AMSTERDAM – Prolonged oral treatment with norfloxacin improved the survival of patients with Child-Pugh class C liver disease versus no antibiotic prophylaxis in a randomized, double-blind, placebo-controlled, phase III multicenter trial.
Fewer patients (15.3% vs. 24.5%) treated with norfloxacin for 6 months died by the 6-month mortality primary endpoint than did those treated with placebo, with a hazard ratio of 0.59 (95% confidence interval, 0.35-0.99; P = .047) favoring prolonged antibiotic treatment. Adjustments for the concomitant use of nonselective beta-blockers and corticosteroids did not greatly alter the significance of the findings (adjusted HR, 0.58; 95% CI, 0.34-0.98; P = .042).
Dr. Richard Moreau
“The results of this study provide evidence that 6 months of norfloxacin therapy reduces the risk of death in the short term, but not in the long term,” he observed in an official EASL press release.
The occurrence of infections at 6 months and 12 months were secondary outcomes of the study and showed that fewer infections overall (23.9% vs. 35.0%, P = .04) had occurred in the norfloxacin group versus the placebo group at 6 months, which was sustained at 12 months, suggesting an overhanging effect of the antibiotic treatment.
There was no difference between the groups in the incidence of other secondary endpoints including septic shock, systolic blood pressure, liver transplantation, kidney dysfunction, encephalopathy, and variceal bleeding at 6 months, Dr. Moreau reported on behalf of the NORFLOCIR study group.
Norfloxacin is a fluoroquinolone antibiotic and earlier data (Gastroenterology 2007;133:818-24) had suggested that its prolonged use could improve survival in patients with advanced cirrhosis significantly at 3 months and nonsignificantly at 12 months. This was a small study, however, and although several other small-sized trials followed, the long-term use of fluoroquinolone therapy to improve outcomes in patients cirrhosis remained debated,” Dr. Moreau said during his presentation of the study’s findings.
There was also the concern that such prolonged antibiotic use might up the risk for infection with gram-positive bacteria, he observed, but the current study’s finding showed that this was not the case. The cumulative incidence of gram-positive (3.4% vs. 8.1%, P = .08) infections was numerically although not significantly lower in the antibiotic-treated patients at 6 months while the cumulative incidence of gram-negative infections was significantly lowered (3.2% vs. 13.0%, P less than .005).
The study does have its limitations, Dr. Moreau conceded. Fewer patients were recruited than anticipated, 291 rather than a planned sample size of 392 patients, which was caused by a combination of factors – slow recruitment, termination of funding, and time expiry of the trial drug. Nevertheless, the study findings are strengthened by the fact it was conducted in 18 centers throughout France and that liver transplantation was taken into account as a potential competing risk.
During the trial, 144 patients with Child-Pugh class C cirrhosis were randomized to receive oral norfloxacin at a dose of 400 mg/day and 147 were randomized to a matching placebo daily for 6 months. Patients were followed for 6 additional months.
Just 3% of patients were lost to follow-up by the time of the primary endpoint assessment at 6 months, with just over half (55%) modifying their consent and almost half (46%) discontinuing the study because of death (15%), liver transplant (9%), elevated systolic blood pressure (9%), or patient decision (12%).
Patients included in the study were mostly middle-aged (55 years or older), male (more than 65%), and had alcoholic cirrhosis (greater than 74%) or alcoholic hepatitis (39%), with around 88% having ascites.
Dr. Moreau had nothing to disclose. The study was sponsored by the French government.