Another weak phage therapy paper

The rise of diabetes in the developed world has brought along a rise in persistent ulcers and abscesses.  These infections don’t respond particularly well to either systemic or topical antibiotics and as a result, an unfortunately high proportion are resolved by amputation.  This is nobody’s notion of an acceptable medical outcome.

Phage therapy has been used in wound and burn treatment for decades in some countries, and should have advantages over antibiotics in treating diabetic ulcers.  Unlike antibiotics, phage tend to be highly specific in their action, targeting intended pathogens (S. aureus, Pseudomonas, Streptococcus,  Acinetobacter) while leaving commensal bacteria alone.  Antibiotics are much more indiscriminate, killing the good bacteria along with the bad.  As some skin commensals, such as S. epidermidis, have been reported to secrete immune-stimulating compounds, it would seem that a treatment which spares them might confer a significant clinical advantage.

Phage have also been reported to be able to penetrate biofilms, which antibiotics often fail to do. Biofilms are characteristic of persistent infections, making their resident bacteria much more resistant to eradication.

Phage also have the power of replication: one phage-infected bacterial cell will give rise to tens or hundreds of phage progeny.  These progeny can then go on to infect other bacterial cells, creating a chain-reaction that wipes out the pathogen community at a wound site.

Phage treatment of diabetic ulcers would thus seem to have great potential to improve the care of these stubborn infections.  It has a high therapeutic ceiling: specific killing of pathogens while sparing normal skin flora; penetration of biofims; ability to replicate and persist. It could be a genuine advance in the treatment of disease.

That’s why papers like the one from Mendes et al (Wound healing potential of topical bacteriophage therapy on diabetic cutaneous wounds) is such a disappointment.  The authors did indeed see a positive response to phage treatment of diabetic ulcers in two animal models (mice and pigs), and the responses sometimes were strong enough to probably not be random.  But that’s about all you can say – the differences between treated and untreated wounds just wasn’t all that great.  Given the fact that most preclinical results, even very strong and powerful results, usually fade when translated to clinical settings, it is hard to get excited by marginally observable effects in animal models.

Why such weak results?  Phage therapy really should work for this indication, and I think that it can be made to work.  But I gagged when I read this description in Methods:  “S. aureus … P. aeruginosa … and A. baumannii lytic bacteriophages were isolated from sewage water from the Lisbon area.”

No, no, NO!

Bacteriophage are highly diverse creatures that have evolved under intense selective pressure to thrive and survive in specific environments.  There is no reason to expect that a sewage phage – which probably had been living and competing in the environment of the lower intestine – would prosper in the entirely different environment of a diabetic ulcer.  Doing a wound study with sewer phage is either naive or lazy.  There is no way it is good science.

That the phage fared poorly in wounds is implied by the doses used in the experimental treatment: 10 – 100 times the number of bacteria in the wounds.  At this concentration, phage do not have to even successfully infect a host in order to kill it.  The degradative enzymes they use to gain entry to the cell are sufficient to do the job.  The authors probably found in preliminary experiments that low doses of phage had no effect, and rather than find better phage, simply upped the dose.

Phage therapy is a potentially promising approach for treating diabetic ulcers and deserves to be pursued.  But it is unlikely that random phages picked up in the environment will be effective. Screening and selecting phages that work in the environment of a diabetic ulcer – the proper approach –  will require a lot of hard and frustrating work.  That’s just how drug development is.  Random chemicals rarely turn out to have the efficacy, tox profile and PK/PD required of useful drugs.  It is naive, and ultimately harmful, to expect development of phage therapeutics to be any less difficult.  Advocates of phage therapy need to call out weak studies like this if there is ever going to be any progress.