From the AGA Journals

Norfloxacin might benefit patients with advanced cirrhosis and low ascites fluid protein levels

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Benefit is still unclear

Prolonged antimicrobial use in patients with decompensated cirrhosis is an area of unclear mortality benefit and may actually increase risk in some patients given antimicrobial resistance. This randomized double-blind, placebo-controlled trial by Moreau et al. evaluates the mortality associated with long-term fluoroquinolone therapy in patients without indications for primary or secondary prophylaxis. Although the study had limited statistical power to detect clear benefit, the authors found that 6-month mortality was not reduced in patients with Child-Pugh class C cirrhosis who received treatment with daily oral fluoroquinolone therapy for 6 months. Subgroup analysis of individuals with ascites fluid total protein levels lower than 15 g/L showed a survival benefit at 6 months.

Determining quantifiable risk for known factors associated with liver disease mortality is a pressing issue, especially in the pretransplant setting where infectious risk is compounded post transplant with changes in gut flora, addition of potent immunosuppressants, and increased metabolic demands. Biologic measurements that correlate with increased complications and mortality, like low protein ascites, are helpful in complex clinical settings.Studying patients with advanced and decompensated liver disease in a systematic, longitudinal manner with any pharmacologic intervention is a particular challenge given the unpredictable nature of decompensation events and variable outcomes from those events. However, attempts to quantify risk and benefit even in this unpredictable patient population is worthwhile to stratify patients for interventions and minimize risk of liver-related and overall mortality – as well as peritransplant complications and posttransplant survival.

Julia J. Wattacheril, MD, MPH, is a physician- scientist and director of the Nonalcoholic Fatty Liver Disease Program in the Center for Liver Disease and Transplantation at Columbia University Irving Medical Center–New York Presbyterian Hospital, New York; an assistant professor, department of medicine, division of digestive and liver diseases at the Columbia University Vagelos College of Physicians and Surgeons. She has no conflicts.



Six months of once-daily norfloxacin therapy did not reduce 6-month mortality among patients with Child-Pugh class C cirrhosis who had not recently received fluoroquinolone therapy.

Mortality based on the Kaplan-Meier method was 14.8% in the norfloxacin group versus 19.7% for patients receiving placebo (P = .21). “Norfloxacin, however, appear[ed] to increase survival of patients with low ascites fluid protein concentrations,” wrote Richard Moreau, MD, of Hôpital Beaujon, Paris, and his associates. The results of the multicenter, double-blind trial of 291 patients were published in the December issue of Gastroenterology.

Patients with advanced cirrhosis often develop spontaneous bacterial peritonitis and other severe bacterial infections, with potentially grave outcomes. These are often enteric gram-negative bacteria that cross the intestinal barrier, enter the systemic circulation, and travel to the site of infection.

Long-term fluoroquinolone therapy (typically with norfloxacin) might help prevent these bacterial infections, the translocation of bacterial products, systemic inflammation, and consequent end-organ dysfunction, such as acute kidney disease. However, long-term antibiotic therapy also raises the specter of multidrug resistance, which is especially concerning when it involves a crucial antibiotic class such as fluoroquinolones, the researchers noted. “[In] patients receiving prolonged fluoroquinolone therapy, the development of infections by multidrug resistant bacteria might obscure the beneficial effect of fluoroquinolones on survival,” they added.

Four previous blinded and placebo-controlled trials have investigated fluoroquinolone therapy and mortality patients with cirrhosis, but they were small, usually included mortality only as a secondary outcome, and yielded mixed results. Hence, the researchers enrolled 291 patients with advanced (Child-Pugh class C) cirrhosis from 18 clinical sites in France and randomly assigned them to receive either norfloxacin (400 mg once daily) or placebo for 6 months. Patients were evaluated monthly during treatment and then at 9 months and 12 months. The primary outcome was survival at 6 months.

In a post hoc analysis, the researchers examined cumulative death rates at 6 months after accounting for liver transplantation as a competing risk of death and including survival data for patients who developed spontaneous bacterial peritonitis. Taking this approach, the estimated cumulative rate of death at 6 months was 15.5% (95% confidence interval, 10.1-21.9) in the norfloxacin group and 24.8% (95% CI, 18.1-32.1) in the placebo group, for a hazard ratio of 0.59 (95% CI, 0.35-0.99). Among patients whose ascites fluid levels were less than 15 g/L, the hazard ratio for death at 6 months was 65% lower in the norfloxacin group than in the placebo group (HR, 0.35; 95% CI, 0.13-0.93). Norfloxacin showed no such benefit for patients with ascites fluid protein levels above 15 g/L.

Norfloxacin therapy “could reduce the incidence of death among patients with ascitic fluid protein concentrations of less than 15 g/L but not among those with ascitic fluid protein concentration of 15 g/L or more,” the researchers concluded. “Norfloxacin may prevent some infections, especially gram-negative bacterial infections, but not the development of [spontaneous bacterial peritonitis] and other noninfectious, liver-related complications.”

The study was funded by Programme Hospitalier de Recherche Clinique National 2008 of the French Ministry of Health. Dr. Moreau reported having no conflicts of interest. Two coinvestigators disclosed ties to Gore Norgine, Exalenz, and Conatus.

SOURCE: Moreau R et al. Gastroenterology. 2018 Aug 22. doi: 10.1053/j.gastro.2018.08.026.

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