Macrolides as Adjunctive Treatment in Sepsis: A Systematic Review and Meta-Analysis

Abstract

RATIONALE Sepsis remains a leading cause of mortality and hospitalization costs. Individual randomized controlled trials (RCTs) on macrolides with their posited immunomodulatory effects showed no clear effect on mortality among septic patients. This study aimed to determine the effectiveness of adding macrolides to standard care in reducing mortality, shortening stay in the intensive care unit (ICU) and hospital, and duration of mechanical ventilation among adult patients with sepsis. METHODS We searched electronic databases (PubMed, CINAHL Plus with Full Text, CENTRAL, ClinicalTrials.gov, ISRCTN Registry and Herdin) until March 2018 for RCTs comparing macrolides with standard care or placebo in adults with sepsis or septic shock. We also examined Philippine journals and reference lists and attempted to contact authors for unpublished data. Two authors independently extracted data and appraised study characteristics, quality, and outcomes. Statistical analysis was done using RevMan 5.3. RESULTS We found three completed randomized trials with 847 participants. Most patients had Gram negative infections and received carbapenem-based antibiotics. Pooled analysis of the moderate to high quality studies showed no significant effect on all-cause mortality at one month (RR 1.00, 95% CI: 0.77, 1.30) and no heterogeneity (I 2 =0). Planned subgroup analyses by macrolide type were likewise inconclusive: azithromycin versus placebo (RR 1.70, 95% CI: 0.31, 9.28) and clarithromycin versus placebo (RR 0.98, 95% CI: 0.75, 1.29). Azithromycin did not reduce long-term all-cause mortality at 180 days nor 360 days. No significant difference in ICU and hospital length of stay, and duration of mechanical ventilation was observed. CONCLUSIONS Few high-quality RCTs on macrolide therapy for sepsis are currently available. Add-on macrolides to standard management of septic adult patients did not significantly reduce mortality, shorten length of stay, nor hasten liberation from mechanical ventilation.