Bacteriophage treats antibiotic-resistant bacterial infection

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Ygggdrasil
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Bacteriophages, viruses that infect bacteria, have long interested scientists as a potential therapy for bacterial infections. Today, in the journal Nature Medicine, scientists report the first clinical use of genetically-engineered bacteriophages to treat an antibiotic-resistant bacterial infection:

For the first time, scientists have used genetically modified viruses to treat a patient fighting an antibiotic-resistant infection.

Isabelle Carnell-Holdaway, 17, began the experimental treatment after doctors lost all hope. She was struggling with a life-threatening infection after a lung transplant. With the new treatment, she has not been completely cured. But the Faversham, England, teenager has recovered so much that she has resumed a near-normal life.

"I think it's amazing," Carnell-Holdaway says. "It kind of shows that there is completely no limit to what they can come up with really."
https://www.npr.org/sections/health...help-save-a-patient-with-a-superbug-infection
While the success provides a nice proof of principle, only one individual has been treated so far, so more work is needed to establish the safety and efficacy of the treatment. Furthermore, additional challenges remain in the development of bacteriophage therapy, including the fact that bacteriophages are often specific to only one species or subspecies of bacteria as opposed to antibiotic drugs which can often treat a wider swath of bacteria. However, given the rise of antibiotic resistant bacteria and the difficulties developing new antibiotic drugs, the continued development of bacteriophage therapy is promising.

Citation to the paper discussed: Dedrick et al. Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med 25: 730 2019. https://www.nature.com/articles/s41591-019-0437-z

Abstract:
A 15-year-old patient with cystic fibrosis with a disseminated Mycobacterium abscessus infection was treated with a three-phage cocktail following bilateral lung transplantation. Effective lytic phage derivatives that efficiently kill the infectious M. abscessus strain were developed by genome engineering and forward genetics. Intravenous phage treatment was well tolerated and associated with objective clinical improvement, including sternal wound closure, improved liver function, and substantial resolution of infected skin nodules.
 
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  • #2
Drakkith
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Time to give three cheers for bacteriophages? 🤔
 
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256bits
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the fact that bacteriophages are often specific to only one species or subspecies of bacteria as opposed to antibiotic drugs which can often treat a wider swath of bacteria
A benefit, yes.
Side effects, such as gut bacteria becoming "collateral damage", ( with antibiotic treatment,) and the minimizing of such side effects by this targeting of particular bacterial infection would be a plus.
 
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What exactly is new here? Does it really change anything that the infection is resistant to antibiotics as far as the bacteriophage treatment is concerned

So is it the first time they've used bacteriophages against these types of bacteria, regardless of resistance?
 
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jim mcnamara
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Q1. Answer: a lot, it is a big deal, I percieve that you are likely an ESL person, so it may be hard for me to get your true intent here.
Q2. Answer: yes. Why else do it? Alternative: Surely, you do not want to watch a patient die?
Q3. Answer: I do not know, the article indicates they worked in vitro (in a "test tube") first. So, yes per the article.

Bacteriophages are viruses. It would not be ethical to just say, 'hmm let's inject this glop of viruses into someone's brain and see what happens.' And then inject. So getting approval is hard, and is granted only with a lot of solid research for years beforehand.

I am guessing you are not a Biologist. Try the first link to an NPR report in @Ygggdrasil 's post. It will help clear up things for you.

The real important part of this is a rather bleak assumption/fact: we are coming into an era where antibiotics will fail more and more often. We need a plan B before the resistant bacteria start winning. Or else we should start, now, planning for a lot more infectious disease mortality worldwide.
 
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Ygggdrasil
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What exactly is new here? Does it really change anything that the infection is resistant to antibiotics as far as the bacteriophage treatment is concerned

So is it the first time they've used bacteriophages against these types of bacteria, regardless of resistance
From the paper:
Therapeutic bacteriophages are a plausible alternative treatment to antibiotics8, but have not been used for mycobacterial infections in humans9,10,11; however, personalized intravenous phage treatments for other bacterial infections have been described (Supplementary Information)12,13.
The idea of bacteriophage treatment is not new, and it has been used for treating bacterial infections previously (esp. in former countires of the former Soviet Union, where access to antibiotic drugs was limited during the cold war). The rise in recent years of antibiotic resistant bacteria, however, has revitalized interest in phage therapy, though no treatments have yet been approved by the FDA. Before phage therapy can become more widely used, scientists will need to demonstrate the safety and efficacy of the treatments, so this study is important in advancing those goals. People who want to run larger clinical trials on more patients can reference this study to learn more about conducting phage therapy and use it as an example to show that phage therapy can be conducted safely and effectively.

Targeting antibiotic-resistant mycobacterial infections is of particular importance because there are not many drugs that target mycobacteria. Mycobacteria have different cell walls than most other common (gram positive) bacteria and, therefore, are not susceptible to some of the most widely used classes of antibiotics, such as penicillin and its relatives. There is great medical need for more therapies against mycobacterial infections, and this study provides hope that bacteriophages could fill that unmet medical need.
 
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Q1. Answer: a lot, it is a big deal, I percieve that you are likely an ESL person, so it may be hard for me to get your true intent here.
As mentioned bacteriophage therapy is hardly a new concept. I was curious what made this study generate so much buzz.

Q2. Answer: yes. Why else do it? Alternative: Surely, you do not want to watch a patient die?
I think you misread my question. I get that it's nice to have an extra tool against resistant bacteria, but as mentioned phages aren't new. So I was wondering if there was more to it than a naive reading suggested.

I was a bit too terse as usual, sorry for that.
 
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Thanks @Ygggdrasil, nice summary and point taken about gram negative.
 
  • #9
Laroxe
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As a number of people have pointed out the potential of phage therapy has been known about for many years. The main problem was not in the idea, it was in our own immune system. If you inject live viruses into a body, even a virus that doesn't cause illness in humans, our immune system develops antibodies, few of these viruses survive long enough in a person to effectively treat an infection.
When I first saw this I thought the genetic modifications would have tried to reduce the immunogenic potential of the virus's, but apparently not, I suspect that these viruses are no longer active in this girls body and in fact will never be again. I can see the huge potential in using phage therapy, but we really need to get around the fact our body recognises the virus as alien. They describe the perhaps desperate search for more phages that attack this bacteria, which again will only have another short term effect. As far as I know, in Russia which houses the biggest collection of known phages they tend to be used for local infections on the bodies surface, this avoids some of the antibody responses.
We now know, that bacteria frequently excgange genetic material, even across species. An area frequently exchanged, is one that has the information for antibiotic resistence, a bug can develop multiple resistances without ever being exposed to the drugs. This exchange of information appears to be far more common and involves a much wider range of abilities that was ever thought. Because this ability seems to only be relevant for specific parts of their genome with capacity limits its unlikely that an ability will be maintained if it isn't functional. It may be that once we have control of antibiotic use and are able to use them in a strategic way the genes for resistance may be replaced, but bacteria are always having to deal with antibiotics in nature, so maybe not. However if a bacteria becomes resistant to the chemicals used to prevent them growing in another bacteria's territory, this could become part of the evolutionary arms race, we may see new antibiotics deployed. Remember humans didn't create these drugs, they are simply weapons in a war that's been going on for a lot longer than we've been around.
 
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Ygggdrasil
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In this particular case, the girl treated with phage therapy had just received a lung transplant and was taking immunosuppressive drugs as a result, so phage immunogenicity likely was not as big a problem compared to treating a healthy individual. However, antibiotic-resistant bacterial infections are a very big concern among immunocompromised individuals, so this could still be a useful treatment for that population.
 
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Laroxe
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In this particular case, the girl treated with phage therapy had just received a lung transplant and was taking immunosuppressive drugs as a result, so phage immunogenicity likely was not as big a problem compared to treating a healthy individual. However, antibiotic-resistant bacterial infections are a very big concern among immunocompromised individuals, so this could still be a useful treatment for that population.
An excellent point, and it makes sense, though this limits the population that might benefit, it certainly should stimulate further investigation. There is probably quite a lot of information available, but it will by necessity be all from case report's. This will be a problem in trying to go through the normal testing processes as each phage would be like a different drug. They might just change the criteria for their use to make the process faster and easier, they have done this for other drugs.
 
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This will be a problem in trying to go through the normal testing processes as each phage would be like a different drug. They might just change the criteria for their use to make the process faster and easier, they have done this for other drugs.
I agree. The article notes that the three phage combination that they identified for their patient's infection does not work on bacteria of the same species isolated from different patients. Indeed, the study was supposed to treat two different patients, but unfortunately the second patient died before they could identify suitable bacteriophages to treat that patient. A major bottleneck will definitely be identifying the correct combination of phages (or learning how to engineer the phages) to treat the particular subtypes of bacteria present in each individual patient's infection.

As an aside, here's a nice article on some of the basic science work done collecting and categorizing phages across the world that enabled scientists to find the phages to treat the patient's infection:
In 2010, when Lilli Holst scraped a lump of soil from the underside of a rotting eggplant, she had no idea that this act would help to save the life of a British teenager, eight years later and 6,000 miles away.

Holst, an undergraduate at the University of KwaZulu-Natal, in South Africa, was participating in a project in which students search through local soil samples for new phages—viruses that infect and kill bacteria. Holst found several, and gave them all names. In a worm farm, she discovered Liefie. In an aloe garden, Lixy. And from that decaying eggplant, Muddy.
https://www.theatlantic.com/science...iruses-cured-a-dying-girls-infections/589075/
 
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I bet you it's just a matter of time before bacteria find a way to develop resistance to these bacteriophages as well. I can't imagine this is a permanent cure-all.
 
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pinball1970
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I bet you it's just a matter of time before bacteria find a way to develop resistance to these bacteriophages as well. I can't imagine this is a permanent cure-all.
Lateral gene transfer via elements like plasmids is quick and has scuppered many anti biotics effectiveness in decades. The bacteria find a work around then the genetic engineering guys will have to keep up in what is just another biological arms race.
 
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Ygggdrasil
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I bet you it's just a matter of time before bacteria find a way to develop resistance to these bacteriophages as well. I can't imagine this is a permanent cure-all.
The researchers were also concerned with resistance, so to help avoid the possibility of the bacteria gaining resistance, they used a cocktail of three different phages targeting the bacteria. The hope would be that while the bacteria might evolve resistance to one phage, the other two would still be able to kill the bacteria, and evolving resistance to all three phages would hopefully be rate. Phages are also capable of evolution and could theoretically co-evolve with the bacteria to evade resistance.

They also monitored the patient for signs of resistance throughout six months of treatment and did not see signs of resistance evolving. They write in their paper "M. abscessus isolates were recovered from skin nodule swabs at 20, 72, 107, and 121 d after treatment initiation but remained sensitive to each phage in the cocktail (Extended Data Fig. 5). It is plausible that phage resistance is associated with reduced virulence."
 
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The researchers were also concerned with resistance, so to help avoid the possibility of the bacteria gaining resistance, they used a cocktail of three different phages targeting the bacteria. The hope would be that while the bacteria might evolve resistance to one phage, the other two would still be able to kill the bacteria, and evolving resistance to all three phages would hopefully be rate. Phages are also capable of evolution and could theoretically co-evolve with the bacteria to evade resistance.

They also monitored the patient for signs of resistance throughout six months of treatment and did not see signs of resistance evolving. They write in their paper "M. abscessus isolates were recovered from skin nodule swabs at 20, 72, 107, and 121 d after treatment initiation but remained sensitive to each phage in the cocktail (Extended Data Fig. 5). It is plausible that phage resistance is associated with reduced virulence."
But it seems there is a double barrier for these phages: resistance from the bacteria, and the host's immune response. Are these phages useful only in severely immunocompromised patients like the lung transplant patient noted above? That would really limit their usefulness.
 
  • #17
Excuse me, the first? The Russian medical World have been doing this for decades.
 
  • #18
I bet you it's just a matter of time before bacteria find a way to develop resistance to these bacteriophages as well. I can't imagine this is a permanent cure-all.
Well, the Viruses and Bacteria have been battling each other for millions of years on this. At the moment the Viruses aren't everywhere and neither are the Bacteria. So even if the Viruses kill 100% of the Bacteria they come in contact with, there's plenty of room for both species to evolve when they're apart...
 
  • #19
jim mcnamara
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Ok. @ProfQuatermass please provide a reasonable citation. Thanks. Why? A priori you would know that people who publish in the field know the literature and would not make unsupported claims.
 

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