Timing of nebulized colistimethate sodium following bronchodilator airway conditioning in hospital-acquired pneumonia: a target trial emulation study

Background Evidence for nebulized colistimethate sodium (CMS) in hospital-acquired pneumonia (HAP) remains inconsistent, potentially due to heterogeneity in airway conditions and delivery timing. We evaluated whether timely initiation of nebulized CMS following bronchodilator airway pre-treatment was associated with microbiological outcomes in critically ill patients. Methods We conducted a multicenter retrospective cohort study using target trial emulation among adult ICU patients with HAP who received nebulized CMS following bronchodilator nebulization. Two per-protocol strategies were compared: initiation within 90 min of bronchodilator nebulization (LE90) versus later initiation (GT90). Cloning, censoring, and inverse probability of censoring weighting were applied to address time-dependent confounding. The primary outcome was 14-day cumulative incidence of microbiological clearance, treating death as a competing event. Results Among 218 eligible patients, timely initiation was associated with a higher weighted cumulative incidence of microbiological clearance at day 14 (71.9% vs. 52.6%; absolute difference 19.3%, 95% CI 4.8–32.5; P = 0.012) and a shorter restricted mean time alive and not microbiologically cleared (6.85 vs. 10.08 days; difference −3.23 days, 95% CI −4.30 to −2.08; P < 0.001). Findings were consistent across subgroups and robust in sensitivity analyses. No significant differences were observed in clinical success, superinfection, mortality, ICU length of stay, or ventilator-free days. Bronchospasm incidence was similar between strategies. Conclusion Timely initiation of nebulized CMS within a defined post-bronchodilator window was associated with higher microbiological clearance and reduced persistent infection, without increased airway adverse events. These findings are hypothesis-generating and require prospective validation, particularly with respect to patient-centered outcomes.