ArticlesEfficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (PhagoBurn): a randomised, controlled, double-blind phase 1/2 trial
Introduction
Lytic bacteriophages replicate by infecting and multiplying within a specific bacterium until the bacterium is destroyed, and the released virions promote this infecting cycle. An estimated 1 × 1032 phages exist in nature. Phages were discovered by Frederik Twort in 1915 and phage therapy was first described by Felix d'Herelle in 1917 as a complex process.1 10 years after these discoveries antibiotics emerged and their ease of use resulted in phage therapy being essentially abandoned. With the emergence of antibiotic resistance, phage therapy now seems to be a promising alternative to antibiotics, with some successful case reports2, 3, 4 supported by a large fundamental knowledge base.5, 6 As natural biological regulators, bacteriophages fit within the WHO One Health strategy for animals, humans, and the environment.7 However, to our knowledge, no randomised controlled trial has ever investigated phage therapy in humans.
Initiated in 2010, this study (PhagoBurn) is the first randomised controlled trial to investigate phage therapy. The trial was designed with the cooperation and scrutinisation of three drug safety agencies (National Agency for the Safety of Medicines and Health Products [ANSM], France; Federal Agency for Medicines and Health Products [AFMPS], Belgium; and Swissmedic, Switzerland) to ensure it complied with good manufacturing and clinical practices. The trial's objective was to target infected burn wounds because these infections are the main cause of sepsis and death in patients with burns.8 Two features of phage therapy that were considered in the trial design were that treatment with phages could reduce the risks associated with iterative antibiotic use on burn wounds and resistant strains of bacteria, and that, according to recommendations by the French Society for Burn Injuries,9 infected burns should be treated topically because of poor diffusion of systemic antibiotics in burn wounds; therefore, a topically administered phage therapy should remain active until it reaches its target.
This study aimed to evaluate the efficacy and tolerability of a pre-assembled cocktail of 12 natural lytic anti-Pseudomonas aeruginosa bacteriophages compared with standard of care in patients with infected burn wounds.
Section snippets
Study design and participants
In this multicentre, double-blind, randomised phase 1/2 trial, participants were recruited from Hôpital d'instruction des armées Percy in Paris, France, and five other specialised burn centres in hospitals in Lyon, Nantes, Metz, Toulon, and Marseille in France, and the Queen Astrid Military Hospital in Brussels, Belgium, and two other burn centres in hospitals in Liège and Loverval in Belgium. The study was coordinated and overseen in France by the French Ministry of Defence, and in Belgium it
Results
Between July 22, 2015, and Jan 2, 2017, 27 patients with infected burn wounds were recruited, 16 (59%) during the first recruitment period (July 22, 2015, to Jan 2, 2016) and 11 (41%) during the second (May 31, 2016, to Jan 2, 2017). Patients were randomly assigned to the PP1131 group (n=13) or the standard of care group (n=14). In the standard of care group, one patient was not exposed to treatment because they were randomly assigned to the group on the day the trial was suspended (Jan 2,
Discussion
We found that daily bacterial burden in the most infected wound was successfully reduced by two quadrants or more in half of participants at the end of phage treatment. However, the median time to achieve this endpoint was significantly longer for those in the PP1131 group than for those in the standard of care group. This result was independent of systemic use of antibiotics active against the infecting strain, either ongoing at day 0 or introduced later during study treatment. To our
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