BACKGROUND: Pseudomonas aeruginosa is the most common and significant life-threating pathogen for CF patients. The transition from non-mucoid to mucoid PaPI indicates disease progression, after which the lung function deterioration would be exacerbated. To treat continuous deterioration of lung function, CF patients need to use lung maintenance therapies chronically for an average of 20 years. However, majority of evidence identifies only short-term follow-up. Moreover, no guideline suggests when a treatment change is needed, nor the order of prescribing those treatments. OBJECTIVES: To investigate the comparative effectiveness of different treatment regimes to delay the acquisition of mucoid PaPI. METHODS: Using the Cystic Fibrosis Foundation Patient Registry, this retrospective cohort was applied to emulate an RCT under a casual inference framework. Pediatric patients (n=4970) who were diagnosed with non-mucoid PaPI before mucoid PaPI during 2006-2011 were included. A rational treatment change score was created using machine-learning method including patients’ demographic characteristics, clinical signals and treatment histories. According to different thresholds of the score, which steered the decision of treatment change, 25 regimes were built. Each patient was hypothetically randomized to follow all regimes independently. A fixed parameterization of the dynamic logistic marginal structural model with the constant-time hazard was applied to investigate the effectiveness of different regimes. RESULTS: Using the effect of patients whose treatment changes followed a specific regime as the reference, patients whose treatment changes did not follow any regime caused 17% greater hazard of mucoid PaPI during 6-year follow-up. Compared with the reference regime, the hazard ratio ranged from 0.98 to 1.07 for other regimes. CONCLUSIONS: In this study, changing treatments irrationally, not followed any clinical signals, caused the worst outcome. The differences of effect were trivial among regimes. To achieve better outcomes, physicians should follow a regime, logically the optimal one, in changing lung maintenance therapy.