Modulator Therapy: Rates and Stages of Respiratory Microbiome Restoration in Cystic Fibrosis Patients Chronically Infected with <em>Pseudomonadota</em>

Chronic lung infection with Pseudomonadota (PCH) in patients with cystic fibrosis (pwCF) is difficult to eradicate. CFTR modulators have a potential role in the prevention of airway infections, but their ability to eradicate chronic infection remains to be investigated. The aim of our study was to evaluate the impact of combination (antibacterial (AT) and modulator (MT)) therapy on the lung microbiome composition (LMC) in the pwCF cohort. The microbiome of sputum samples longitudinally collected from Russian adult pwCF chronically infected with Pseudomonadota CF pathogens (PCH) was analyzed. MT resulted in a trend of bacterial load reduction. LMC did not undergo significant changes in PCH pwCF receiving MT for less than three years. Two-component MT resulted in a temporary decrease in the proportion of the CF pathogen only when combined with a course of AT. Three-component MT has been successful in inducing favorable microbiome changes (with abundance and diversity of anaerobic taxa) over a period of more than 3 years, but not for all cases of Burkholderiales infection. Respiratory system damaged by bronchiectasis is susceptible to new infections, so patient management requires constant monitoring of the LMC and replenishment of the therapeutic landscape with both new modulators and new antibacterial drugs.