Understanding antibiotic resistance
Understanding antibiotic resistance

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Understanding antibiotic resistance

2.1 Phage therapy

Phage therapy to treat bacterial infections exploits the bactericidal lysis step of bacteriophage infection to kill bacteria. It was first developed more than 90 years ago by researchers in the former Soviet Union and is routinely used to treat chronic infections in former Soviet states such as Georgia. In the next activity, you will look at some of the advantages and disadvantages of this treatment.

Activity 3 The advantages and disadvantages of phage therapy

Allow about 10 minutes

Listen to the following interview with Martha Clokie, a phage researcher, who discusses the advantages and disadvantages of phage therapy. While you are listening, note down any advantages and disadvantages of phage therapy in Table 1 below. You may also like to think about any ways in which phage therapy is similar to and different from antibiotic treatment.

Download this audio clip.Audio player: Audio 1
Skip transcript: Audio 1 Interview with Martha Clokie on phage therapy.

Transcript: Audio 1 Interview with Martha Clokie on phage therapy.

MARTHA CLOKIE
There's much more of an awareness that we need to develop alternatives to antibiotics, such as bacteriophages. So there's a lot of interest there from doctors who previously were not as interested in this approach.
INTERVIEWER
And what about their use in Georgia? It's been pretty successful, from the sound of things. But why are we still tinkering around the edges in this country?
MARTHA CLOKIE
Well, that's exactly what the Georgians ask. They've used them historically, so they have a long history of using them. They have doctors who are trained to use them, and they use them in specific ways, very often. So, for example, if somebody presents with a respiratory condition that's chronic, they will be given phages. And, whereas, if they have an acute condition, they'll be given antibiotics. So they use phages to prevent antibiotic resistance, and they use them in specific ways. In the West, we still don't have an appropriate regulatory pathway for phages to be used. So there are no regulated phage products that we can use. In order for something to be regulated, you need to go through appropriate clinical trials. So we are getting there, because there are several clinical trials going on at the moment for different conditions. So that's new since we spoke last.
INTERVIEWER
I want to ask a historical question – why hasn't phage therapy been developed more in this country and in the States? We've known about phages for 100 years, but we've really focused on antibiotics rather than phages. Why is that?
MARTHA CLOKIE
Well, I think bacteriophages were just thought to be unnecessary. Antibiotics were thought to be the silver bullet. They worked. In a way, to use an antibiotic, you have to know much less about the bacteria that you're trying to treat. With phages, they have this exquisitely specific relationship between the phage and the pathogen. So if you want to treat an E. coli infection, you need to make sure your virus will target that particular E. coli strain. And I think because it was a more complicated product to develop, from the specificity point of view and also in terms of making a standard product, it is more complicated to make up a phage mixture than it is to make a pure antibiotic. That was thought that it wasn't a necessary thing.
INTERVIEWER
And, in Georgia, is what you're suggesting that, although they are using it and relatively effectively using phages to treat actual bacterial infections, they haven't necessarily gone through the same procedures that we would have done in terms of clinical trials and assessments?
MARTHA CLOKIE
That's right. And it's partly because they've always used them. So their argument has been, well, we've used them and we know they work, therefore, why do we need to do these other assessments?
INTERVIEWER
Which is sort of fair enough, I suppose.
MARTHA CLOKIE
I think we can learn, probably, in the West, we can learn a lot from the way that the Georgians use phages. And, probably, we can combine that with the way in which we want to develop antimicrobials. So I think it's good to take a real collaboration between phage scientists – people who are used to drug development – and doctors at the front end who are seeing patients that they can't treat. So it's going to be these sort of collaborations, so we can figure out how, what conditions are going to be most suitable for using phages for, how will phages be used, how will they be combined, how will we do our dosing, our formulation, our delivery. All these bits of work need to be sort of done as it were in parallel to come together.
INTERVIEWER
So probably in the future, most effective as part of the combined therapy for complex infections. Is there any chance that bacteria will develop resistance to phages in the same way that they have done to antibiotics?
MARTHA CLOKIE
Well, bacteria are really good at evolving resistance to anything. So if you chuck anything in a bacteria, it will become resistant to it. Now the advantage of phages is that, very often, the thing that the bacteriophage actually needs to hook onto is really important for that bacteria. So, for example, if it loses the surface protein on the outside to stop the bacteria from attaching to it, then it can't colonise anymore. So there's been plenty of evidence to show that often when bacteria become resistant to phages, they become less virulent pathogens. So they can't colonise and cause infection. So, at the moment, I think the first generation of bacteriophage products that will be developed will be when we have mixtures of different bacteriophages that kill in different ways. Now, if you were exposing a bacteria to phages that kill using different mechanisms, then it's much, much harder for them to become resistant. So these types of resistance studies are really important, but we can circumvent the problems that we've had using antibiotics by using them correctly and in the correct combinations to actually slow down these resistance rates.
End transcript: Audio 1 Interview with Martha Clokie on phage therapy.
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Audio 1 Interview with Martha Clokie on phage therapy.
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Advantages Disadvantages
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Similarities to antibiotic treatment Differences from antibiotic treatment
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Discussion

Advantages Disadvantages
Resistance is less likely to develop (bacteria that are resistant to phage therapy are also often less virulent).
  • Require more information about the bacteria causing the infection because they are often very specific for a particular bacterial types
  • More difficult to make than antibiotics
  • No regulatory pathway and very few clinical trials in the UK or the west
Similarities to antibiotic treatment Differences from antibiotic treatment
  • Bactericidal
  • Phage therapy is specific for each bacterial strain
  • Broad-spectrum antibiotic treatments can target many different pathogens

Historically, phage therapy has relied on identifying bacteriophages that target the infection-causing bacteria and then administering these bacteriophages to infect and lyse the bacterial cells. However, more recently, the isolation of phage-derived enzymes known as lysins has opened the possibility of developing new phage-based pharmaceuticals.

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