Friday, December 10, 2010

Phage therapy - a secret we ignore at our peril

G.W. (Bill) Riedel, PhD, MCIC

If I suggested that a cure for the cholera outbreak in Haiti could be found in the same rivers thought to be responsible for the outbreak in the first place, most people would consider me crazy; however, 1896 the British bacteriologist, Ernest Hankin reported on the presence of marked antibacterial activity (against Vibrio cholerae) which he observed in the waters of the Ganges and Jumna rivers in India, and he suggested that an unidentified substance (which passed through fine porcelain filters and was heat labile) was responsible for this phenomenon and for limiting the spread of cholera epidemics. Several other scientists made similar observations; however, in 1917 the French-Canadian microbiologist, Felix D’Herelle, working at the Pasteur Institute, realized that the antibacterial activity was due to viruses which he named bacteriophages (phages for short) and he soon experimented with the possibility of using phages to cure and prevent bacterial infections. He subsequently worked all over the world, including Russia, Tbilisi, Georgia, where his efforts survive to this day in the form of the Phage Therapy Center ( ) that treats patients from all over the world.

Bacteriophages are viruses which are parasitic to bacteria and cannot multiply without infecting specific bacterial hosts. Each phage can only infect a specific bacterial host as it has to be able to link with special surface structures of the bacterial cell and once attached the phage injects its DNA into the bacterial host causing the infected bacterium to produce 50 to 200 daughter phages in as little as 30 minutes. Lytic phages then disrupt the bacterial cell, killing it and each daughter phage then looks for a new bacterium to infect and kill.

Prior to the discovery of the electron microscope in 1940 it was not possible to see bacteriophages and early phage biology depended on the observation that the addition of phages to broth cultures in which bacteria had grown resulted in clearing of the turbid broth and death of bacteria. When phages were added to solid media on which bacteria had grown clear zones (plaques) could be seen. Generally speaking, phage biology was not well understood and results from phage therapy treatments tended to be variable. Additionally antibiotics appeared and interest in phage therapy in the West ceased until antibiotic-resistance and superbugs resulted in renewed research in the West. It is interesting that many reviews dwell excessively on early work on phage therapy, rather than focusing on current knowledge. For individuals interested in the history of phage therapy the book by Thomas Haeusler entitled, Viruses vs. Superbugs, a solution to the antibiotics crisis? published in 2006 is recommended as an informative and more positive read on the history of phage therapy ( see ).

A more timely and productive approach to scientific information on phage therapy can be found in two review articles published this year:

• Monk et al. 2010 Bacteriophage applications: where are we now? Letters in Applied Microbiology, 51, 363-369.
• Kutter et al. 2010 Phage therapy in clinical practice: Treatment of human infections, Current Pharmaceutical Biotechnology, 11, 69-86.

Some readers of these two references may be surprised at the breadth of application of phages in the control of bacteria, ranging from prevention and cure of bacterial infections in humans and animals, to preventing foodborne disease, to disinfecting hospitals and food processing equipment, to controlling bacterial rot of tomatoes and peppers (Some authors use phage therapy for control of bacterial infections in humans and animals and refer to the other applications as biocontrol). The remainder of this article will describe some of these applications and try to indicate their regulatory status where applicable.

The first question every presenter on phage therapy is asked is: If I had an infection where antibiotics are failing is there any place where I can be treated with phages right now? There are two countries where treatment with pages is routinely available in Europe and they are Georgia ( ) and Poland ( ) ( Russia probably also uses phage therapy but much less information is available). More recently the Wound Care Center in Lubbock, Texas has used phage therapy as can be seen in the article entitled, The Next Phage, Popular Science, March 31, 2009 ( ).

The regulatory approaches in Georgia and Poland towards phage therapy are significantly different. As can be seen in the Canadian film: Killer Cure: The Amazing Adventures of Bacteriophage, phage therapy is routinely practiced not only on Georgian patients but the Phage Therapy Center caters to patients from many countries and many applications enjoy full regulatory approval.

In Poland at The Hirszfeld Institute and of Immunology and Experimental Therapy phage therapy is carried out under medical experimentation, ethical and compassionate use regulatory provisions similar to those that exist in most countries. A broad range of infections have been treated since the initial anti-staphylococcal treatment in 1925. Because of the regulatory provision all patients treated must have previously been treated with conventional methods, such as antibiotics and these treatments must have failed. Interestingly since the 1980’s their work with phages has been published in English language scientific journals. Very high success rates have been obtained for “infections caused by different species of bacteria: Escherichia, Klebsiella, Proteus, Enterobacter, Pseudomonas, and Staphylococcus aureus, with an average success rate of 85%.” Their success rates for treating Pseudomanas aeruginosa and Staphylococcus aureus, including MRSA strains have been reported to be even higher. One shudders to think of the public health impact similar programs in other countries could have.

Rediscovering Phage Therapy in the Rest of the World:

A complete detailed description of research in phage therapy is beyond this brief paper; however, significant research consisting of Phase I trails completed or planned have been reported for Britain, Belgium, Australia and India.

Perhaps regulatory approvals for some non-medical applications of phage therapy (biocontrol) granted in the USA should be of interest. The Food and Drug Administration has amended the US food additive regulations to provide for the safe use of a bacteriophages on ready-to-eat meat against Listeria monocytogenes (see ) and ) . The idea that ready-to-eat meat can be treated if contaminated with Listeria bacteria while a doctor could not get a pharmaceutical grade phage therapy product when faced with a patient suffering listeriosis, strikes this author as absurd, especially considering recalls of various foods due to contamination with listeria. The approved product is manufactured by Intralytix ( ) and ListShield targets Listeria mnocytogenes in foods and food processing facilities. Agriphage commercially available from Omnilytics ( ) is primarily used to treat bacterial damage of tomatoes and peppers and has been recognized as being compatible with organic food production. Biocontrol applications have recently been described in a book entitled: Bacteriophages in the Control of Food- and Waterborne Pathogens, Editors: Parviz M. Sabour and Mansel W. Griffiths, ASM Press, 2010. Interestingly both editors are Canadian, one of them a government employee and the other a university professor, in spite of the fact that there have been no regulatory approvals for phage therapy products in Canada.

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