Mike the Mad Biologist

Phage Therapy

Since I’m going away for a long weekend, I’ll leave you with this post about phage therapy from the archives.

So Aetiology, in her new digs, wants a post. Well, here’s one, inspired by a comment: phage therapy. “Phage therapy” is short for bacteriophage therapy. Bacteriophage are viruses that kill bacteria (literally, “bacteria devourers”). The basic concept of phage therapy is to introduce the phage into an infected patient. The phage infect the bacterium-an infection of an infection! Then the phage multiply within the bacterium, lyse (explode from the inside) the host bacterium and move onto the next bacterium. Essentially, you have a self-manufacturing antibiotic.

So that’s the concept, but does it actually work? Typically, the phage are administered in a pH buffered solution and ingested (the pH buffer prevents stomach juices from degrading the phage). They are typically not administered intravenously, since it’s thought that bacterial debris from the phage manufacturing process will cause an immune system response (note: phage are cultured by growing them on bacterial cells; the lysed cells-the debris-are present in the phage solution). However, they are effective against most sepsis (bloodstream) infections anyway (it’s not entirely clear how they get into the bloodstream). Success rates are typically equivalent to traditional antibiotics. Phage therapy has two other advantages: it’s very cheap, and the phage are far more robust to heat than some antibiotics (no refrigeration needed).

There can be some treatement side effects. Often, when exposed to phage, bacteria enter what I call ‘panic mode’ (that’s a highly technical term) where the bacteria produce every nasty thing they can including all sorts of toxins (if they have toxin-producing capability). This can happen with traditional antibiotics too; however, the presence of traditional antibiotics can also lower toxin production.

In terms of therapeutic use, right now, they are not being used outside of experimental medical settings (and the occasional bout of desperation). The Soviet Union, and later, Russia used to produce phage for widespread clinical use. The production facilities are located in the Georgian Republic, and due to the civil war, are essentially non-operative (an aside: the Georgian phage researchers should be an inspiration to scientists everywhere. They are real-life Arrowsmiths, often working without pay and refusing to abandon their institute despite having minimal resources, or for that matter, heat or electricity. Despite this privation, they still manage to treat and cure some people, and conduct some research).

Finally, would resistance be a problem? I’m not sure. Resistance to phage can evolve (and depending on the phage, can be quite prevalent). On the other hand, resistance to a phage in a particular bacterial species probably wouldn’t be able to spread (the known transmissible systems appear to be very phage specific).

Ultimately, the advantage and the disadvantage of phage therapy is that is a narrow spectrum treatment: a particular phage works against a certain species (or even a subset of a species). The disadvantage is that you have to know something about the infectious bacterium such as what species it is, and such diagnoses can take several days-time many patients do not have. On other hand, the evolution of resistance will be limited to a much smaller group of bacteria (and you can always try to isolate, or evolve in the laboratory, new phage, making the development process substantially cheaper).

Phage therapy won’t be a magic bullet. But, hopefully, phage therapy will become one more tool we can use to stop the evolution of antibiotic resistance.

Comments

  1. #1 Bill Riedel
    December 18, 2006

    Never before has the superbug crisis been described so eloquently in so few words than in a recent article entited, “Hospital scourge: Millions of patients are infected by bacteria, and may die”, which appeared in the Globe and Mail, Sept. 30, 2006; but now that the problem has been described we need solutions!

    The absurdity of the superbug crisis consists of the fact that it can be demonstrated that we had technology, namely bacteriophage therapy, long before we created the antibiotic-resistance superbug crisis through massive abuse of antibiotics and other antimicrobials. Additionally many politicians, bureaucrats, scientists and members of the public health community are or should be well informed about phage therapy which can cure many superbug infections. In spite of a voluminous literature attesting to the scientific validity and medical effectiveness of phage therapy (see http://www.phage.org and find phage therapy references), there are still phage therapy deniers who would resist the careful deployment of these weapons of mass-destruction for specific pathogens in the war with superbugs. Superbugs are winning most battles with an estimated 17 million human casualties due to microbial infections worldwide annually ( 17 million is roughly half the population of Canada or California; the total casualties of WW II are estimated to have been 55 million in about 6 years – superbugs kill more people every 4 years) . Many of these infections are acquired by patients after entering hospitals for unrelated illnesses, making hospitals significant killing fields in the war with superbugs. In Canada as many as 30 patients are dying of such infections daily and some say that an equal number of amputaions are also performed to stop such infections. We have known the magnitude of the problem at least since the early 1970′s when Ottawa bacteriologist Dr. J.C. N. Westwood was on the conference and media circuit with essentially the same message that is reflected in current papers and news reports ( J.C.N. Westwood, Current National Patterns – Canada, Proceedings of the International Conference on Nosocomial Infections, Center for Disease Control, Aug. 3-6, 1970, 17). Nothing has significantly changed unless we consider the worsening of the problem as success!

    What is Phage Therapy? Prior to the discovery and widespread use of antibiotics, bacterial infections were treated worldwide by the administration of bacteriophages. Bacteriophages or phages are highly specific viruses that invade bacterial cells and, in the case of lytic phages, disrupt bacterial metabolism and cause the bacterium to die. Interestingly it was the French-Canadian microbiologist, Felix d’Herelle, while working at the Institute Pasteur in Paris in 1917 who is credited with discovering and promoting phage therapy. While the use of phage therapy was discontinued in the West soon after the discovery of antibiotics they continued to be utilized in Eastern Europe and today many infections untreatable with antibiotics can be treated in clinics in Georgia (Europe) and Poland. Once one accepts the fact that it requires microscopes to see the world of bacteria and bacteriophages, phage therapy may be compared to any biological control methodology and can conceptually be described as: What a cat is to a mouse the right bacteriophage is to a specific bacterium or superbug. Phage therapy has been going on in nature as a balancing force in the evolution of microbes for a long time. Medical phage therapy is simply the intervention of humans to ensure that the balance is in favour of bacteriophages over susceptible bacterial pathogens! While there is considerable expertise on phage therapy in Canada at the research level as can be substantiated by googling phage therapy (“pages from Canada” only), medical phage therapy is not currently approved or practised in Canada; however, according to a letter signed by the former federal health minister phage therapy can be made available legally to Canadian patients under the Special Access Program of our Food & Drugs Act! A discussion of phage therapy is currently very timely, not only because too many Canadians are dying of superbug infections; but also because of the recent release of the Canadian film: Killer Cure: The Amazing Adventures of Bacteriophage and the June 2006 release of the English book by Thomas Haeusler entitled Viruses vs. Superbugs, a solution to the antibiotics crisis? ( see http://www.bacteriophagetherapy.info ) – both are available at Ottawa libraries. Additionally, the record of an excellent question-and-answer session with Dr. Roger Johnson of the Public Health Agency of Canada can be found at http://meristem.com/topstories/ts06_08.html . Further, the phage therapy file has dramatically changed during the last few weeks because the US Food and Drug Administration (FDA) has amended the US food additive regulations to provide for the safe use of a bacteriophage preparation on ready-to-eat meat and poultry products as an antimicrobial agent against Listeria monocytogenes (see http://www.fda.gov/OHRMS/DOCKETS/98fr/02f-0316-nfr0001.pdf ). This excellent submission evaluation changes the scientific validity of phage therapy from Eastern European science, which sadly too many of us Westerners dismiss with hubris and bias as not credible, to approved and supported by the all-knowing and all-seeing FDA at least for ready-to-eat meats. Otherwise the US situation is similar to the Canadian situation – much expertise at the research level but little human treatment – apparently there is a small human trail ongoing.

    Superbugs are everybody’s business because superbugs make everybody their business and North Americans should study the above references because sooner or later everybody will be faced with an infection or know a relative or friend who will be suffering or dying with one. Withholding such treatment from patients when antibiotics are failing ought to be a crime; however, those who have the money and time to travel when faced with an infection where antibiotics are failing may be able to get phage therapy treatment in Georgia ( http://www.phagetherapycenter.com ) or Poland – http://www.aite.wroclaw.pl/phages/phages.html . What is even more surprising that an international phage therapy company would probably be willing and able to set up a phage therapy clinic in Canada if the right regulatory climate existed. Since January 1, 2000 as many 82,000 Canadians may have died of such bacterial infections and there is not even a memorial for them. Would it not be nice if the Canadian governments got together and funded the Felix d’Herelle Center for Phage Therapy to provide the phage therapy treatment option to patients when antibiotics fail and we have nothing left to offer them, as a memorial to past superbug victims? Apparently some people are starting to wear blue ribbons in memory of superbug victims to give visibility to the problem and in the UK there are some interesting, costly financial settlements as a result of MRSA infections.

  2. #2 Lab Rat
    August 5, 2008

    This is what I’m working on! Phage therapies for Campylobacter.

    Just one thing you missed and I’d like to point out (if you don’t mind) concerning resistance. Bacteria can develop resistance to phages but, as the receptors that the phage use to get into the bacteria are usually based around the bacterial virulence factors, resistant bacteria are likely to be less clinically virulent. Also it is possible (although I’m not sure how much research has been done on this) that at the phages are ‘living’ (or as living as viruses can be) they can evolve with the bacteria, as they do naturally and quite frequently, to attack the resistant bacteria.

    Just thought you might find that interesting :)

    ~Lab Rat

  3. #3 Annie
    April 21, 2009

    laaaaaaaaaa

  4. #4 Marc Abian
    August 2, 2009

    It would be my guess that phage evolve much quicker than bacteria so would be able to cope with bacterial resistance.

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