Phages treat antibiotic-resistant bacteria

A technology first pioneered about a Century ago - but then largely abandoned with the advent of antibiotics - has received a shot in the arm and saved the life of a patient at Great Ormond Street, thanks to modern technology. This is “phage therapy” - the use of viruses that kill bacteria - to fight infections. Chris Smith spoke to Graham Hatfull from the University of Pittsburgh...

Graham - The headline is we’ve used bacteriophages to treat a patient with an infection with a very nasty antibiotic resistant organism. Colleagues of ours at Great Ormond Street Hospital in London, they had patients that had cystic fibrosis, had a double lung transplant but then had suffered with very serious bacterial infections that became, essentially, untreatable because they were resistant to all of the antibiotics that they could throw at them. And so what we did was to find bacteriophages that infected the very specific bacterial strain that the patient was infected with, that was administered to the patient and we saw really great clinical outcomes and survival of the patient.

Chris - Where did you get the bacteriophage that you ultimately ended up using? How did you go and find it?

Graham - We've been studying these bacteriophages for quite a long time and so we have a library of about 15,000 individual bacteriophages, and from what we know about them we could whittle that down to a shortlist and we were able to identify three phages which worked well against this particular bacterial pathogen.

Chris - And how long did it take you to do that?  Because one of the critical things with someone who is extremely unwell is that you don't have much time and if you administer antibiotics that's great because usually you can get them off-the-shelf and give them to the patient straightaway. I'm presuming that you just can't find a phage and turn it round and administer it in the same sort of timeline that you can with an antibiotic at present?

Graham - Yes. It took several months, especially because we not only had to screen amongst our favourite candidates, but we had to do some genetic engineering to take what were rather poor candidates and turn them into being effective antibacterial drugs. These kinds of infections caused by Mycobacteria tend to progress relatively slowly, so in this case we had a period of time - it was six months or so - where the patient was essentially hanging in there, and we were able to get the phages within sufficient time in order to be able to administer them with a good outcome.

Chris - And how did you manipulate the phages to get them so that they would hit the sweet spot, as it were, and take out just the right bacterium?

Graham - So one of the issues we face is that not all of the phages are lytic, they don't always kill when they infect the bacteria. What we needed to do was to go in and use genetic engineering to remove one particular gene which was causing that problem, and thus convert what was really not a very useful phage into being one that was going to be effective therapeutically.

Chris - How did you administer the phages once you'd found the ones that you wanted and you knew you'd optimised them?

Graham - There's really two routes of administration: deliver them intravenously and then some phage solution on gauze was added to both the sternal wound from the transplant as well as onto the skin nodules that appear as a sort of common manifestation of these kinds of diseases.

Chris - And how do you know that you've actually got rid of the bacteria? How do you know that there are not some hiding in there that are now resistant to all known antibiotics and your phage and could come back?

Graham - Again, that's a great question and obviously something that we worry about a lot. Rather than using one phage, we specifically made a cocktail of three phages in order to try to battle that problem of resistance. The bacteria could become resistant against one phage but then they should still be susceptible to the others that we're giving in the cocktail.

Chris - We are in what a UK Chief Medical Officer described as an "antibiotic apocalypse" situation, so do you think there's going to be a big comeback for phages then?

Graham - I think there's a real opportunity to try to find the kinds of infections that phages could really be useful to treat. There are particular types of diseases and infections where they could find a use. And one can imagine using phages in a smart way where you essentially combine them with antibiotics in order to essentially enhance the utility of the antibiotics and to try to help reduce the incidence of resistance to antibiotics.

Graham Hatfull, on how the bacteriophage, first discovered in 1915 by English researcher Frederick Twort, could be set to help us fight antibiotic-resistant infections a hundred years on. Those results were reported in Nature Medicine.