita K, White MB, Monteith P, Noble NA, Sikaroodi M, Gillevet PM (2012a) Colonic mucosal microbiome differs from stool microbiome in cirrhosis and hepatic encephalopathy and is linked to cognition and inflammation. Am J Physiol Gastrointest Liver Physiol 303(6):G675–G685PubMedCrossRefGoogle Scholar
  7. Bajaj JS, O’Leary JG, Reddy KR, Wong F, Olson JC, Subramanian RM, Brown G, Noble NA, Thacker LR, Kamath PS (2012b) Second infections independently increase mortality in hospitalized patients with cirrhosis: the north american consortium for the study of end-stage liver disease (NACSELD) experience. Hepatology 56(6):2328–2335PubMedCrossRefGoogle Scholar
  8. Bajaj JS, Pinkerton SD, Sanyal AJ, Heuman DM (2012c) Diagnosis and treatment of minimal hepatic encephalopathy to prevent motor vehicle accidents: a cost-effectiveness analysis. Hepatology 55(4):1164–1171PubMedCrossRefGoogle Scholar
  9. Bass NM, Mullen KD, Sanyal A, Poordad F, Neff G, Leevy CB, Sigal S, Sheikh MY, Beavers K, Frederick T, Teperman L, Hillebrand D, Huang S, Merchant K, Shaw A, Bortey E, Forbes WP (2010) Rifaximin treatment in hepatic encephalopathy. N Engl J Med 362(12):1071–1081PubMedCrossRefGoogle Scholar
  10. Blei AT, Cordoba J (2001) Hepatic encephalopathy. Am J Gastroenterol 96:1968–1976PubMedCrossRefGoogle Scholar
  11. Brigidi P, Swennen E, Rizzello F, Bozzolasco M, Matteuzzi D (2012) Effects of rifaximin administration on the intestinal microbiota in patients with ulcerative colitis. J Chemother 14(3):290–295Google Scholar
  12. Bucci L, Palmieri GC (1993) Double-blind, double-dummy comparison between treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy. Curr Med Res Opin 13:109–118PubMedCrossRefGoogle Scholar
  13. Conn HO, Leevy CM, Vlahcevic ZR, Rodgers JB, Maddrey WC, Seeff L, Levy LL (1977) Comparison of lactulose and neomycin in the treatment of chronic portal-systemic encephalopathy. A double blind controlled trial. Gastroenterology 72(4 Pt 1):573–583PubMedGoogle Scholar
  14. Fera G, Agostinacchio F, Nigro M, Schiraldi O, Ferrieri A (1993) Rifaximin in the treatment of hepatic encephalopathy. Eur J Clin Res 4(1):57–66Google Scholar
  15. Fernández J, Acevedo J, Castro M, Garcia O, de Lope CR, Roca D, Pavesi M, Sola E, Moreira L, Silva A, Seva-Pereira T, Corradi F, Mensa J, Ginès P, Arroyo V (2012) Prevalence and risk factors of infections by multiresistant bacteria in cirrhosis: a prospective study. Hepatology 55(5):1551–1561PubMedCrossRefGoogle Scholar
  16. Festi D, Mazzella G, Orsini M, Scottili S, Sangermano A, Li Bassi S, Ferrieri A, Falcucci M, Grossi L, Marzio L, Roda E (1993) Rifaximin in the treatment of chronic hepatic encephalopathy: results of a multicenter study of efficacy and safety. Curr Ther Res 54(5):598–609CrossRefGoogle Scholar
  17. Gustot T, Durand F, Lebrec D, Vincent JL, Moreau R (2009) Severe Sepsis in cirrhosis. Hepatology 50(6):2022–2033PubMedCrossRefGoogle Scholar
  18. Huang E, Esrailian E, Spiegel BMR (2007) The cost-effectiveness and budget impact of competing therapies in hepatic encephalopathy: a decision analysis. Aliment Pharmacol Ther 26:1147–1161PubMedCrossRefGoogle Scholar
  19. Jalan R (2010) Rifaximin in hepatic encephalopathy: more than just a non-absorable antibiotic? J Hepatol 53(3):580–582PubMedCrossRefGoogle Scholar
  20. Jiang ZD, DuPont HL (2005) Rifaximin: in vitro and in vivo antibacterial activity–a review. Chemotherapy 51(Suppl 1):67–72PubMedCrossRefGoogle Scholar
  21. Kalambokis GN, Mouzaki A, Rodi M, Pappas K, Fotopoulos A, Xourgia X, Tsiansos EV (2012) Rifaximin improves systemic hemodynamics and renal function in patients with alchol-related cirrhosis and ascites. Clin Gastroenterol Hepatol 10(7):815–818PubMedCrossRefGoogle Scholar
  22. Leevy CB, Phillips JA (2007) Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy. Dig Dis Sci 52:737–741PubMedCrossRefGoogle Scholar
  23. Loft S, Sonne J, Dossing M, Andreasen PB (1987) Metronidazole pharmacokinetics in patients with hepatic encephalopathy. Scand J Gastroenterol 22(1):117–123PubMedCrossRefGoogle Scholar
  24. Mantry PS, Munsaf S (2010) Rifaximin for the treatment of hepatic encephalopathy. Transplant Proc 42(10):4543–4547PubMedCrossRefGoogle Scholar
  25. Marco F, Amato PS, D’Arienzo A (1984) Rifaximin in collateral treatment of portal-systemic encephalopathy: a preliminary report. Curr Ther Res 36:668–674Google Scholar
  26. Mas A, Rodés J, Sunyer L, Rodrigo L, Planas R, Vargas V, Castells L, Rodríguez-Martínez D, Fernández-Rodríguez C, Coll I, Pardo A (2003) Spanish Association for the Study of the Liver Hepatic Encephalopathy Cooperative Group. Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol 38(1):51–58PubMedCrossRefGoogle Scholar
  27. Massa P, Vallerino E, Dodero M (1993) Treatment of hepatic encephalopathy with rifaximin: double-blind, double-dummy study versus lactulose. Eur J Clin Res 4:7–18Google Scholar
  28. Morgan MH, Read AE, Speller DC (1982) Treatment of hepatic encephalopathy with metronidazole. Gut 23(1):1–7PubMedCrossRefGoogle Scholar
  29. Neff GW, Kemmer N, Kaiser T, Zacharias V, Majoras N, Safdar K (2007) Outcomes in adult and pediatric liver transplantation among various ethnic groups. Transplant Proc 39(10):3204–3206PubMedCrossRefGoogle Scholar
  30. Neff GW, Jones M, Broda T, Jonas M, Ravi R, Novick D, Kaiser TE, Kemmer N (2012) Durability of rifaximin response in hepatic encephalopathy. J Clin Gastroenterol 46(2):168–171PubMedCrossRefGoogle Scholar
  31. Orlandi F, Freddara U, Candelaresi MT, Morettini A, Corazza GR, Di Simone A, Dobrilla G, Cavallini G (1981) Comparison between neomycin and lactulose in 173 patients with hepatic encephalopathy: a randomized clinical study. Dig Dis Sci 26(6):498–506PubMedCrossRefGoogle Scholar
  32. Paik YH, Lee KS, Han KH, Song KH, Kim MH, Moon BS, Ahn SH, Lee SJ, Park HJ, Lee DK, Chon CY, Lee SI, Moon YM (2005) Comparison of rifaximin and lactulose for the treatment of hepatic encephalopathy: a prospective randomized study. Yonsei Med J 46(3):399–407PubMedCrossRefGoogle Scholar
  33. Parini P, Cipolla A, Ronci M, Antionio M, Salzetta A, Mazzella G, Roda E (1992) Effect of paromomycin in the treatment of portal-systemic encephalopathy. Curr Ther Res 52:34CrossRefGoogle Scholar
  34. Poh Z, Chang PE (2012) A current review of the diagnostic and treatment strategies of hepatic encephalopathy. Int J Hepatol 2012:480309PubMedGoogle Scholar
  35. Poordad FF (2007) Review article: the burden of hepatic encephalopathy. Aliment Pharmacol Ther 1:3–9CrossRefGoogle Scholar
  36. Prakash R, Mullen KD (2010) Mechanisms, diagnosis and management of hepatic encephalopathy. Nat Rev Gastroenterol Hepatol 7:515–525PubMedCrossRefGoogle Scholar
  37. Riggio O, Mannaioni G, Ridola L, Angeloni S, Merli M, Carlà V, Salvatori FM, Moroni F (2010) Peripheral and splanchnic indole and oxindole levels in cirrhotic patients: a study on the pathophysiology of hepatic encephalopathy. Am J Gastroenterol 105(6):1374–1381PubMedCrossRefGoogle Scholar
  38. Sanyal A, Bass N, Poorad F, Sheikh MY, Mullen K, Sigal S, Frederick T, Brown, Jr R, Bhandari B, Sedghi S, Merchant K, Huang S, Shaw A, Bortey E, Forbes W (2010) Rifaximin decreases venous ammonia concentrations and time-weighted average ammonia concentrations correlate with overt hepatic encephalopathy (HE) as assessed by Conn Score in a 6-months study. Program and abstracts of the 45th Annual Meeting of the European Association for the Study of the Liver Abstract 195Google Scholar
  39. Sanyal A, Younossi ZM, Bass NM, Mullen KD, Poordad F, Brown RS, Vemuru RP, Mazen Jamal M, Huang S, Merchant K, Bortey E, Forbes WP (2011) Randomised clinical trial: rifaximin improves health-related quality of life in cirrhotic patients with hepatic encephalopathy – a double-blind placebo-controlled study. Aliment Pharmacol Ther 34(8):853–861PubMedCrossRefGoogle Scholar
  40. Shawcross DL, Sharifi Y, Canavan JB, Yeoman AD, Abeles RD, Taylor NJ, Auzinger G, Bernal W, Wendon JA (2011) Infection and systemic inflammation, not ammonia, are associated with Grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis. J Hepatol 54:640–649PubMedCrossRefGoogle Scholar
  41. Sidhu SS, Goyal O, Mishra BP, Sood A, Chhina RS, Soni RK (2011) Rifaximin improves psychometric performance and health-related quality of life in patients with minimal hepatic encephalopathy (the RIME Trial). Am J Gastroenterol 106(2):307–316PubMedCrossRefGoogle Scholar
  42. Stepanova M, Mishra A, Venkatesan C, Younossi ZM (2012) In-hospital mortality and economic burden associated with hepatic encephalopathy in the United States from 2005 to 2009. Clin Gastroenterol Hepatol 10(9):1034–1041PubMedCrossRefGoogle Scholar
  43. Strauss E, Tramote R, Silva EP, Caly WR, Honain NZ, Maffei RA, de Sá MF (1992) Double-blind randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology 39(6):542–545PubMedGoogle Scholar
  44. Tarao K, Ikeda T, Hayashi K, Sakurai A, Okada T, Ito T, Karube H, Nomoto T, Mizuno T, Shindo K (1990) Successful use of vancomycin hydrochloride in the treatment of lactulose resistant chronic hepatic encephalopathy. Gut 31(6):702–706PubMedCrossRefGoogle Scholar
  45. Testa R, Eftimiadi C, Sukkar GS, De Leo C, Rovida S, Schito GC, Celle G (1985) Drugs Exp Clin Res 11(6):387–392PubMedGoogle Scholar
  46. U.S. Food and Drug Administration (2010) Briefing Document for Gastrointestinal Drugs Advisory Committee Meeting 23 February 2010. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/GastrointestinalDrugsAdvisoryCommittee/UCM201081.pdf. Accessed 3 December 2012

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Division of Gastroenterology, Hepatology and NutritionVirginia Commonwealth University and McGuire VA Medical CenterRichmondUSA

Personalised recommendations