Amoxicillin-clavulanate not associated with improved survival outcomes in patients with severe alcohol-related hepatitis receiving prednisolone

1. In this randomized clinical trial, among 284 patients with severe alcohol-related hepatitis, mortality at 60 days was 17.3% in the amoxicillin-clavulanate group, compared with 21.3% in the placebo group.

2. Infection rates at 60 days were significantly lower in the amoxicillin-clavulanate group at 29.7%, compared with the placebo group at 41.5%.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Severe alcohol-related hepatitis is associated with a mortality rate as high as 30% at 2-month follow-up. To improve mortality rates, oral prednisone is given to patients with severe alcohol-related hepatitis. However, despite receiving corticosteroid treatment, approximately 30% of patients with severe alcohol-related hepatitis will develop a bacterial or fungal infection. The benefits of prophylactic antibiotics for hospitalized patients with severe alcohol-related hepatitis remain unclear. Hence, this study aimed to determine the efficacy of amoxicillin-clavulanate, compared with placebo, on mortality in patients hospitalized with severe alcohol-related hepatitis being treated with prednisolone. A total of 292 patients were randomized in a 1:1 allocation to receive prednisolone combined with amoxicillin-clavulanate (n=145) or prednisolone combined with placebo (n=147), of which 284 were analyzed. The primary outcome was all-cause mortality at 60 days. No significant difference in 60-day mortality was found between patients randomized to amoxicillin-clavulanate and placebo. The most common serious adverse events were liver failure, infections, and gastrointestinal disorders. A limitation of this study was the fixed duration for antibiotic administration, as a longer or shorter duration of antibiotics may have been associated with a different outcome. Strengths, however, were that the study followed a rigorous methodology and performed an in-depth statistical analysis.  Overall, this study found that in patients hospitalized with severe alcohol-related hepatitis, amoxicillin-clavulanate combined with prednisolone was not associated with an improvement in 60-day survival compared with placebo.

Click to read the study in JAMA

Click to read an accompanying editorial in JAMA

Relevant Reading: Corticosteroids reduce risk of death within 28 days for patients with severe alcoholic hepatitis, compared with pentoxifylline or placebo – a meta-analysis of individual data from controlled trials

In-Depth [randomized controlled trial]: This study investigated the efficacy of amoxicillin-clavulanate, compared with placebo, in patients hospitalized with severe alcohol-related hepatitis treated with prednisolone. The primary outcome of this study was all-cause mortality at 60 days. Secondary outcomes included 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. A total of 292 patients (mean age, 52.8 [SD, 9.2] years; 80 [27.4%] women) were randomized (1:1 allocation) to receive prednisolone combined with amoxicillin-clavulanate (n=145) or placebo, of which 284 were analyzed. No significant difference in 60-day mortality was found between patients randomized to amoxicillin-clavulanate and 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]). Rates of infection 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 – 0.9]; P = .02). No significant differences were identified in the remaining 3 secondary outcomes. At 60-day follow-up, patients reported 230 adverse events, of which 68 were in the amoxicillin-clavulanate group and 77 were in the placebo group.

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