[Ylide (OP)]

In honor of the new category, does anyone know a good literature source for research on the use of bacteriophagic viruses in antibiotic treatment?  I'm giving a presentation in a few weeks for a class and I want to use that topic.  


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[chris]

A great choice for a topic ! You could start with a few naked scientist references :

http://www.thenakedscientists.com/html/shows/2004.01.11.htm

The above is a good reference because it touches on an extension of bacteriophage therapy - reawakening dormant integrated phages and conferring bactericidal effects upon them.

http://www.thenakedscientists.com/html/shows/2002.01.20.htm click full-length text for the whole story

This is a study in which phage therapy saved the lives of experimental mice challenged with a virulent bacterial strain.

Chris


"I never forget a face, but in your case I'll make an exception"
 - Groucho Marx

[Ylide (OP)]

Thanks Chris!  That's precisely what I'm looking for.  I'm on dialup right now so I only read the text caption at the bottom...do you know any names of researchers or what university they were from so I can do a literature search on them?

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[chris]

Sorry, I buggered up and put the same reference in twice. I've now changed it.

The 2004 link (top one, which also contains a link to the 2002 reference) was by scientists at the university of Warwick - full details in the article.

Chris

P.S. The audio is set up so that dial-up users can receive it as the band width is low (32 kbps). This means that you can listen to the show in the background whilst browsing elsewhere on the site or internet !

"I never forget a face, but in your case I'll make an exception"
 - Groucho Marx

[Ylide (OP)]

Did you know they've been using successfully using phage therapy to treat bacterial infections in the Republic of Georgia since the 1940's?    

I also came across a lab that found the enzyme that phages use to lyse the bacyerial cell when it's done replicating and ready to spill the next generation of phages into the environment.  They've isolated it and are successfully using it to destroy bacterial colonies without even involving phages.  



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[cuso4]

Russia also have been using phage therapy for ages. If I was diagnosed a serious bacterial infection I would insist on using phage therapy instead of antibiotics treatment.

Angel

[chris]

Er I don't think you would somehow. If you had meningitis I can't see you accepting a trial medicine in place of something that is known to be a reliable cure for yourself or a loved one.

Phage therapy has its place but is not, by a long chalk, about to usurp the role of standard antimicrobial therapy. It is being developed more as an adjunct to standard therapy, and to tackle more difficult infections where antimicrobial resistance is a problem !

Chris

"I never forget a face, but in your case I'll make an exception"
 - Groucho Marx

[Ylide (OP)]

Why would you want to use antibiotic treatment if fully developed phage therapy were an option?  Antibiotics are often ineffective, can have bad side effects, and are nonselective for beneficial enterics vs. pathogens.  Phages are generally specific to a species (or at least a genus) and have no documented pathogenic effect eukaryotic cells.  Antibiotic treatment is a back-and-forth war of attrition that involves mutation, response, mutation, response, ad-nauseam.  Why not nip it in the bud with something allegedly less vulnerable to spontaneous resistance.  

In a few cases where bacteria have mutated such that the phage was unable to attack them, the mutations caused them to be less virulent.  The phages sought out the encapsulation layer of the bacteria, the bacteria shed it in a random mutation, and the phages had no "handle" on which to grab, but the lack of encapsulation allowed for the test organism's immune system (bird or mouse, can't remember) to deal with it.  

There's also some really cool work going on that interferes with the chemical methods of communication between bacteria that they use to decide when to transfer genetic material, emit toxins, and reproduce.  The woman who discovered it was featured in Scientific American a few months ago.  I'll dig it up if anyone's interested.



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[chris]

Well for a start there's the problem of tissue penetration. Phages are all well and good if they can reach the site of infection. But in the context of meningitis, for example, where the bugs are within the meninges, access becomes a problem. The antibiotic molecules used are extremely small and have excellent CNS penetration. In the context of a life threatening infection you do not mess around, nor allow the worry of some subsequent diarrhoea influence your choice of therapy.

I've seen a man with bacterial meningitis go from alert, conscious and able to share a joke, to barely rousable with a rash spreading in front of my eyes. Another 30 minutes and he would have been irretrievable. As it was a regular doses of intravenous broadspectrum antibiotics saved his life. And he didn't get any diarrhoea either !

I am a big supporter of phage therapy but everything has its place and it should not be used just because it is new.

(By the way, the inter-bacterial signalling you are referring to, cannnabinoid, is called "quorum sensing".)

Chris

"I never forget a face, but in your case I'll make an exception"
 - Groucho Marx

[Ylide (OP)]

Yes, the term quorum sensing was in the article.  She also nicknamed it "bacterial esperanto" since it didn't seem to be species-specific.  (or even genus or family specific)

Thanks for the example...I was wondering about tissue penetration while I was researching this.  In things like staph or enteric infections or even tuberculosis, I guess it's not really a problem as it's pretty much open access, but the meninges sure are a pain to get to.  Could you inject a serum of the phage directly into the spinal fluid without too many complications?  I'm curious to know how the phages would seek out the bacteria when they'd have all that area to cover.  Maybe they're sensitive to chemical signals given off by the bacteria?

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[alastair84]

quote:Originally posted by cuso4

Russia also have been using phage therapy for ages. If I was diagnosed a serious bacterial infection I would insist on using phage therapy instead of antibiotics treatment.

Angel

omg that makes me laugh! Russia has been trialing bacteriophage technology yes, but phage therapy has no where near come close to any sort of viable effective treatment that rivals antibiotics.
Phage therapy potential was realised ages ago ....50-60years or more? but the first few trials and experiments (many of them in russia) were inconsistant and not conclusive. since then the interest has faded as not many people could produce experiments with decent results. i think some form of bacteriophage tech is used in sewage treatments somewhere?

[Ylide (OP)]

When the bacteria are antibiotic resistant, and its a localized infection (i.e. staph. skin infection or something along those lines) phage therapy is a good option.  Healthcare professionals throwing antibiotics at every little infection is what got us into the problem to begin with...well, that combined with stupid patients that don't finish the entirety of their prescription.



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[Ylide (OP)]

Oh, and you might want to look into current phage therapy and research before decrying it as archaic and inconclusive.  It's certainly not perfected, but give it time.  It beats throwing more money and time into the back and forth battle of new antibiotic -> resistance -> new antibiotic -> resistance.  

For what it's worth, I read that a lab has isolated the compound used by phages to lyse bacterial cells, synthesized it, and are using it to decimate bacterial colonies very successfully.  Most bacterial defenses against phages involve changing their surface protein markers to avoid attachment or using endonucleases to chop up the invading phage DNA, so this stuff absolutely brutalizes them.





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[alastair84]

i did, I did a mini-review on phagetherapy. I did not say current phage therapy was "archaic and inconclusive", all i'm saying is that it has a very very long way to go in terms of systemic infection treatment rivalling antibiotics and if anybody things otherwise they are kidding themselves.
Still, there is potential to be realized.

[chris]

We're actually quite a bit closer than you think. I recently interviewed a phage researcher from the UK who was come up with an excellent application for bacteriophages that will make a big impact on nosocomial (hospital acquired) infections.

I won't say any more until the piece has been broadcast...because no one is doing what he's got planned, and it's a great story !

Chris

"I never forget a face, but in your case I'll make an exception"
 - Groucho Marx

[phdkso]

Is anyone interested in revisiting bacteriaophage therapy? I just finished the 2003 book on phage therapy and am updating my presentation for Nov. 10, 2004. Below is book review:

GESUND DURCH VIREN - EIN AUSWEG AUS DER ANTIBIOTIKA-KRISE.
German book by Thomas Häusler, Piper, München, September 2003, 275 Seiten - amazon.de Preis: EUR 15,90.

Healthy Through Viruses - a way out of the antibiotic-resistance crisis.

In 1969 the Surgeon General of the United States, William H. Stewart announced that; it is time to close the books on microbial infections! The war against epidemics due to pathogens has been won. Seldom has medical dogma pronounced by the highest ranking medical officer of the USA
been rendered absurd so rapidly. Actually infections due to pathogens did temporarily decrease during the 1960's; however, only to return twenty years later with increased vehemence.

After the political collapse of the Soviet Union the number of cases of consumption doubled there within only seven years.  Today  in the area of Aral Sea one of 300 inhabitants is sick with tuberculosis - a dramatically high number. Between 1972 to 1992 in New York a disease epidemic due to multi-resistant mycobacteria was rampant with approximately 400 new infections per year and it cost an estimated billion dollar to control this outbreak.  Nosocomial infections - hospital acquired infections - and multi-resistant pathogens, terms which until recently were familiar only to experts, are today topics of the public press. And it is not surprising because in Germany  alone 20000 people die annually of nosocomial infections.

The prospects for the future are still gloomier. While it took approximately fifty years for 95 per cent of Staphylococcus aureus strains to become resistant to penicillin, today certain problem bacteria need only a few years to acquire resistance even to totally new classes of antibiotics. Additionally,  the pharmaceutical industry no longer has many success-promising chemical substances in the research pipeline as they had a decade ago.  At the same time; however, the need for effective antibiotics continues to increase:  Ever more patients must be protected against the threat of infections because of weakened immune systems or because they are organ transplant recipients.

New hope is promised by a therapy which is substantially older than penicillin:  treatment with bacteriophages.  On August 2, 1919 their discoverer, the French Canadian Felix d’Herelle, administered a cloudy broth containing Shigella phages to a deathly-ill boy at the Pasteur Institute in Paris, curing him of dysentery. After an early, world-wide boom, this therapy today exists essentially only in the former Soviet republic of  Georgia and is only now again receiving attention in the West, even if many infection control specialists remain sceptical.

This paradigm shift is the background for an unusually well researched, outstandingly well written and scientifically based book by the Swiss journalist Thomas Häusler.  From the beginnings to the present the author, who also holds a doctorate in biochemistry, describes all aspects of a concept (bacteriophage therapy), whose therapeutic potential is not easily communicated during times of AIDS and SARS.

Bacteriophages are actually extremely dangerous viruses, however with an important difference; they have specialized in attacking bacterial cells and they do no harm to animal cells. When a phage discovers a bacterium to which it possesses the correct key - that is to say:  that on the bacterial cell surface there are suitable receptors to which the phage can attach with its tentacle-like extensions - then the phage will inject its hereditary DNA into the bacteria cell within minutes.  Taking-over the bacterial cell’s biochemical apparatus hundreds of phage copies are then produced.  Special enzymes [(Holine and lysine)?] break the cell wall open from the inside, the victim dies, and the released daughter phages attack any remaining bacterial cells like a pack of hungry wolves.

The advantages of the therapy are obvious.  Bacteriophages are very specific parasites and, contrary to antibiotics, do not damage the useful bacteria, which live in and on the body. Due to their mode of action they can not induce resistance, and if a pathogen is insensitive, then it most likely that there exists another virus (phage), which will act as the bacteria killer. Phages are "intelligent" medicines:  They increase just where they are needed (while antibiotics often do not even get to where they are to work).

The high specificity, with which phages look for their bacterial victims, is at the same time also their therapeutic Achilles' heel.  Either the infection control specialist must have a cocktail containing very many different types of phages, or a phage specifically effective against the pathogen of each patient  must be custom-made through detailed microbiological analytical work and must then be mass-produced.  In both cases regulatory authorities tend to loath recognizing such manually manufactured anti-infective agents as medicines.

For chronic infections on outside and internal body surfaces due to multi-resistant pathogens,  which can not be treated with current methods, phage therapy could become a kind miracle medicine. Additionally, phages could bring an end to feeding antibiotics in large-scale animal production.

Throughout the book, interviews with researchers, who are active at the front new developments, are skillfully intertwined with descriptions of actual patient outcomes. The middle part of the book is also outstanding in describing the trails and errors of phage therapy as practiced between 1930 and 1990. Here journalist Häusler points out, what influence political events have on the medical research - from the "Great Patriotic War" of Russia against Nazi Germany to the collapse of the Soviet Union and up to September 11, 2001.  A long list of footnotes, a detailed list of references and numerous instructive illustrations supplement the text excellently.

A book dealing with an explosive topic, as one cannot make it better.  

( Original in German by Hermann Feldmeier at amazon.de

phdkso

[chris]

Sounds great - what's your background ?

Chris

"I never forget a face, but in your case I'll make an exception"
 - Groucho Marx

[phdkso]

I am a retired microbiologist (PhD) with food, drug, cosmetic, toy and environmental microbiology experience both in industries and regulatory agencies. In the early 60's I worked in the summer in a dairy laboratory and because we had a coliform problem we hired a just retired university professor as a consultant. It so happened that I was responsible for growing the cultured buttermilk starters. When they turned to water the professor started telling me all about phages and being of the age where he remembered phage therapy, I was told all about it and he concluded that phage therapy would make a come-back when antibiotic resistance is a major. I tried a few times in the 70's to interest colleagues in using pahges to reduce salmonella in poultry but then went into drug, cosmetic and mediacl device microbiology.

Having had lots of experience with antimicrobial substances and therefore resistance, I always thought about phage therapy. When I retired in 1998 I googled "bacteriophages as antibiotics" and was surprised that it had become a old-new-again research area. Since then I have organized a symposium on phage therapy and public health in Chicago. I have given a number of talks and have appeared on TV.

Reading English, German and French has helped me get a good feeling for the subject. You can see some of my comments/papers at http://www.phages.org [nofollow] and click forum - look for G.W. (Bill) Riedel.

Here in Canada the news reports that actor C. Reeves was in hospital in part for an infected pressure wound - if you go to the Georgian Phage Therapy Center website at http://www.phagetherapy.org [nofollow] it will become clear that that is the type of wound very suitable for phage therapy - IF PHAGES FOR THE PARTICULR organism are available.

Yesterday when I signed on I could not think of a favourite saying. I have written a piece from the point of view of a microbiologist who is well informed about phage therapy and is allowed to die of a superbug infection. The piece ends with:

WHY DID YOU LET ME DIE RATHER THAN PHAGE ME?

I should mention that I DO NOT think phage therapy will replace antibiotics; but because it works by a different mechanism it is important where antibiotic-resistance has become a problem and it is my opinion that the science is sufficiently advanced that it can be used as a last resort (topical and oral preparations only). In Canada that would be under the Special Access Program of our Food and Drugs Act - similar to the treatment of 9 paptients in Hannover, Germany - treatment was apparently successfull in 7 cases. According to Polish work (published in English) with over 1000 patients succes is about 90% with infections caused by a range of pathogens.

Cheers, phdkso - (you guess what that stands for!)

Also see: http://www.cheminst.ca/sections/ottawa/phage.PDF [nofollow] for my handout entitled: PHAGE THERAPY - ON THE THRESHOLD OF LIFE WHERE CHEMISTRY AND BIOLOGY MEET TO CONQUER SUPERBUGS.

phdkso

[chris]

Great stuff. You should write an article about phages and phage therapy for The Naked Scientists columns :

http://www.thenakedscientists.com/HTML/articles/article/columnmenu.htm

That would be one popular article !

Chris

"I never forget a face, but in your case I'll make an exception"
 - Groucho Marx

[phdkso]

Chris:

I will think about writing the paper you suggested. Meanwhile I wonder if members of this group might comment on the moral and ethical issues raised below - I would like to touch on them in my up-coming presentation.

Thanks for any comments.

Superbugs Can be Conquered!


While the mere mention of multiple antibiotic-resistant superbugs may strike humans with fear, for the right bacteriophage they represent opportunity to fulfil their lifecycle, destiny or raison d'être and their presence excite the reproductive machinery of the phage into action. In stealth, moon lander fashion phage soon has commandeered the reproductive system of superbug and in a short time (30 minutes) superbug bursts open releasing more than 200 copies of phage, each looking for a superbug to conquer -- considering that superbug multiplies by dividing in two, while phage produces about 200 offspring for every superbug killed, clearly with those odds superbug is superbug no more and looks more like a victim -- all this is simply to say, that what a cat is to a mouse, the right phage is to a superbug.
While much is being written about the antibiotic-resistant, superbug crisis and 2002 to 2007 has been dubbed the "Window of Superbug Vulnerability" because new effective antibiotics will not likely be available until then, Phage Therapy/Medicine is a technology being used to treat patients in some countries. In view of the patient risk due to antibiotic failure, it is obvious that any discussion of the bacterial antibiotic resistance phenomenon which does not include consideration of the mitigating role phage therapy/medicine can play, is medically and scientifically incomplete and/or worse intentionally or intellectually  dishonest. It is clear that the antibiotic-resistance superbug phenomenon is a human-created, regulatory/scientific misadventure due solely to massive abuse of antibiotics since their discovery. As early as 1945 it was obvious that when natural pathogens are exposed to natural antibiotics they will undergo natural selection and acquire resistance - or as can be seen in ‘Rankin on Thursday: Where communism succeeded ....’
( http://www.scoop.co.nz/stories/HL9910/S00096.htm [nofollow] ): “An elementary application of Evolution 101 tells us that bacteria evolve. In an antibiotic-rich environment, selective pressure favours those bacteria strains that are resistant to antibiotics. It’s virtually a tautology.” However, had we continued to use phage therapy together with antibiotics there might not be the antibiotic-resistant superbug crises today since the two antibacterial methodologies act in completely different modes. Rankin also states that: “The wonder is that we have got away with abusing antibiotic therapy for so long.”  
My latest definition of Phage Therapy/Medicine is that it is a natural, old-new-again (medical ) technology with a 100 year documented scientific history, that was used world-wide before the 1940's, and has a 70 year history of continuous use in the former USSR. There are commercial products on the market in Georgia, Poland and Russia which are used to treat patients on a daily basis.
The issue of knowingly withholding these commercial products from patients suffering from antibiotic-resistant, superbug infections needs to be viewed from legal, ethical and moral standpoints. Clearly, from scientific, ethical, moral, if not legal, points of view knowing that phage therapy products are commercially available will not satisfy the state-of-the-art argument as defence that everything that could be done for patients was done when negative treatment outcomes occur. With information on phage therapy widely available in the scientific, medical and even popular literature and much of it neatly collected and easily accessible by clicking http://www.phage.org [nofollow] - then clicking “links” and going to “phage therapy references” it can be reasonably argued that any scientist, health professional and perhaps even politicians as well as health policy wonks working on the antibiotic-resistance superbug issue or treating superbug infections “ought to have known” that phage therapy/medicine is a currently practised treatment methodology. In other words, as health professionals and health policy professionals we know or ought to know that many of the 44,000 North Americans (see The Killers Within) whose "lives" we prematurely celebrate each year at wakes after they die from antibiotic-resistant superbug infections could have their funerals delayed if we adopted and practised currently commercially available phage therapy technology ---- that ought to be a crime! While some patients, like Canadian Alfred Gertler, from countries where phage therapy is not available can travel to countries such as Georgia to get phage medicine treatment for infections not responding to antibiotics
( http://www.cbsnews.com/stories/2002/09/19/48hours/main522596.shtml [nofollow] ), doctors, relatives and non-mobile patients from such countries face an additional dilemma because commercially available phage therapy products may be legally available for import on a case by case basis upon request to the appropriate regulatory agency under special access programs provided for under pharmaceutical product regulatory legislation  - but can the bureaucratic processes be accomplished in time when a superbug infection rages?
When considering regulatory approval for these products we are not talking about the approval of a new, promising molecule with unproven pharmaceutical potential; but rather we are talking about the re-approval and re-introduction of products/technology which were previously used and which are today quite well understood from a scientific point of view ( http://www.phages.org/PhageInfo.html [nofollow] ). .......


phdkso