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Studies investigating the association between macrolides and outcomes in both pulmonary and nonpulmonary critically ill patients are limited. We aimed to examine the association between azithromycin use and clinical outcomes in severe sepsis patients with and without pneumonia receiving mechanical ventilation.A retrospective cohort of 105 patients admitted to an adult intensive care unit (ICU) with severe sepsis in an urban university hospital were included in the study. Multivariable linear regression was performed to assess the relationship between azithromycin use and the following outcomes: 28-day ICU-free days and 28-day ventilator-free days.In univariate analysis, patients receiving azithromycin had nearly 6 more ICU-free days on average than did patients not receiving azithromycin (P = .005). The increased ICU-free days remained in multivariable analysis adjusting for age, sex, race, ICU type, and presence of shock (P = .005). In stratified analysis examining the association of azithromycin use in severe sepsis patients without pneumonia (n = 74), the results were similar to the full cohort.Azithromycin was associated with more ICU-free days in severe sepsis patients with and without pneumonia. Further investigations are warranted to better elicit the association of macrolide use on clinical outcomes in severe sepsis patients, especially those without pneumonia.