Articles
Efficacy 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

https://doi.org/10.1016/S1473-3099(18)30482-1Get rights and content

Summary

Background

Wound infections are the main cause of sepsis in patients with burns and increase burn-related morbidity and mortality. Bacteriophages, natural bacterial viruses, are being considered as an alternative therapy to treat infections caused by multidrug-resistant bacteria. We aimed to compare the efficacy and tolerability of a cocktail of lytic anti-Pseudomonas aeruginosa bacteriophages with standard of care for patients with burns.

Methods

In this randomised phase 1/2 trial, patients with a confirmed burn wound infection were recruited from nine burn centres in hospitals in France and Belgium. Patients were eligible if they were aged 18 years or older and had a burn wound clinically infected with P aeruginosa. Eligible participants were randomly assigned (1:1) by use of an interactive web response system to a cocktail of 12 natural lytic anti-P aeruginosa bacteriophages (PP1131; 1 × 106 plaque-forming units [PFU] per mL) or standard of care (1% sulfadiazine silver emulsion cream), both given as a daily topical treatment for 7 days, with 14 days of follow-up. Masking of treatment from clinicians was not possible because of the appearance of the two treatments (standard of care a thick cream, PP1131 a clear liquid applied via a dressing), but assignments were masked from microbiologists who analysed the samples and patients (treatment applied while patients were under general anaesthetic). The primary endpoint was median time to sustained reduction in bacterial burden by at least two quadrants via a four-quadrant method, assessed by use of daily swabs in all participants with a microbiologically documented infection at day 0 who were given at least one sulfadiazine silver or phage dressing (modified intention-to-treat population). Safety was assessed in all participants who received at least one dressing according to protocol. Ancillary studies were done in the per-protocol population (all PP1131 participants who completed 7 days of treatment) to assess the reasons for success or failure of phage therapy. This trial is registered with the European Clinical Trials database, number 2014-000714-65, and ClinicalTrials.gov, number NCT02116010, and is now closed.

Findings

Between July 22, 2015, and Jan 2, 2017, across two recruitment periods spanning 13 months, 27 patients were recruited and randomly assigned to receive phage therapy (n=13) or standard of care (n=14). One patient in the standard of care group was not exposed to treatment, giving a safety population of 26 patients (PP1131 n=13, standard of care n=13), and one patient in the PP1131 group did not have an infection at day 0, giving an efficacy population of 25 patients (PP1131 n=12, standard of care n=13). The trial was stopped on Jan 2, 2017, because of the insufficient efficacy of PP1131. The primary endpoint was reached in a median of 144 h (95% CI 48–not reached) in the PP1131 group versus a median of 47 h (23–122) in the standard of care group (hazard ratio 0·29, 95% CI 0·10–0·79; p=0·018). In the PP1131 group, six (50%) of 12 analysable participants had a maximal bacterial burden versus two (15%) of 13 in the standard of care group. PP1131 titre decreased after manufacturing and participants were given a lower concentration of phages than expected (1 × 102 PFU/mL per daily dose). In the PP1131 group, three (23%) of 13 analysable participants had adverse events versus seven (54%) of 13 in the standard of care group. One participant in each group died after follow-up and the deaths were determined to not be related to treatment. The ancillary study showed that the bacteria isolated from patients with failed PP1131 treatment were resistant to low phage doses.

Interpretation

At very low concentrations, PP1131 decreased bacterial burden in burn wounds at a slower pace than standard of care. Further studies using increased phage concentrations and phagograms in a larger sample of participants are warranted.

Funding

European Commission: Framework Programme 7.

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

References (24)

  • A Sulakvelidze et al.

    Bacteriophage therapy

    Antimicrob Agents Chemother

    (2001)
  • TM Viertel et al.

    Viruses versus bacteria-novel approaches to phage therapy as a tool against multidrug-resistant pathogens

    J Antimicrob Chemother

    (2014)
  • Cited by (0)

    View full text