The antibiotic resistance crisis resolved by bateriophages (part 4)

Yesterday at ECCMID was the long-awaited presentation of the Phagoburn trial: A randomized controlled trial of bacteriophages against Pseudomonas aeruginosa infections in burn wound patients. Bacteriophages have regained considerable attention recently. Proposed as an answer to the rising problems in treating bacterial infections by some, others have remained sceptic due to the absence of evidence of effectiveness coming from well-designed studies, see parts 1, 2 & 3. The Phagoburn trial, though, would the first to deliver high-quality data. So what was presented?

Patrick Jault, lead investigator, presented the long and winding road leading to ECCMID. How they successfully applied for an FP7-HEALTH-2013-INNOVATION call, and got 3.8M€ to produce the phages (June 2013-July 2015), run the RCT (July 2015-January 2017) and then publish the findings (January 2017-now). While searching for useful phages in French sewage systems they got “entrapped” in the regulatory maze with French authorities. Where the investigators wanted to produce phages targeted for the pathogens in an individual patient (personalized medicine), the authorities decided that it should be a fixed product, to be developed as medicinal product. So, it became a cocktail of 12 phages active against >95% of clinically relevant P. aeruginosa isolates and with good efficacy in mice when applied intravenously or intraperitoneally. Therefore, the mode of application in the RCT would be topical.

As it is a medical product “some aspects” (of production, purity, quality control, stability) need to be described, which resulted in an IMPD of 650 pages. The vials with the cocktail were produced and stored on the shelf. Before use, through impregnating dressings with the cocktail to be put on the infected wounds, 2 dilution steps were needed. The phages would be used for 7 days, with microbiological monitoring for primary and secondary endpoints at the end of treatment (day 7) and at the final visit (day 21).

So far, all clear, but then it turned vague, as Jault moved on to the results. In all 25 patients had been enrolled, but no data were presented how these were distributed over the phage and control group, neither were outcome data presented. Yet, the slides with crude microbiology results per patient revealed that apparently 13 patients served as control (=standard care) with 1 “clinical failure”, 10 “therapeutic success” and 2 “disconcordant” (meaning that the different microbiological tests yielded disconcordant results). Among the 12 patients that received phages these figures were – on the slide – 5 “clinical failure”, 5 “therapeutic success” and 2 “disconcordant”. That doesn’t look good for the phages. A possible explanation, brought forward, is that putting all phages together before storage reduced phage survival at the shelf. Now authorities agree to store them separately…..

The investigators decided not to present the outcome results in a more transparent matter (1 table would have been enough), “as a manuscript has been submitted”. I don’t think that that precludes sharing of results at a scientific meeting. If so, we better stop having such meetings, and just read journals. Apart from that though, the investigators deserve a lot of respect for going all the way in using phages for scientific evaluation. It looks like the Phagoburn study, when published, will not provide the evidence to adopt this approach widely, but it certainly contributes to designing and executing future studies. One of the lessons learned seems that phages should be used as personalised medicine, tailored to the infecting strains of an individual patient, rather than as a one-size-fits-all approach.

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