Personalized inhaled bacteriophage therapy for treatment of multidrug-resistant Pseudomonas aeruginosa in cystic fibrosis

Bacteriophage (phage) therapy, which uses lytic viruses as antimicrobials, is a potential strategy to address the antimicrobial resistance (AMR) crisis. Cystic fibrosis (CF), a disease complicated by recurrent Pseudomonas aeruginosa pulmonary infections, is an example of AMR’s clinical impact. Using a novel personalized phage therapy strategy that selects phages for a predicted evolutionary ‘trade-off’, nine CF adults (8 female, 1 male) median age 32 (range 22-46) years were treated with phages on a compassionate basis because their clinical course was complicated by multi-drug resistant or pan-drug-resistant Pseudomonas that was refractory to prior courses of standard antibiotics. Individuals received nebulized cocktail or single phage therapy without adverse events. 5-18 days after phage therapy, sputum Pseudomonas decreased by a 104 CFU/mL median, or 102 CFU/mL mean difference (p = 0.006, Two-way ANOVA with Dunnett’s multiple comparisons test) without altering sputum microbiome, and analysis of sputum Pseudomonas showed evidence for ‘trade-offs’ that decreased antibiotic resistance or bacterial virulence. In addition, an improvement of 6 (median) and 8 (mean) percent predicted FEV1 (ppFEV1) was observed 21-35 days after phage therapy (p = 0.004, Wilcoxon signed rank t test) may reflect the combined effects of decreased bacterial sputum density and phage-driven trade-offs. These results show that a personalized, nebulized phage therapy ‘trade off’ strategy may affect clinical and microbiologic endpoints, which must be evaluated in larger clinical trials.