Macrolide Therapy in Critically Ill Patients with Community-Acquired Pneumonia: Protocol for a Systematic Review and Meta-Analysis

Background Several studies have suggested that macrolide therapy may be associated with reduced mortality in critically ill adult patients with community-acquired pneumonia (CAP). The objective of this systematic review is to examine the influence of macrolide versus non-macrolide antimicrobial therapy on mortality in this population. Methods We will identify studies through electronic database searches of MEDLINE, Embase, Cochrane Library, Web of Science, Scopus, and reference lists from database inception to October 2025. Eligible studies will include randomized controlled trials (RCTs) and observational studies (prospective or retrospective). Two reviewers (AQ, ML) will independently screen titles, abstracts, and full texts for inclusion, extract data, and assess risk of bias. Risk of bias will be assessed using the Cochrane Risk of Bias 2 tool for randomized trials and the Newcastle-Ottawa Scale for observational studies. Conflicts will be settled by consensus, or with senior author (WS) input. Where appropriate, pooled mortality estimates will be calculated using random-effects meta-analysis models. Statistical heterogeneity will be assessed using the I² statistic. Additional planned subgroup analyses a priori include: combination therapies (beta-lactam [BL]/macrolide vs. BL/fluoroquinolone vs. BL/doxycycline), high vs. low risk of bias, only RCTs, only prospective studies, only prospective cohort studies within observational designs, confirmed Streptococcus pneumoniae , adjusted estimates, vasoactive support, invasive mechanical ventilation, extracorporeal life support (ECLS), and corticosteroid use for treatment of CAP. Meta-regression will be conducted to explore sources of heterogeneity using the following covariates: year of publication, patient age, illness or pneumonia severity scores (if reported), and proportions of patients with vasoactive support, invasive mechanical ventilation, ECLS, or who receive corticosteroid therapy for CAP. Discussion This review will summarize and assess the impact of macrolide therapy on mortality in critically ill patients with CAP. Findings will help inform clinical practice and may support updates to national and international guidelines for the management of severe CAP. Systematic review registration: This protocol is registered with PROSPERO (CRD420251084417).