The acquisition of P.aeruginosa by cystic fibrosis (CF) patients initiates a brisk inflammatory response in the airways, long before symptomatic pulmonary disease develops. Antimicrobial therapy forP.aeruginosa ameliorates this process but does not eradicate the organism. To develop therapeutic strategies to prevent or delay the acquisition of Pseudomonas the efficacy of carbohydrates which compete for binding of the major P.aeruginosa adhesin, pilin, were tested. Pilin recognizes a GalNacβ41-Gal moiety available on asialylated glycolipids. GalNac, galactose, glucose and maltose in varying concentrations each inhibited less than 25% of the P.aeruginosa PAO1 binding. Dextran (5 mM), a polymer of D-glucose was highly effective in blocking > 75%of the adherence of PAO1 to primary respiratory epithelial cells or to transformed cell lines. Competitive binding experiments were done using FITC-labeled dextran to determine if dextran has specificity for the pilus-adhesin or the epithelial receptor. Dextran blocked anti-asialoGM1antibody from recognition of asialoGM1 but did not block cholera toxin binding to GM1, suggesting that it is specific for the pilin adhesin and is not simply blanketing the epithelial surface. In a mouse model of acuteP.aeruginosa pneumonia mice exposed to an aerosol of 10 mM dextran were completely protected from mortality (0/21) as compared with the 20% mortality in the controls. In only 10% of the dextran treated animals were any PAO1 recovered from the lungs 24 hours after inoculation, as compared with a 55% rate of significant Pseudomonas pneumonia in the controls. Aerosolized carbohydrates may be useful in preventing the initial adherence ofP.aeruginosa to the airway.