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 [See
Graphic], often over a hundred in half an hour.
These "young" phages burst from the host cell (killing it) and
infect more bacteria (also see "Can
any phage be used for therapeutic purposes?").
Click
here to see simulation of the
above described process (Requires RealPlayer).
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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. All
therapeutic phages developed by Intralytix are lytic.
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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.
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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%.
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Why
is there so much controversy about the efficacy of phages?
Phages were 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 naïve 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:
* 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.
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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).
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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.
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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:
