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Bacteriophages

Phages - General Information

Copy of my letter sent to the editor of the Eastern Daily Press, 11th Oct. 2007.

General Information about Bacteriophages
What are phages and how do they "work"?

Bacteriophages (phages) are viruses that infect bacteria. Typical phages
have hollow heads (where the phage DNA or RNA is stored) and tunnel
tails, the tips of which have the ability to bind to specific molecules on the
surface of their target bacteria. The viral DNA is then injected through the
tail into the host cell, where it directs the production of progeny phages
often over a hundred in half an hour. These "young" phages burst from
the host cell (killing it) and infect more bacteria.

Can therapeutic phages be developed against any infection?

Therapeutic phages can potentially be developed against any bacterial
infection. Obviously, because of their "mode of action", phages can not
be used to treat viral infections (e.g., influenza or herpes).

Can any phage be used for developing therapeutic phage
preparation?

No. In general, there are two major types of phages, lytic and
lysogenic.Only the lytic phages (also known as virulent phages) are a
good choice for developing therapeutic phage preparations.Lytic phages
multiply inside the cell, and release a burst of phages through the
membrane, thus lysing the cell. Lysogenic phages, on the other hand,
integrate their DNA into the host DNA creating a prophage. Prophage can
escape from the original host (by cutting not only its DNA back, but
possibly some genes of the host bacterium as well) and can integrate
into a different one (the process is called transduction). Such phages
are inappropriate candidates for phage therapy because of their "mode
of action," and because they can lead to transfer of virulence genes and
those mediating resistance to antibiotics.

How safe are the therapeutic phages?

Phages are considered to be very safe for therapeutic use. So far only a
very few side-effects have been reported in the patients undergoing
phage therapy; those that were seen seemed directly associated with
the therapeutic process. For example, pain in the liver area (lasting
several hours) was reported in one study conducted in Poland. The
authors suggested that this might be related to extensive liberation of
endotoxins as the phage were destroying the bacteria most effectively. It
should be mentioned that this also happens when antibiotics are used.

Are there any reports on phage-based clinical trials?

Yes. The first reported application of phages for treating infectious
diseases of bacterial origin came from Bruynoghe and Maisin in France in
1921. The international literature contains several hundred reports on
phage therapy, with the majority of the publications coming from
researchers in the former Soviet Union and Eastern European countries.
Many of those studies were of poor scientific quality, as they did not
include follow ups and appropriate controls. In some cases, successful
treatment with phages was reported for diseases of viral and/or
allergenic origin which does not make much scientific sense. In the
English language, the most detailed descriptions have come from the
Institute of Immunology and Experimental Medicine of the Polish Academy
of Sciences [Slopek S., et al., 1983, Slopek S., et al., 1987]. Briefly,
phage therapy was used on 550 patients, at 10 clinical and hospital
departments, in three different cities. Major infecting agents included
Staphylococci, Pseudomonas, Escherichia, Klebsiella, and Salmonella.
Rates of success ranged from 75 to 100% (92% overall). The overall
success rate was even higher (94%) for the 518 cases were antibiotic
therapy was shown to be ineffective. Medline citations (published during
1966-1996) on the therapeutic use of phages in humans were recently
reviewed in the Journal of Infection [Alisky J., et al]; the overall reported
success rate for phage therapy was found to be in the range of
80-95%.

Why is there so much controversy about the efficacy of phages?


Phages were previously never given a fair and scientifically
well-thought-through evaluation; quite often, the conclusions made about
the phage therapy or even the nature of phages were unbelievably nave
as assessed from what we know about phages today. Among specific
reasons contributing to the early problems of phage therapy, as well as
the questions on their efficacy, were:

* Failure to select specific phages against the target bacteria in vitro,
before using them in in-vivo models and/or in patients;



* Lack of availability and/or reliability of bacterial laboratories for carefully
identifying the pathogens involved, therefore making selection of specific
phage impossible;



* Use of single phages in infections which involved mixtures of different
bacteria;


* Failure to neutralize gastric acidity prior to oral phage administration;



* Lack of knowledge that when treating bloodstream infections,
endotoxins can be released as a result of lysis of bacteria which could
lead to a further deterioration of the patient's condition (which is a
potential problem with antibiotics as well);



* Lack of understanding of the heterogeneity and "mode of action" of
phage (e.g., differences between lytic and lysogenic phages in respect
to their ability to act as therapeutic agents);


How do phages compare to antibiotics?
General comparisons between phages and antibiotics are described
below:

Advantages:

Bacteriophages.
Very specific*, affects the targeted bacterium only; therefore,
"dysbiosis" (and chances of developing secondary infections) is
avoided.

No side effects have been described so far - Is able to self-reproduce
as long as corresponding host-bacteria are present in the environment.
Therefore the need to repeatedly administer the phage is greatly
reduced.

Since phage is targeted to receptors on bacterial membrane or capsule,
which are important virulence determinants, development of
phage-resistance usually means changes in those structures and may,
therefore, lead to attenuation of the strains in virulence.

Selecting a new phage (e.g., against phage-resistant bacteria) is a rapid
process and frequently can be accomplished in days.

Production is simple and relatively inexpensive .

Antibiotics.
Can be used without knowing exact characteristics of the
disease-causing bacteria.


Disadvantages

Bacteriophages.
Because of the high specificity of phages, the disease-causing
bacterium has to be identified before the phage therapy can be started.

Antibiotics. Non-specific action that targets not only the pathogenic microorganisms
but also a normal microflora. This can affect the microbial balance in the
gut, which, in turn, often leads to serious secondary infections.

Multiple side effects, including yeast infections, intestinal disorders, and
allergies. - Repeated administrations are often needed

Antibiotic resistant bacterial strain remains pathogenic.

Developing a new antibiotic (e.g., against drug-resistant bacteria) is a
time consuming process and may take several years.

Production is expensive.


* Some researchers consider the high specificity of phages to be their
disadvantage against antibiotics, as explained in "disadvantages"
section. However, there is an extensive experience in developing
"cocktails" of phages, which include active phages against selected
pathogens.

Have phages ever been licensed for human use?

Yes. Phage therapy products were licensed for sale in the United States
in 1930s. The Ministry of Health of the former Soviet Union routinely
licensed active phage preparations for the use in humans. ; It is likely that
therapeutic phages used (and sold) in Eastern Europe were also
licensed by appropriate public health authority (e.g., ministry of health).

Have phages ever been produced for commercial use?

Yes. In the 1930s, a large US pharmaceutical company listed phages
among its biological therapies and offered them for sale. Phages were
used at the Institute Pasteur in Paris, France, and were sold in Eastern
Europe, and all over the territory of the former Soviet Union.

Can the bacteria develop resistance against phages?
Bacteria can develop resistance against both antibiotics and phages.
However, there are some very important differences to favor phages in
this context:

Development of a new antibiotic is a very expensive and time consuming
process; it can take over 10 years and several million dollars to develop,
and to bring to the market, a new antibiotic. Developing of a new phage,
on the other hand, can potentially be accomplished in days, at a much
lower expense.



Science may approach a point when no effective antibiotics can be
chemically developed (at least for a while) to treat certain multi-drug
resistant micro-organisms. Since selection of active phages is a natural
process, evolutionary arguments support the idea that active phage can
be selected against every resistant bacterium, by an ever ongoing
process of natural selection.

Thomas Hausler's excellent book on the history of phage therapy; from the early days under Stalin's rule to modern times.






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Thomas Hausler's excellent book 'Viruses-v-Superbugs'




 
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