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.

Phage Therapy: An Alternative Approach to Combat Multi-drug Resistant Infections in Cystic Fibrosis

“…The use of phages offers several benefits like their self-replicating capacity which allows them to replicate easily, moreover they are also much cheaper and faster to prepare in contrast with antibiotics. Further, they are pretty specific, and no phage replication occurs in human tissues, supporting the observation of remarkable safety in reported cases of treatments [46,47].…”

“…Beside the treatment of pwCF with mycobacterial or pseudomonal infections, cases of compassionate treatment with phage in patients with infection with Burkholderia spp [74,75], and Achromobacter spp infections [70,72,82] have also been reported. Even in this type of infection, however, the effects of phage therapy, as well as the outcome of patients, proved to be very heterogeneous .…”

Automating Predictive Phage Therapy Pharmacology

“…These are all as found in situ while treating infections caused by what are typically somewhat uncharacterized bacterial strains and, in many cases, also in combination with antibiotics [ 41 , 57 , 86 , 87 , 88 , 89 ], which can have antagonistic impacts on phage infection abilities [ 41 , 51 , 85 , 90 ]. In particular for the latter, note that of 18 clinical phage therapy studies that I was able to obtain—published in 2023 or, at the time of writing, which are published but still online ahead of print—at least 16 indicate treatments using phages in combination with antibiotics [ 57 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 ]. See also [ 109 ], where 79 of the 114 clinical phage treatments reported “were administered in combination with standard-of-care antibiotics”.…”

Phage therapy: breathing new tactics into lower respiratory tract infection treatments

“…Achromobacter responded successfully to phage therapy in a 12-year-old CF patient after lung transplant without any recurrence through the 2 years of follow-up [ 45 ]. Metagenome analysis of blood and sputum in a patient with CF who underwent phage therapy showed a 92% and 86% decrease, respectively, in Achromobacter DNA sequence with improvement of lung function at 1-month follow-up [ 46 ].…”