Gastroenterology
Volume 133, Issue 3 , Pages 1029-1031, September 2007

A Pill a Day Can Improve Survival in Patients With Advanced Cirrhosis

  • Bruce A. Runyon

      Affiliations

    • Corresponding Author InformationAddress requests for reprints to: Bruce A. Runyon, MD, Division of Gastroenterology/Hepatology, Loma Linda University Medical Center, Loma Linda, California 92354. fax: (909) 558-0274.

Division of Gastroenterology/Hepatology, Loma Linda University Medical Center, Loma Linda, California

Article Outline

 

See “Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis” by Fernandez J, Navasa M, Planas R, et al, on page 818.

The past 25 years have witnessed an incredible increase in our database regarding complications of cirrhosis and a much more complete picture of how these complications work together to shorten the life of the patient. The explosion of information that I described almost 20 years ago regarding the pathogenesis, diagnosis, and treatment of spontaneous bacterial peritonitis (SBP) has continued.1 Prevention of SBP was a concept that was still in its infancy in 1988. Diuresis had been shown to increase ascitic fluid opsonic activity and theoretically provide better defense against colonizing bacteria.2 The early studies which described risk factors for SBP, for example, low-protein ascites, gastrointestinal hemorrhage, and prior SBP, then led to randomized trials proving that selective intestinal decontamination in these subgroups of patients helped to prevent this potentially fatal infection.3, 4, 5, 6, 7, 8 A more recent randomized trial has shown that IV ceftriaxone is even better than oral norfloxacin in preventing infections in the setting of gut bleeding; this study helps to solve the dilemma of how to deliver an oral medication to patients who are frequently vomiting blood.9

Why should selective intestinal decontamination prevent SBP? Most of the organisms that cause SBP originate in the gut.10 As cirrhosis progresses, the gut appears to become less able to contain bacteria, which can then translocate to extraintestinal sites.11 Overgrowth of a particular organism in the gut predictably leads to translocation of that organism.12 Once these bacteria escape the gut, they can then colonize and infect a locus minoris resistenciae, that is, an area of the body that is lacking in defenses, such as low-protein ascites. Simplistically, selective intestinal decontamination reduces the bacterial numbers in the gut and can thus prevent translocation, SBP, and even prolong the survival of rats with cirrhosis and ascites.13, 14 Primary prophylaxis was shown to prolong the survival of rats with cirrhosis in 1999.14

When SBP was first described in detail in 1964, mortality was 100%.15 As of 1999, hospitalization mortality was reduced to 10%.16 A reduction in mortality by 90% in 35 years is real medical progress. How did this happen? The recognition that SBP was common and that paracentesis was safe, combined with a high index of suspicion and a low threshold for diagnostic paracentesis, frequently led to detection of this infection at an early treatable phase.1, 17, 18 Paracentesis was routinely performed at the time of admission of patients with cirrhosis and ascites or when there were symptoms or signs consistent with SBP, such as abdominal pain, fever, confusion, azotemia, leukocytosis, or acidosis.18 Bedside culture of the fluid in blood culture bottles was shown to be superior to older methods of culture (and explained the culture-negative cases of the past) and frequently confirmed the presence of bacteria and permitted narrowing the spectrum of antibiotic coverage.10, 19, 20 Cefotaxime was shown to be superior with less nephrotoxicity compared with aminoglycoside-based regimens.21 Albumin was shown to help prevent hepatorenal syndrome in the setting of SBP.16 Thus, fatal renal failure owing to aminoglycosides or the infection itself could be avoided.

SBP and gastrointestinal hemorrhage were shown to work together to harm the patient. Hemorrhagic shock was shown to increase translocation.22 Bacterial infection was shown to be associated with uncontrollable variceal hemorrhage.23 Antibiotic prophylaxis was not only shown to prevent infection in the setting of gut bleeding, but was also shown to help prevent rebleeding.24 A study that reported a reduction in mortality in variceal hemorrhage from 43% to 15% over a 20-year period demonstrated that antibiotic prophylaxis was independently associated with improved survival.25

With survival of SBP improved dramatically, prevention came more sharply into focus. Clearly patients in these subgroups who were at high risk for SBP benefited from selective intestinal decontamination.5, 6, 7 The benefit of selective intestinal decontamination in patients who did not meet these criteria were less clear. One randomized trial was performed comparing primary continuous prophylaxis with norfloxacin to inpatient-only prophylaxis in patients with cirrhosis and ascitic fluid total protein level ≤1.5 g/dL or serum bilirubin level >2.5 mg/dL.22 SBP was reduced in the continuous treatment group at the expense of more resistance of gut flora to norfloxacin in that group.26

This brings us to the study at hand. The authors enrolled patients with cirrhosis and low-protein ascites (<1.5 g/dL) plus either (a) advanced liver failure (Child-Pugh score ≥9 points with serum bilirubin ≥3 mg/dL) or (b) impaired renal function defined as serum creatinine ≥1.2 mg/dL, blood urea nitrogen ≥25 mg/dL or serum sodium ≤130 mEq/L; they were randomized to norfloxacin or placebo.27 This is one of the first trials in this area of investigation to choose survival as a primary endpoint. Other trials were not designed to look at this endpoint and therefore did not demonstrate a survival advantage (Table 1). In fact, in the treatment of any complication of advanced cirrhosis, it has been traditionally extremely difficult to show a survival advantage. Trials regularly demonstrated better control of the complication under investigation, but the patients died anyway. They developed a new fatal complication. Frequently even meta-analyses have failed to demonstrate a survival advantage. This is always discouraging. The study at hand is one of a small, elite group that demonstrates a survival advantage, as well as a reduction in SBP and a reduction in hepatorenal syndrome.27 This is indeed remarkable. It is probable that translocation is common and silent in patients with advanced cirrhosis. Pieces of bacterial DNA can be found in the serum and ascitic fluid of such patients and the presence of DNA correlates with shorter survival.28 Reducing the bacterial content of the gut with selective intestinal decontamination would be predicted to reduce SBP and the hepatorenal syndrome that can follow. Intuitively, one could envision that this could improve survival as it was shown to do in rats with cirrhosis and ascites. It is interesting that the survival advantage was quite impressive at three months (94% vs 62%; P = .003), but only 60% versus 48% by 1 year (P = .05). Bacteria become resistant to antibiotics predictably over time.29 Perhaps the narrowing of the difference in the survival curves at 1 year is due to development of resistance followed by overgrowth and translocation of the resistant bacteria.11, 12, 13, 14 Mother Nature abhors a vacuum; if the usual flora are reduced, more unusual organisms take their place.

Table 1. Prevention of Spontaneous Bacterial Peritonitis
Study designNResultsPMortalityP
Norfloxacin vs no drug in inpatients with AFTP <1.5 g/dL63SBP 0% vs 23%<.05Infection-related mortality (0% vs 13%)NS
Hospitalization mortality (6% vs 16%)NS
Norfloxacin vs placebo in patients with prior SBP80SBP recurrence (12% vs 35%).01418% vs 25%NS
Norfloxacin vs no drug in patients with cirrhosis & gut hemorrhage119Infection (10% vs 37%).0017% vs 12%NS
Norfloxacin vs ceftriaxone in patients with cirrhosis and gut hemorrhage111Infection (33% vs 11%).0039% vs 11%NS
Trimethoprim/sulfamethoxazole vs no drug in patients with cirrhosis and ascites67SBP or bacteremia (3% vs 27%).0257% vs 20%.15

AFTP, ascitic fluid total protein; NS, not significant; SBP, spontaneous bacterial peritonitis.

Adapted with permission from Runyon.18

Why not just give all patients with cirrhosis selective intestinal decontamination? This became popular shortly after selective intestinal decontamination was shown to prevent SBP in early trials. Fortunately, this practice seems to have waned. We should reserve use of selective intestinal decontamination for patients who meet the inclusion criteria of the randomized trials.6, 7, 8, 18, 27 There are disadvantages to selective intestinal decontamination. Prolonged exposure to quinolones pretransplant was shown to be a risk factor for posttransplant fungal infections in a prospective study.30 The risks must be weighed against the benefits when the use of any drug is being considered in patients with advanced cirrhosis.

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References 

  1. Runyon BA. Spontaneous bacterial peritonitis: an explosion of information. Hepatology. 1988;8:171–175
  2. Runyon BA, Van Epps D. Diuresis of cirrhotic ascites increases its opsonic activity and may help prevent spontaneous bacterial peritonitis. Hepatology. 1986;6:396–399
  3. Runyon BA. Low-protein-concentration ascitic fluid is predisposed to spontaneous bacterial peritonitis. Gastroenterology. 1986;91:1343–1346
  4. Bleichner G, Boulanger R, Squara P, et al. Frequency of infections in cirrhotic patients presenting with acute gastrointestinal hemorrhage. Br J Surg. 1986;73:724–726
  5. Tito L, Rimola A, Gines P, et al. Recurrence of spontaneous bacterial peritonitis in cirrhosis: frequency and predictive factors. Hepatology. 1988;8:27–31
  6. Soriano G, Guarner C, Teixido M, et al. Selective intestinal decontamination prevents spontaneous bacterial peritonitis. Gastroenterology. 1991;100:477–481
  7. Rimola A, Bory F, Teres J, et al. Oral, nonabsorbable antibiotics prevent infection in cirrhotics with gastrointestinal hemorrhage. Hepatology. 1985;5:463–467
  8. Gines P, Rimola A, Planas R, et al. Norfloxacin prevents spontaneous bacterial peritonitis recurrence in cirrhosis: results of a double-blind, placebo-controlled trial. Hepatology. 1990;12:716–724
  9. Fernandez J, Ruiz del Arbol L, et al. Norfloxacin vs ceftriaxone in the prophylaxis of infections in patients with advanced cirrhosis and hemorrhage. Gastroenterology. 2006;131:1049–1056
  10. Runyon BA, Canawati HN, Akriviadis EA. Optimization of ascitic fluid culture technique. Gastroenterology. 1988;95:1351–1355
  11. Runyon BA, Squier SU, Borzio M. Translocation of gut bacteria in rats with cirrhosis to mesenteric lymph nodes partially explains the pathogenesis of spontaneous bacterial peritonitis. J Hepatol. 1994;21:792–796
  12. Guarner C, Runyon BA, Young S, et al. Intestinal bacterial overgrowth and bacterial translocation in an experimental model of cirrhosis in rats. J Hepatol. 1997;26:1372–1378
  13. Runyon BA, Borzio M, Young S, et al. Effect of selective bowel decontamination with norfloxacin on spontaneous bacterial peritonitis, translocation, and survival in an animal model of cirrhosis. Hepatology. 1995;21:1719–1724
  14. Guarner C, Runyon BA, Heck M, et al. Effect of long-term trimethoprim-sulfamethoxazole prophylaxis on ascites formation, bacterial translocation, spontaneous bacterial peritonitis and survival in cirrhotic rats. Dig Dis Sci. 1999;44:1957–1962
  15. Conn HO. Spontaneous peritonitis and bacteremia in Laennec’s cirrhosis caused by enteric organisms. Ann Intern Med. 1964;60:568–580
  16. Sort P, Navasa M, Arroyo V, 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
  17. Runyon BA. Paracentesis of ascitic fluid: a safe procedure. Arch Intern Med. 1986;146:2259–2261
  18. Runyon BA. Management of adult patients with ascites caused by cirrhosis. Hepatology. 2004;39:841–856
  19. Runyon BA, Hoefs JC. Culture-negative neutrocytic ascites: a variant of spontaneous bacterial peritonitis. Hepatology. 1984;4:1209–1211
  20. Runyon BA, Antillon MR, Akriviadis EA, et al. Bedside inoculation of blood culture bottles with ascitic fluid is superior to delayed inoculation in the detection of spontaneous bacterial peritonitis. J Clin Microbiol. 1900;28:2811–2812
  21. Felisart J, Rimola A, Arroyo V, et al. Cefotaxime is more effective than is ampicillin-tobramycin in cirrhotics with severe infections. Hepatology. 1985;5:457–462
  22. Llovet JM, Bartoli R, Planas R, et al. Selective intestinal decontamination with norfloxacin reduces bacterial translocation in ascitic cirrhotic rats exposed to hemorrhagic shock. Hepatology. 1996;23:781–787
  23. Goulis J, Armonis A, Patch D, et al. Bacterial infection is independently associated with failure to control bleeding in cirrhotic patients with gastrointestinal hemorrhage. Hepatology. 1988;27:1207–1212
  24. Hou M-C, Lin H-C, Liu T-T, et al. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology. 2004;39:746–753
  25. Carbonell N, Pauwels A, Serfaty L, et al. Improved survival after variceal bleeding in patients with cirrhosis over the past two decades. Hepatology. 2004;40:652–659
  26. Novella M, Sola R, Soriano G, et al. Continuous versus inpatient prophylaxis of the first episode of spontaneous bacterial peritonitis with norfloxacin. Hepatology. 1997;25:532–536
  27. Fernandez J, Navasa M, Planas R, et al. Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis. Gastroenterology. 2007;133:818–824
  28. Zapater P, Frances R, Gonzalez-Navajas JM, et al. La presencia de AND bacterianoes un oredictor pronostico a corto plazo en pacientes cirrotocos con ascitis (Resultados de un studio multicentrico nacional). Gastroenterol Hepatol. 2006;29(Suppl 1):117
  29. Aparicio JR, Such J, Pascual S, et al. Development of quinolone-resistant strains of Escherichia coli in stools of patients with cirrhosis undergoing norfloxacin prophylaxis: clinical consequences. J Hepatol. 1999;31:277–283
  30. Wade JJ, Rolando N, Hayllar K, et al. Bacterial and fungal infections after liver transplantation: an analysis of 248 patients. Hepatology. 1995;21:1328–1336

PII: S0016-5085(07)01393-5

doi:10.1053/j.gastro.2007.07.017

Refers to article:

  • Primary Prophylaxis of Spontaneous Bacterial Peritonitis Delays Hepatorenal Syndrome and Improves Survival in Cirrhosis , 05 July 2007

    Javier Fernández, Miquel Navasa, Ramón Planas, Silvia Montoliu, David Monfort, German Soriano, Carmen Vila, Alberto Pardo, Enrique Quintero, Victor Vargas, Jose Such, Pere Ginès, Vicente Arroyo
    Gastroenterology September 2007 (Vol. 133, Issue 3, Pages 818-824)

Gastroenterology
Volume 133, Issue 3 , Pages 1029-1031, September 2007

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