Skip to main content

Advertisement

SpringerLink
Log in

Efficacy and safety of alternating norfloxacin and rifaximin as primary prophylaxis for spontaneous bacterial peritonitis in cirrhotic ascites: a prospective randomized open-label comparative multicenter study

  • Original Article
  • Published:
Hepatology International Aims and scope Submit manuscript

Abstract

Background and aim

Primary prevention of spontaneous bacterial peritonitis (SBP) is an important strategy to reduce morbidity and mortality in cirrhotic patients with ascites. Efficacy and safety of alternating rifaximin and norfloxacin as primary prophylaxis is questionable.

Methods

Three hundred thirty-four cirrhotic patients with high SAAG (≥1.1) ascites, protein level in ascitic fluid less than 1.5 g/dL with advanced liver disease (Child-Pugh score >9 points with serum bilirubin level >3 mg/dL) or renal impairment (serum creatinine level >1.2 mg/dL, blood urea nitrogen level >25 mg/dL, or serum sodium level <130 mEq/L) were included in an open-label, randomized study aimed at comparing alternating use of norfloxacin and rifaximin vs. norfloxacin or rifaximin alone as primary prophylaxis for SBP. Both intention-to-treat and per-protocol efficacy analyses were done after 6 months of treatment by assessment of ascitic fluid neutrophil count. Safety analysis was done for all intention-to-treat populations.

Results

Alternating norfloxacin and rifaximin showed superior prophylaxis by intention-to-treat (74.7 vs. 56.4 % vs. 68.3 %, p < 0.048). Pairwise analysis showed that alternating regimen had lower probability to develop SBP when compared to a norfloxacin-based regimen in intention-to-treat (p = 0.016) and per protocol analysis (p = 0.039). There was no difference among the studied groups regarding the incidence and severity of adverse events reported.

Conclusions

Alternating norfloxacin- and rifaximin-based primary prophylaxis for SBP showed higher efficacy with the same safety profile when compared with monotherapy of norfloxacin.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Kalambokis GN, Mouzaki A, Rodi M, Tsianos EV. Rifaximin for the prevention of spontaneous bacterial peritonitis. World J Gastroenterol 2012;18:1700–1702

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Koulaouzidis A. Diagnosis of spontaneous bacterial peritonitis: an update on leucocyte esterase reagent strips. World J Gastroenterol 2011;17:1091–1094

    Article  PubMed  PubMed Central  Google Scholar 

  3. Biecker E. Diagnosis and therapy of ascites in liver cirrhosis. World J Gastroenterol 2011;17:1237–1248

    Article  PubMed  PubMed Central  Google Scholar 

  4. Fernandez J, Navasa M, Gomez J, Colmenero J, Vila J, Arroyo V, et al. Bacterial infections in cirrhosis: epidemiological changes with invasive procedures and norfloxacin prophylaxis. Hepatology 2002;35:140–148

    Article  PubMed  Google Scholar 

  5. Koo HL, DuPont HL. Rifaximin: a unique gastrointestinal-selective antibiotic for enteric diseases. Curr Opin Gastroenterol 2010;26:17–25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Vlachogiannakos J, Saveriadis AS, Viazis N, Theodoropoulos I, Foudoulis K, Manolakopoulos S, et al. Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis. Aliment Pharmacol Ther 2009;29:992–999

    Article  CAS  PubMed  Google Scholar 

  7. Vlachogiannakos J, Viazis N, Vasianopoulou P, Vafiadis I, Karamanolis DG, Ladas SD. Long-term administration of rifaximin improves the prognosis of patients with decompensated alcoholic cirrhosis. J Gastroenterol Hepatol 2013;28:450–455

    Article  CAS  PubMed  Google Scholar 

  8. Richardson L. Alternating antibiotics render resistant bacteria beatable. PLoS Biol 2015;13:e1002105

    Article  PubMed  PubMed Central  Google Scholar 

  9. Fagiuoli S, Colli A, Bruno R, Burra P, Craxi A, Gaeta GB, et al. Management of infections in cirrhotic patients: report of a consensus conference. Dig Liver Dis 2014;46:204–212

    Article  PubMed  Google Scholar 

  10. Angeli P, Gines P, Wong F, Bernardi M, Boyer TD, Gerbes A, et al. Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites. Gut 2015;64:531–537

    Article  CAS  PubMed  Google Scholar 

  11. Arroyo V, Gines P, Gerbes AL, Dudley FJ, Gentilini P, Laffi G, et al. Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club. Hepatology 1996;23:164–176

    Article  CAS  PubMed  Google Scholar 

  12. Salerno F, Gerbes A, Gines P, Wong F, Arroyo V. Diagnosis, prevention and treatment of hepatorenal syndrome in cirrhosis. Gut 2007;56:1310–1318

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Sigal SH, Stanca CM, Fernandez J, Arroyo V, Navasa M. Restricted use of albumin for spontaneous bacterial peritonitis. Gut 2007;56:597–599

    Article  PubMed  PubMed Central  Google Scholar 

  14. Sort P, Navasa M, Arroyo V, Aldeguer X, Planas R, Ruiz-del-Arbol L, et al. Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis. N Engl J Med 1999;341:403–409

    Article  CAS  PubMed  Google Scholar 

  15. Hsieh WJ, Lin HC, Hwang SJ, Hou MC, Lee FY, Chang FY, et al. The effect of ciprofloxacin in the prevention of bacterial infection in patients with cirrhosis after upper gastrointestinal bleeding. Am J Gastroenterol 1998;93:962–966

    Article  CAS  PubMed  Google Scholar 

  16. Narahara Y, Kanazawa H, Sakamoto C, Maruyama H, Yokosuka O, Mochida S, et al. The efficacy and safety of terlipressin and albumin in patients with type 1 hepatorenal syndrome: a multicenter, open-label, explorative study. J Gastroenterol 2012;47:313–320

    Article  CAS  PubMed  Google Scholar 

  17. Uriz J, Gines P, Cardenas A, Sort P, Jimenez W, Salmeron JM, et al. Terlipressin plus albumin infusion: an effective and safe therapy of hepatorenal syndrome. J Hepatol 2000;33:43–48

    Article  CAS  PubMed  Google Scholar 

  18. Fernandez J, Navasa M, Planas R, Montoliu S, Monfort D, Soriano G, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 2007;133:818–824

    Article  CAS  PubMed  Google Scholar 

  19. Runyon BA. Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis. Gastroenterology 1986;91:1343–1346

    CAS  PubMed  Google Scholar 

  20. Guarner C, Sola R, Soriano G, Andreu M, Novella MT, Vila MC, et al. Risk of a first community-acquired spontaneous bacterial peritonitis in cirrhotics with low ascitic fluid protein levels. Gastroenterology 1999;117:414–419

    Article  CAS  PubMed  Google Scholar 

  21. Llach J, Rimola A, Navasa M, Gines P, Salmeron JM, Gines A, et al. Incidence and predictive factors of first episode of spontaneous bacterial peritonitis in cirrhosis with ascites: relevance of ascitic fluid protein concentration. Hepatology 1992;16:724–747

    Article  CAS  PubMed  Google Scholar 

  22. Andreu M, Sola R, Sitges-Serra A, Alia C, Gallen M, Vila MC, et al. Risk factors for spontaneous bacterial peritonitis in cirrhotic patients with ascites. Gastroenterology 1993;104:1133–1138

    CAS  PubMed  Google Scholar 

  23. Follo A, Llovet JM, Navasa M, Planas R, Forns X, Francitorra A, et al. Renal impairment after spontaneous bacterial peritonitis in cirrhosis: incidence, clinical course, predictive factors and prognosis. Hepatology 1994;20:1495–1501

    Article  CAS  PubMed  Google Scholar 

  24. Gines A, Escorsell A, Gines P, Salo J, Jimenez W, Inglada L, et al. Incidence, predictive factors, and prognosis of the hepatorenal syndrome in cirrhosis with ascites. Gastroenterology 1993;105:229–236

    CAS  PubMed  Google Scholar 

  25. Bataller R, Gines P, Guevara M, Arroyo V. Hepatorenal syndrome. Semin Liver Dis 1997;17:233–247

    Article  CAS  PubMed  Google Scholar 

  26. Angeli P, Wong F, Watson H, Gines P, Investigators C. Hyponatremia in cirrhosis: results of a patient population survey. Hepatology 2006;44:1535–1542

    Article  CAS  PubMed  Google Scholar 

  27. Rimola A, Garcia-Tsao G, Navasa M, Piddock LJ, Planas R, Bernard B, et al. Diagnosis, treatment and prophylaxis of spontaneous bacterial peritonitis: a consensus document. International Ascites Club. J Hepatol 2000;32:142–153

    Article  CAS  PubMed  Google Scholar 

  28. Runyon BA. Practice Guidelines Committee AASLD. Management of adult patients with ascites due to cirrhosis. Hepatology 2004;39:841–856

    Article  PubMed  Google Scholar 

  29. Moore KP, Wong F, Gines P, Bernardi M, Ochs A, Salerno F, et al. The management of ascites in cirrhosis: report on the consensus conference of the International Ascites Club. Hepatology 2003;38:258–266

    Article  PubMed  Google Scholar 

  30. Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut 2006;55(Suppl 6):vi1–12

    PubMed  PubMed Central  Google Scholar 

  31. Riggio O, Angeloni S. Ascitic fluid analysis for diagnosis and monitoring of spontaneous bacterial peritonitis. World J Gastroenterol 2009;15:3845–3850

    Article  PubMed  PubMed Central  Google Scholar 

  32. Runyon BA. A pill a day can improve survival in patients with advanced cirrhosis. Gastroenterology 2007;133:1029–1031

    Article  CAS  PubMed  Google Scholar 

  33. Sandhu BS, Sanyal AJ. Management of ascites in cirrhosis. Clin Liver Dis 2005;9:715–732, viii

  34. Dupeyron C, Mangeney N, Sedrati L, Campillo B, Fouet P, Leluan G. Rapid emergence of quinolone resistance in cirrhotic patients treated with norfloxacin to prevent spontaneous bacterial peritonitis. Antimicrob Agents Chemother 1994;38:340–344

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hanouneh MA, Hanouneh IA, Hashash JG, Law R, Esfeh JM, Lopez R, et al. The role of rifaximin in the primary prophylaxis of spontaneous bacterial peritonitis in patients with liver cirrhosis. J Clin Gastroenterol 2012;46:709–715

    Article  CAS  PubMed  Google Scholar 

  36. DuPont HL, Jiang ZD. Influence of rifaximin treatment on the susceptibility of intestinal gram-negative flora and enterococci. Clin Microbiol Infect 2004;10:1009–1011

    Article  CAS  PubMed  Google Scholar 

  37. DuPont HL, Jiang ZD, Okhuysen PC, Ericsson CD, de la Cabada FJ, Ke S, et al. A randomized, double-blind, placebo-controlled trial of rifaximin to prevent travelers’ diarrhea. Ann Intern Med 2005;142:805–812

    Article  CAS  PubMed  Google Scholar 

  38. Darkoh C, Lichtenberger LM, Ajami N, Dial EJ, Jiang ZD, DuPont HL. Bile acids improve the antimicrobial effect of rifaximin. Antimicrob Agents Chemother 2010;54:3618–3624

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Mostafa T, Badra G, Abdallah M. The efficacy and the immunomodulatory effect of rifaximin in prophylaxis of spontaneous bacterial peritonitis in cirrhotic Egyptian patients. Turk J Gastroenterol 2015;26:163–169

    Article  PubMed  Google Scholar 

  40. Rasaratnam B, Kaye D, Jennings G, Dudley F, Chin-Dusting J. The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis. A randomized trial. Ann Intern Med 2003;139:186–193

    Article  PubMed  Google Scholar 

  41. Albillos A, de la Hera A, Gonzalez M, Moya JL, Calleja JL, Monserrat J, et al. Increased lipopolysaccharide binding protein in cirrhotic patients with marked immune and hemodynamic derangement. Hepatology 2003;37:208–217

    Article  CAS  PubMed  Google Scholar 

  42. Ruiz-del-Arbol L, Monescillo A, Arocena C, Valer P, Gines P, Moreira V, et al. Circulatory function and hepatorenal syndrome in cirrhosis. Hepatology 2005;42:439–447

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank all staff members of inpatient and outpatient departments in all sharing centers for their help in collection of our data.

Author contribution statement

M. Assem initiated the collaborative project, designed the trial, implemented the trial for the all countries, and drafted and revised the paper. M. Elsabaawy monitored data collection in Egypt, and revised the draft paper. M. Abdelrashed monitored data collection in Saudi Arabia, and drafted the paper. S. Elemam implemented the trial in Saudi Arabia and analyzed the data. Both S. Khodeer and W. Hamed analysed the data and drafted the paper. A. Abdelaziz monitored data collection for the whole trial especially for laboratory results and analyzed the data. G. El-Azab wrote the statistical analysis plan, designed data collection tools, monitored data collection for the whole trial, analyzed the data, and drafted and revised the paper.

Author information

Authors and Affiliations

  1. Hepatology Department, National Liver Institute, Menoufia University, Shebeen El Koom, Menoufia, 52311, Egypt

    M. Assem, M. Elsabaawy & G. El-Azab

  2. Internal Medicine Department, Al Noor Hospital, M.O.H, Mecca, Saudi Arabia

    M. Abdelrashed

  3. Tropical Medicine Department, King Khalid Hospital, M.O.H, Tabuk, Saudi Arabia

    S. Elemam

  4. Internal Medicine Department, Faculty of Medicine, Tanta University, Tanta, Egypt

    S. Khodeer

  5. Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt

    W. Hamed

  6. Clinical Pathology Department, National Liver Institute, Menoufia University, Shebeen El Koom, Menoufia, 52311, Egypt

    A. Abdelaziz

Authors
  1. M. Assem
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M. Elsabaawy
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M. Abdelrashed
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. S. Elemam
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. S. Khodeer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W. Hamed
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. A. Abdelaziz
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G. El-Azab
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Assem.

Ethics declarations

Funding

All participating centers shared in the fund.

Conflict of interest

M. Assem, M. Elsabaawy, M. Abdelrashed, S. Elemam, S. Khodeer, W. Hamed, A. Abdelaziz, G. El-Azab declare no competing interests, either financial or non-financial.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study protocol was approved by the local ethics committee at each participating center and written informed consent was obtained from patients before entering the study. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Assem, M., Elsabaawy, M., Abdelrashed, M. et al. Efficacy and safety of alternating norfloxacin and rifaximin as primary prophylaxis for spontaneous bacterial peritonitis in cirrhotic ascites: a prospective randomized open-label comparative multicenter study. Hepatol Int 10, 377–385 (2016). https://doi.org/10.1007/s12072-015-9688-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12072-015-9688-z

Keywords

Search

Navigation