Effect of Prophylactic Antibiotics on Mortality in Severe Alcohol-Related Hepatitis

Abstract

ImportanceThe benefits of prophylactic antibiotics for hospitalized patients with severe alcohol-related hepatitis are unclear.ObjectiveTo determine the efficacy of amoxicillin-clavulanate, compared with placebo, on mortality in patients hospitalized with severe alcohol-related hepatitis and treated with prednisolone.Design, Setting, and ParticipantsMulticenter, randomized, double-blind clinical trial among patients with biopsy-proven severe alcohol-related hepatitis (Maddrey function score ≥32 and Model for End-stage Liver Disease [MELD] score ≥21) from June 13, 2015, to May 24, 2019, in 25 centers in France and Belgium. All patients were followed up for 180 days. Final follow-up occurred on November 19, 2019.InterventionPatients were randomly assigned (1:1 allocation) to receive prednisolone combined with amoxicillin-clavulanate (n = 145) or prednisolone combined with placebo (n = 147).Main Outcome and MeasuresThe primary outcome was all-cause mortality at 60 days. Secondary outcomes were all-cause mortality at 90 and 180 days; incidence of infection, incidence of hepatorenal syndrome, and proportion of participants with a MELD score less than 17 at 60 days; and proportion of patients with a Lille score less than 0.45 at 7 days.ResultsAmong 292 randomized patients (mean age, 52.8 [SD, 9.2] years; 80 [27.4%] women) 284 (97%) were analyzed. There was no significant difference in 60-day mortality between participants randomized to amoxicillin-clavulanate and those randomized to placebo (17.3% in the amoxicillin-clavulanate group and 21.3% in the placebo group [P = .33]; between-group difference, −4.7% [95% CI, −14.0% to 4.7%]; hazard ratio, 0.77 [95% CI, 0.45-1.31]). Infection rates at 60 days were significantly lower in the amoxicillin-clavulanate group (29.7% vs 41.5%; mean difference, −11.8% [95% CI, −23.0% to −0.7%]; subhazard ratio, 0.62; [95% CI, 0.41-0.91]; P = .02). There were no significant differences in any of the remaining 3 secondary outcomes. The most common serious adverse events were related to liver failure (25 in the amoxicillin-clavulanate group and 20 in the placebo group), infections (23 in the amoxicillin-clavulanate group and 46 in the placebo group), and gastrointestinal disorders (15 in the amoxicillin-clavulanate group and 21 in the placebo group).Conclusion and RelevanceIn patients hospitalized with severe alcohol-related hepatitis, amoxicillin-clavulanate combined with prednisolone did not improve 2-month survival compared with prednisolone alone. These results do not support prophylactic antibiotics to improve survival in patients hospitalized with severe alcohol-related hepatitis.Trial RegistrationClinicalTrials.gov Identifier: NCT02281929

A randomized study of ceftriaxone for the prevention of infections in hospitalized patients with advanced cirrhosis

“…Similarly, results from a study of protocolized use of amoxicillin-clavulanate in patients with severe alcohol-associated hepatitis did not show an increased incidence of C. difficile . 22 We did not observe any proven cases of CTX-resistant infection in this cohort. No fungal infections were observed in this study.…”

“… 20 , 21 Other sub-groups, however, have not demonstrated survival benefit with antibiotic prophylaxis, including those with severe acute alcohol-associated hepatitis and acute liver failure. 22 , 23 …”

Gut Microbiome-Centered Therapies for Alcohol-Associated Liver Disease

“…A recently published multicenter, double-blind, randomized, placebocontrolled trial of Augmentin (amoxicillin/clavulanic acid) and prednisolone for 30 days in 280 patients with SAH did not show improvement of 2-month survival. 56…”

Management of alcoholic hepatitis: A clinical perspective

“…Initial studies on the empirical administration of amoxicillin/ clavulanic acid in addition to prednisolone therapy (the AntibioCor trial) showed a reduced cumulative incidence of infections (41.5% vs. 29.7%), while there was no beneficial effect on 2-month mortality. 67 Response to steroid treatment should be assessed by using the Lille score or by considering changes in bilirubin levels or the MELD score. 7,10 The Lille score is a dynamic score incorporating data from the beginning (day 1) and the course of steroid treatment (day 4 or day 7) to assess the response to steroid treatment, determine the risk of death, and evaluate the subsequent need for further steroid therapy.…”