Introduction Previous generations of CFTR modulation have been shown to temporarily decrease the frequency of culture positivity of P. aeruginosa and other respiratory pathogens. Recently, a three-drug combination Trikafta (elexacaftor/ivacaftor/tezacaftor) was approved for individuals with at least one F508del mutation. There is limited data on the effect of CFTR modulators on bacterial density and CF microbiome. Methods Our study included 2 separate forms of data collection: Firstly, a retrospective chart evaluation of routine respiratory cultures 1.5 years before and after initiation of Trikafta. Respiratory culture density was recorded based upon the growth fraction of standard respiratory plate: none (0/4), scant (1/4), light (2/4), moderate (3/4), and large (4/4). The second data measurement included obtaining next-generation sequencing (NGS) for bacterial and fungal abundance of post-Trikafta initiation patients only. Results There was a significant density decrease in P. aeruginosa (1.5 vs 1.19, p= 0.01), S. aureus (2.47 vs 1.9, p= 0.002), A. denitrificans (1.39 vs,1.14, p=0.02), E. coli (1.09 vs 1.00, p=0.045) before and after initiation of Trikafta. On the NGS the 5 most abundant bacteria after Trikafta initiation were : S. salivarius, S. parasanguinis, R. mucilaginosa, V. atypica, and P. histocola. Conclusion Our study results demonstrate that there is a significant decrease in the density of known CF pathogenic bacteria. NGS post-Trikafta has shown abundance of anaerobic bacteria ( S. salivarius, S. parasanguinis, R. mucilaginosa, V. atypica, and P. histocola) that have been linked to improved clinical lung stability, lower airway inflammation and increased polymicrobial diversity.