Efficacy of Aerosolized Rifaximin versus Tobramycin for Treatment of Pseudomonas aeruginosa Pneumonia in Mice

Abstract

Pseudomonas aeruginosa is a Gram-negative opportunistic bacterial pathogen that can cause chronic lung infections in patients with cystic fibrosis (CF). The current preferred treatment for CF lung infections includes inhaled tobramycin (TOB); however, studies suggest TOB cannot effectively inhibit biofilm formation. Using an NIH small compounds drug library approved for safe use in humans, we identified rifaximin (RFX), a semisynthetic, rifamycin family, nonsystemic antibiotic that inhibits alginate production and growth in P. aeruginosa. Inhibition of alginate production was further analyzed using the uronic acid carbazole assay and a promoter reporter assay that measures the transcription of the alginate biosynthetic operon. Compared to TOB, RFX significantly reduced alginate production in laboratory and CF sputum isolates of P. aeruginosa. In addition, RFX showed a narrow range of MICs when measured with multidrug-resistant bacterial species of clinical relevance, synergistic activities with TOB or amikacin against clinical isolates, as well as reduction toward in vitro preformed biofilms. In C57BL/6 mice, penetration of nebulized TOB into the lungs was shown at a higher level than that of RFX. Further, in vivo assessment using a DBA/2 mouse lung infection model found increased survival rates with a single-dose treatment of nebulized RFX and decreased P. aeruginosa PAO1 biobur-den with a multiple-dose treatment of RFX plus TOB. In addition, mice treated with a single exposure to dimethyl sulfoxide (DMSO), a solvent that dissolves RFX, showed no apparent toxicity. In summary, RFX may be used to supplement TOB inhalation therapy to increase efficacy against P. aeruginosa biofilm infections.