Clinical Efficacy of Azithromycin in Patients With Severe Sepsis: Open Label Pilot Randomized Controlled Trial

Abstract

PURPOSE: Azithromycin (AZ) is a macrolide that has shown increased survival in patients with community-acquired pneumonia and bacteremic pneumococcal pneumonia. Immunomodulatory properties are claimed to be associated with the beneficial effects of macrolides. However, limited data are available about the clinical efficacy in patients with severe sepsis. Our aim was to assess the efficacy of AZ in addition to standard of care (SOC) therapy compared to SOC antimicrobial therapy in a pilot randomized controlled trial (RCT) in critically ill patients with severe sepsis. METHODS: This is an open-label RCT that compared AZ/SOC vs. SOC in critically ill patients with severe sepsis with at least one organ failure according to the ACCP guidelines. The study was performed at two tertiary teaching hospitals. The Per-Protocol (PP) interventions included patients that received at least 3 days of AZ (500 mg daily of 5 days of therapy) vs. appropriate SOC for at least 3 days. Exclusion criteria were: 1) immunosuppressed, 2) allergy to macrolides, 3) QTc prolongation and the use of concomitant medications that may prolong the QTc. The primary outcome was 28-day mortality and the secondary outcomes were short- (ICU and in-hospital mortality), long-term mortality (at 180-days and 365-days) and length of stay (LOS) in the ICU and in the hospital. RESULTS: We enrolled 47 subjects in the PP analysis that completed at least 3-days of antimicrobial treatment (n=22 AZ/SOC and n=25 SOC). The primary outcome of 28-day mortality was similar in both groups (AZ/SOC, n=3 [14%] vs. SOC, n=2 [8%], p=0.5). The secondary outcomes were ICU mortality (AZ/SOC, n=2 [9%] vs. SOC n=1 [4%], p=0.5), in-hospital mortality (AZ/SOC, n=2 [9%] vs. SOC n=2 [8%], p=0.9), 180-day mortality (AZ/SOC, n=4 [18%] vs. SOC, n=5 [21%], p=0.5), and 360-day mortality (AZ/SOC n=5 [24%] vs. SOC n=9 [39%], p=0.2). The ICU LOS was AZ/SOC median (IQR) 7 (4-16) vs. 8 (4-13) days, p=.5; and hospital LOS AZA/SOC median (IQR) 19 (7-26) vs. 18 (13-28) days, p=.9; respectively. CONCLUSIONS: In this pilot open label RCT the use of AZ in addition to SOC was not associated with better survival or shorter LOS in the PP analysis of severe septic patients who received at least 3-days of antimicrobial therapy.