As I’ve mentioned before, PT suffers from a lack of well-designed clinical trials. Part of this lack can be attributed to a mind-set of true-believerism among PT practitioners. Part of it can be attributed to a dearth of funding required to design and execute trials – not just for PT, but for anti-infective therapy in general. And this lack of funding can in turn be attributed to the scarcity of patients eligible for PT. Despite all the hype around the impending antibiotic resistance apocalypse, antibiotic therapy failure is just not very common. The Phagoburn trial, although well-designed, fizzled out for just this reason.
So case studies are often all we are left with. Usually these are improvised in response to a patient who has failed conventional therapy. The quality of information suffers accordingly, as physicians are understandably focused on saving their patient rather than following a strict pre-specified protocol and making measurements that are informative but intrusive and time-consuming.
A recent case study of a patient suffering from Pseudomonas septicemia falls into this category of promising but incomplete. Originally treated for Enterobacterperitonitis, he suffered several complications including gangrene leading to amputation and eventually pressure sores infected with MDR Pseudomonas leading to severe sepsis.
He was treated with colistin, a last-ditch antibiotic that is last-ditch because of its high kidney toxicity. When his kidneys began to fail, phage therapy was tried.
The notable aspect of this case is the use of a phage cocktail that had been produced under a fairly robust quality control system.
The crux of the results are summarized in this figure:
Almost immediately upon initiation of PT, the patient’s temperature dropped and his blood cultures became negative. This is not proof that PT was effective, but it is highly suggestive and is the most likely explanation.
These results are in contrast to a comparable case study of phage therapy of an Acinetobacterinfection, where it took many days to see a strong clinical response, making the link between therapy and response much more questionable.
I criticized the Acinetobacter study authors for not appreciating or understanding the unfavorable pharmacokinetics of systemic phage therapy. It’s not clear if the authors of the current Pseudomonas study show any greater understanding. They wrote that the patient was dosed with 50 microliters IV of the phage prep (at 1e9/mL) over 6 hours. If that is correct, it is an almost impossibly small dose – 5e7 phage, which would be immediately diluted in the plasma compartment to about 1e4 phage/mL, far too low to be effective.
But this was a typo. I emailed the corresponding author, Serge Jenner, and he quickly confirmed that the actual dose was 50 mL. Although still too low in my view, this is 50X the dose in the Acinetobacter study.
Even at 50 mL, the rapid response is remarkable and unexpected from the known slow kinetics of phage infection of target bacteria. My guess is that the primary foci of infection (the pressure sores) had highly leaky vascularization (this is common to infections) and had a high local density of target bacteria. Once a few cells were successfully infected by the phage, a chain reaction could ensue in which progeny phage attain a high local density and rapidly infect and kill neighboring bacteria.
But this is speculation. No pharmacokinetic or biodistribution data were reported, and probably were not performed on such a sick patient.
So we have yet another example of the promise of PT, but don’t really know why or how it worked, or under what circumstances it can be made to work again. Inconsistency of results has been a great bugaboo of PT, a complaint of physicians since the 1920s. This paper doesn’t solve that problem, but I hope it provides an incentive to others to do the careful thorough work that is required to make PT a reliable therapy.