Phage therapy

From Wikipedia, the free encyclopedia

Phage therapy is the therapeutic use of lytic bacteriophages to treat pathogenic bacterial infections. Bacteriophages, or "phages" are viruses that invade bacterial cells and, in the case of lytic phages, cause the bacterium to burst and die. Phage therapy is an alternative to antibiotics, being developed for clinical use by many western research groups in Europe and the US. It has been extensively used and developed in the former Soviet Union as well as communist Poland.^[1]

The treatment uses a phage virus to infect and kill specific bacteria whilst not interacting with the surrounding human tissue or with other harmless bacteria. The virus replicates quickly so a single, small dose is usually sufficient.

Phages are currently being used therapeutically to treat bacterial infections that do not respond to conventional antibiotics.

1 History of phage therapy
2 Collecting and testing phages
3 Benefits
4 Risks
5 Application
6 Obstacles
7 Clinics
8 Notes
9 References
10 See also

[edit] History of phage therapy

In Russia from the time of Stalin there has been extensive research and development in this field. Following the discovery of bacteriophages by Frederick Twort and Felix d'Hérelle in 1915 and 1917, phage therapy was thought by many to be the key for the eradication of many human diseases. Commercialization of phage therapy was even undertaken by the large pharmaceutical company, Eli Lilly. However, early uses of phage therapy were often unreliable due to a lack of knowledge regarding the biology of phages and the use of incorrect phage cocktails. As a result, the discovery of antibiotics in 1941 resulted in the loss of interest in further use and study of phage therapy.

Isolated from Western advances in antibiotic production in the 1940s, Russian scientists continued to develop already successful phage therapy to treat the wounds of soldiers in field hospitals. During WWII, the Soviet Union used bacteriophages to treat many soldiers infected with various bacterial diseases. The success rate was as good as, if not better than any antibiotic,^{[citation needed]} and Russian researchers continued to develop and to refine their treatments and to publish their research and results. However, due to the isolation between the U.S.S.R. and the Western world, this knowledge did not proliferate across the world.

There is an extensive library and research centre at the Tbilisi Institute in Georgia. Phage therapy is today a widespread form of treatment in countries that were formerly members of the Soviet Union.

[edit] Collecting and testing phages

In its simplest form, phage treatment works by collecting samples likely to contain viruses, for example effluent outlets, faeces and other sources. They can also be extracted from corpses. The samples are taken and applied to the bacteria that are to be destroyed which have been cultured on growth medium.

The bacteria usually die, and the mixture is centrifuged. The phages collect on the top of the mixture and can be drawn off.

The phage solutions are then tested to see which ones show growth suppression effects (lyseogny) and/or destruction (lyse) of the target bacteria. The phage showing suitable effects on the target bacteria are then amplified on cultures of the target bacteria and distributed.

[edit] Benefits

The most apparent benefit of phage therapy is that although bacteria are able to develop resistance to phages the resistance is much easier to overcome. The reason behind this is that phages replicate and undergo natural selection and have probably been infecting bacteria since the beginning of life on this planet. Although bacteria evolve at a fast rate, so too will phages. Bacteria are most likely to modify the molecule that the phage targets, which is usually a bacterial receptor. In response to this modification phages will evolve in such a way that counteracts this change, thus allowing them to continue targeting bacteria and causing cell lysis. As a consequence phage therapy is likely to be devoid of the problems similar to antibiotic resistance.

Bacteriophages are very specific, targeting only a particular strain of bacteria. Traditional antibiotics have a wide-ranging effect, killing both harmful bacteria and useful bacteria such as those facilitating food digestion. The specificity of bacteriophages reduces the chance that useful bacteria are killed when fighting an infection.

The machinery and regulation pathways in eukaryotes are different from bacteria, therefore preventing eukaryotes acting as hosts to these phages.

Increasing evidence shows the ability of phages to travel to a required site — including the brain, where the blood brain barrier can be crossed — and multiply in the presence of an appropriate bacterial host, to combat problems such as meningitis. However the patient's immune system can, in some cases mount an immune response to the phage (2 out of 44 patients in a Polish trial ^[2].)

Development and production is faster than antibiotics, on condition that the required recognition molecules are known.

Research groups in the West are seeking to develop broad spectrum phage and targeted MRSA treatments in a variety of forms - including impregnated dressings for wounds.

[edit] Risks

Bacteriophage therapy is generally very safe, however fevers can occur with phage treatment. This is thought to be caused by endotoxins released by the bacteria within the patient after they have been lysed by the phage (Herxheimer reaction), of course this can happen with antibiotics also.^[3]

Additionally care has to be performed in manufacture that the phage medium isn't contaminated with bacterial fragments and endotoxins from the production process, it is beneficial if testing on animals is performed to ensure safety.

Lysogenic bacteriophages are also thought to be risky, and are now seldom used thereaputically. These viruses can act as a way for bacteria to exchange DNA, and this can help spread antibiotic resistance or even, theoretically, can make the bacteria pathogenic (see Cholera).

[edit] Application

Phages are "host specific" and it is therefore necessary in many cases to match phages to the patient's infection prior to treatment. Some bacteria, for example clostridium and mycobacterium, have no known therapeutic phages available - however isolation of therapeutic phages can typically require a few months to complete if there are sufficient host bacterial strains available for testing.

Phages can work if applied orally, topically on infected wounds or spread onto surfaces, and used during surgical procedures.

In August 2006, the United States Food and Drug Administration approved spraying meat with phages. This has raised concerns since without mandatory labelling consumers won't be aware that meat and poultry products have been treated with the spray. [3]

According to Phage International, phage therapy can also be used for the treatment of a variety of human afflictions including: laryngitis, skin infections, dysentery, conjunctivitis, salmonella, and other bacterial infections.

A recent review of phage therapy suggested that, "Too many of the clinical studies with phages do not correspond to current standards of clinical and microbiological research and need to be repeated." ^[4]

[edit] Obstacles

The host specificity of phage therapy may make it necessary for clinics to make numerous different cocktails for treatment of the same infection or disease because the bacterial components of such diseases may differ from region to region or even person to person. Such a process would make it difficult for large scale production of phage therapy. Additionally, patent issues may make it difficult for pharmaceutical companies to patent phages for therapy use, thus making them reluctant to devote money for phage therapy research and development.

In addition, due to the specificity of individual phages, for a high chance of success, a mixute of phages is often applied. This means that 'banks' containing many different phages are needed to be kept and regularly updated with new phages, which makes regulatory testing for safety harder and more expensive.

To work, the virus has to reach the site of the bacteria, and unlike antibiotics, viruses do not necessarily reach the same places that bacteria can reach. ^[5]

Finally, some non therapeutic (lysogenic) phages transfer genes between bacteria that code for pathogenicity, notable in cholera. This makes it important to identify the phages being used to show that they are not harmful ones.

[edit] Clinics

[edit] Notes

^ Bacteriophages Show Promise as Antimicrobial Agents, Journal of Infection (1998) 36, 5-15
^ [1]
^ Evergreen PHAGE THERAPY: BACTERIOPHAGES AS ANTIBIOTICS
^ "Phage therapy: the Escherichia coli experience" by Harald Brüssow in Microbiology (2005) Volume 151, pages 2133-2140.
^ [2]