Effects of Long-term Norfloxacin Therapy in Patients With Advanced Cirrhosis.

Richard Moreau, Laure Elkrief, Christophe Bureau, Jean-Marc Perarnau, Thierry Thévenot, Faouzi Saliba, Alexandre Louvet, Pierre Nahon, Adrien Lannes, Rodolphe Anty, Sophie Hillaire, Blandine Pasquet, Violaine Ozenne, Marika Rudler, Isabelle Ollivier-Hourmand, Marie Angèle Robic, Louis d'Alteroche, Vincent Di Martino, Marie-Pierre Ripault, Arnaud Pauwels, Jean-Didier Grangé, Nicolas Carbonell, Jean-Pierre Bronowicki, Audrey Payancé, Pierre-Emmanuel Rautou, Dominique Valla, Nathalie Gault, Didier Lebrec

Journal: Gastroenterology 2019;155(6):1816-1827.e9

PMID: 30144431

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Abstract

BACKGROUND & AIMS

There is debate over the effects of long-term oral fluoroquinolone therapy in patients with advanced cirrhosis. We performed a randomized controlled trial to evaluate the effects of long-term treatment with the fluoroquinolone norfloxacin on survival of patients with cirrhosis.

METHODS

We performed a double-blind trial of 291 patients with Child-Pugh class C cirrhosis who had not received recent fluoroquinolone therapy. The study was performed at 18 clinical sites in France from April 2010 through November 2014. Patients were randomly assigned to groups given 400 mg norfloxacin (n = 144) or placebo (n = 147) once daily for 6 months. Patients were evaluated monthly for the first 6 months and at 9 months and 12 months thereafter. The primary outcome was 6-month mortality, estimated by the Kaplan-Meier method, censoring spontaneous bacterial peritonitis, liver transplantation, or loss during follow-up.

RESULTS

The Kaplan-Meier estimate for 6-month mortality was 14.8% for patients receiving norfloxacin and 19.7% for patients receiving placebo (P = .21). In competing risk analysis that took liver transplantation into account, the cumulative incidence of death at 6 months was significantly lower in the norfloxacin group than in the placebo group (subdistribution hazard ratio, 0.59; 95% confidence interval, 0.35-0.99). The subdistribution hazard ratio for death at 6 months with norfloxacin vs placebo was 0.35 (95% confidence interval, 0.13-0.93) in patients with ascites fluid protein concentrations <15 g/L and 1.39 (95% confidence interval, 0.42-4.57) in patients with ascites fluid protein concentrations ≥15 g/L. Norfloxacin significantly decreased the incidence of any and Gram-negative bacterial infections without increasing infections caused by Clostridium difficile or multiresistant bacteria.

CONCLUSIONS

In a randomized controlled trial of patients with advanced cirrhosis without recent fluoroquinolone therapy, norfloxacin did not reduce 6-month mortality, estimated by the Kaplan-Meier method. Norfloxacin, however, appears to increase survival of patients with low ascites fluid protein concentrations. ClinicalTrials.gov ID: NCT01037959.

Address: Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Département Hospitalo-Universitaire UNITY, Service d'Hépatologie, Clichy, France; Institut National de la Santé et de la Recherche Médicale and Université Paris Diderot, Centre de Recherche sur l'Inflammation, Unité Mixte de Recherche 1149, Paris, France. Electronic address: [email protected].; Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Département Hospitalo-Universitaire UNITY, Service d'Hépatologie, Clichy, France.; Centre Hospitalier Universitaire, Université Paul Sabatier, Hôpital Purpan, Service d'Hépato-Gastroentérologie, Toulouse, France.; Centre Hospitalier Régional Universitaire de Tours, Unité d'Hépatologie, Hépato-Gastroentérologie, Tours, France.; Centre Hospitalier Universitaire de Besançon, Hôpital Jean Minjoz, Service d'Hépatologie et de Soins Intensifs Digestifs, Besançon, France.; Assistance Publique-Hôpitaux de Paris, Hôpital Paul Brousse, Centre Hépato-Biliaire, Villejuif, France.; Centre Hospitalier Régional Universitaire de Lille, Hôpital Huriez, Service des Maladies de l'Appareil Digestif, Lille, France.; Assistance Publique-Hôpitaux de Paris, Hôpital Jean Verdier, Service d'Hépatologie, Bondy, and Université Paris 13, Sorbonne Paris Cité, Equipe Labellisée Ligue Contre le Cancer, Saint-Denis, and Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche 1162, Génomique Fonctionnelle des Tumeur Solides, Paris, France.; Centre Hospitalier Universitaire d'Angers, Service d'Hépato-Gastroentérologie, Angers, France.; Centre Hospitalier Universitaire de Nice, Pôle Digestif and Institut National de la Santé et de la Recherche Médicale U1065 and Université Côte d'Azur, Nice, France.; Hôpital Foch, Service de Médecine Interne, Suresnes, France, France.; Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Unité de Recherche Clinique Paris Nord, Paris and Institut National de la Santé et de la Recherche Médicale, Le Centre D'Investigation Clinique, Module Épidémiologie Clinique 1425, Hôpital Bichat, Paris, France.; Assistance Publique-Hôpitaux de Paris, Hôpital Lariboisère, Service d'Hépato-Gastroentérologie, Paris, France.; Assistance Publique-Hôpitaux de Paris, Groupement Hospitalier Pitié-Salpêtrière, Service d'Hépatologie, Paris, France.; Centre Hospitalier Universitaire Côte de Nacre, Département d'Hépato-Gastroentérologie et de Nutrition, Caen, France.; Centre Hospitalier Universitaire Montpellier, Hôpital Saint Eloi, Département d'Hépato-Gastroentérologie et Transplantation, Montpellier, France.; Centre Hospitalier de Gonesse, Service d'Hépato-Gastroentérologie, Gonesse, France.; Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, Service d'Hépato-Gastroentérologie, Paris, France.; Assistance Publique-Hôpitaux de Paris, Hôpital Saint-Antoine, Département d'Hépatologie, Paris, France.; Centre Hospitalier Universitaire Nancy Brabois, Département d'Hépato-Gastroentérologie and Institut National de la Santé et de la Recherche Médicale U954 and Université Lorraine, Nancy, France.; Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Département Hospitalo-Universitaire UNITY, Service d'Hépatologie, Clichy, France; Institut National de la Santé et de la Recherche Médicale and Université Paris Diderot, Centre de Recherche sur l'Inflammation, Unité Mixte de Recherche 1149, Paris, France.; Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Unité de Recherche Clinique Paris Nord, Paris and Institut National de la Santé et de la Recherche Médicale, Le Centre D'Investigation Clinique, Module Épidémiologie Clinique 1425, Hôpital Bichat, Paris, France; Assistance Publique-Hôpitaux de Paris, Hôpital Beaujon, Département Epidémiologie Biostatistiques et Recherche Clinique, Clichy, France.

DOI: 10.1053/j.gastro.2018.08.026

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MeSH Terms: Anti-Bacterial Agents, Ascites, Double-Blind Method, Female, France, Gram-Negative Bacterial Infections, Humans, Incidence, Kaplan-Meier Estimate, Liver Cirrhosis, Male, Middle Aged, Norfloxacin, Proportional Hazards Models, Prospective Studies, Time Factors, Treatment Outcome