Personalized Inhaled Bacteriophage Therapy Decreases Multidrug-Resistant Pseudomonas aeruginosa

Bacteriophage therapy, which uses lytic viruses as antimicrobials, has received renewed interest to address the emerging antimicrobial resistance (AMR) crisis. Cystic fibrosis (CF), a disease complicated by recurrent P. aeruginosa pulmonary infections that cause lung function decline, is an example where AMR is already a clinical problem. While bacteria evolve bacteriophage resistance, we developed a strategy to select bacteriophages that target bacterial cell surface receptors that contribute to antibiotic resistance or virulence. Thus, in addition to killing bacteria, these phages steer surviving, evolved bacteria to antibiotic re-sensitivity or attenuated virulence. Here, we present outcomes from nine CF adults treated with nebulized bacteriophage therapy for AMR P. aeruginosa using this personalized approach. Results showed that phage therapy: 1) reduced sputum P. aeruginosa , 2) showed evidence for predicted trade-offs in most subjects, and 3) improved lung function, which may reflect the combined effects of decreased bacterial sputum density and phage-driven evolved trade-offs. ### Competing Interest Statement PET is cofounder of Felix Biotechnology, Inc., a company that seeks to develop phages for human therapy. MQA was employed at Felix Biotechnology, Inc. BKC, GLS, KEK, IMO, YS, CG, BK, GR, ZH, CJB, JS, JST, VS, PET, and JLK: Yale University has an institutional conflict of interest related to this project. Yale may receive financial benefit related to the therapy used in this protocol. No reported conflict of interest: MM, SW, CA, NC, SKJ, JR, AK, BSQ, JMR, QAM ### Clinical Trial eIND18757, eIND17849, eIND18680, eIND18690, eIND18988, eIND18842, eIND18989, eIND19023, eIND19024 ### Funding Statement The funding supports for each author: JLK: Cystic Fibrosis (CF) Foundation Clinical Research Scholars Program (CRSP) Award (KOFF19Y5) GLS: CFF 3rd/4th/5th Year Fellowships (STANLE20D0) & NIH Loan Repayment Program BKC & PET: CFF award (TURNER19P0) PET acknowledges support for genetic sequencing from an Illumina, Inc. award to Felix Biotechnology, Inc. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Review Boards of Robert Wood Johnson Medical School, Texas Tech University Health Sciences Center School of Medicine, and Yale University gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors