Pre-existing antiphage immunity and bacterial heteroresistance impact clinical phage therapeutics

Phage therapy is a promising strategy against antibiotic-resistant infections. We followed a 22-year-old patient with cystic fibrosis who qualified for compassionate use phage therapy to treat a chronic, extensively drug-resistant Bordetella bronchialis infection. We isolated Simon, a novel phage capable of powerful antibacterial activity in vitro. Intravenous therapy for 30 days with Simon did not elicit adverse events. Initial assessment of the therapeutic effect was promising but microbiological relapse was seen by day 17. Our investigations determined two main factors that could have played a role in this undulating clinical course. First, we confirmed the presence of anti-Simon antibodies in the patient before, during, and after therapy, with a subset of them cross-reacting against induced prophages from the infecting B. bronchialis. Second, we observed bacterial heteroresistance: the baseline presence of bacterial subpopulations with reduced susceptibility to Simon. These factors should be considered, and screened for, in future clinical phage therapy cases.This BioProject contains genomic data from the following B. bronchialis isolates; one phage-sensitive parent strain isolated from the patient (referred to as 'WT'), one phage resistant strain isolated from the lab, 14 pre-treatment isolates; and 44 post-treatment isolates that evolved in-vivo in the presence of phage Simon. This BioProject also contains genomic data from phage Simon.