Bacteriophage Therapy of Multidrug-resistant Achromobacter in an 11-Year-old Boy With Cystic Fibrosis Assessed by Metagenome Analysis

Abstract

Background: Cystic fibrosis (CF) is a genetic disease associated with lung disease characterized by chronic pulmonary infection, increasingly caused by multiple drug-resistant pathogens after repeated antibiotic exposure, limiting antibiotic treatment options. Bacteriophages can provide a pathogen-specific bactericidal treatment used with antibiotics to improve microbiologic and clinical outcomes in CF. Methods: Achromobacter species isolates from sputum of a chronically infected person with CF, were assessed for susceptibility to bacteriophages: 2 highly active, purified bacteriophages were administered intravenously every 8 hours, in conjunction with a 14-day piperacillin/tazobactam course for CF exacerbation. Sputum and blood were collected for metagenome analysis during treatment, with sputum analysis at 1-month follow-up. Assessments of clinical status, pulmonary status and laboratory evaluation for safety were conducted. Results: Bacteriophage administration was well-tolerated, with no associated clinical or laboratory adverse events. Metagenome analysis documented an 86% decrease in the relative proportion of Achromobacter DNA sequence reads in sputum and a 92% decrease in blood, compared with other bacterial DNA reads, comparing pretreatment and posttreatment samples. Bacteriophage DNA reads were detected in sputum after intravenous administration during treatment, and at 1-month follow-up. Reversal of antibiotic resistance to multiple antibiotics occurred in some isolates during treatment. Stabilization of lung function was documented at 1-month follow-up. Conclusions: Bacteriophage/antibiotic treatment decreased the host pulmonary bacterial burden for Achromobacter assessed by metagenome analysis of sputum and blood, with ongoing bacteriophage replication documented in sputum at 1-month follow-up. Prospective controlled studies are needed to define the dose, route of administration and duration of bacteriophage therapy for both acute and chronic infection in CF.