THERAPY REVIEW Biodrugs 2002; 16 (1): 57-62

1173-8804/02/0001-0057/$25.00/0

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Bacteriophages
Potential Treatment for Bacterial Infections
Donna H. Duckworth and Paul A. Gulig
Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, USA

Contents
Abstract . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
1. Early History of Bacteriophage Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
2. Phage Therapy of Humans in Eastern Europe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
3. Recent Animal Model Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59
4. Limitations to Phage Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60
5. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Abstract Bacteriophages (phages) are viruses of bacteria that can kill and lyse the bacteria they infect. After their
discovery early in the 20th century, phages were widely used to treat various bacterial diseases in people and
animals. After this enthusiastic beginning to phage therapy, problems with inappropriate use and uncontrolled
studies and ultimately the development of antibacterials caused a cessation of phage therapy research in the
West. However, a few institutions in Eastern Europe continued to study and use phages as therapeutic agents
for human infections. The alarming rise in antibacterial resistance among bacteria has led to a review of the
Eastern European studies and to the initiation of controlled experiments in animal models. These recent studies
have confirmed that phages can be highly effective in treating many different types of bacterial infections. The
lethality and specificity of phages for particular bacteria, the ability of phages to replicate within infected animal
hosts, and the safety of phages make them efficacious antibacterial agents. Although there are still several hurdles
to be overcome, it appears likely that phage therapy will regain a role in both medical and veterinary treatment
of infectious diseases, especially in the scenario of emerging antibacterial resistance.

1. Early History of Bacteriophage Research
Bacteriophages (phages) are viruses of bacteria and, as such,
have an exceptional ability to kill the bacteria they infect. The
phage interaction with their host bacteria is very similar to that of
animal viruses with their host cells. Phages first bind to a specific
receptor on the host cell surface. This binding is highly specific
and therefore limits the host range of a phage to a particular spe-
cies, if not strain, of bacteria. The phage genome is injected into
the host bacterium, and phage genes are expressed. With virulent
phages, the phage genome is replicated, and structural compo-
nents are produced, ultimately leading to the lysis of the host cell
and release of hundreds of progeny phage. This process can occur
in as little as 15 minutes. The progeny phage can then continue
the cycle by infecting other bacterial cells. On an agar plate, the
lysis of bacteria in a lawn will form a clear spot called a plaque.
In contrast to virulent phages, temperate phages have the ability
of co-existing with their host bacterial cell indefinitely until a
lytic cycle is induced. The ability of virulent phages to rapidly
kill and lyse infected bacteria, the specificity of phages for par-
ticular bacteria, and the ability of phages to increase in number
during the infection process make phages excellent potential ther-
apeutic agents for fighting bacterial disease. However, temperate
phages are of little use in phage therapy.
The first report of a possible therapeutic effect of phages was
published in 1917 by a self-taught bacteriologist with aspirations
to international fame, Felix d’Herelle.[1] He had often observed
plaques on agar cultures of bacteria where bacteria had been
killed, but he did not make a connection to a possible therapy for
bacterial disease until he was hired to investigate an epidemic of
dysentery among soldiers in a Paris hospital. He looked for this
antibacterial activity in a patient with dysentery to see if it corre-
lated with an improvement in symptoms, much as one would look
for the correlation of antibodies and convalescence. He filtered
the patient’s faeces and incubated the filtrate with cultures of the
58
causative agent of dysentery, Shigella dysenteriae. The faeces of
patients who experienced a spontaneous turnaround in their dis-
ease contained a filterable substance that killed, in fact cleared, broth
cultures of the bacteria.[1] The mysterious agent could be serially
transmitted, showing that it could multiply and thus must be a
‘living germ’. d’Herelle called it ‘bacteriophage’ for its ability to
seemingly ‘eat’ bacteria. His publication began a decade or more
of frenzied activity designed to isolate other phages and use them
as cures for various diseases. In a book published in 1926, The
Bacteriophage and Its Behaviour, d’Herelle described the use of
phages for curing or preventing over a dozen diseases, including
bacillary dysentery, typhoid fever, cholera, and bubonic plague,
as well as wound infections.[2] He also wrote about using phages
to stop epidemics of avian typhosis, haemorrhagic septicaemia of
the buffalo, bubonic plague, dysentery, and silkworm diseases, and
described how he could immunise (i.e., protect) against a number
of diseases using phages. Although his reports were anecdotal
rather than strictly scientific, they were enough to stimulate work
with phages in respected institutions all over the world.
The analysis and use of phages in the western world achieved
a rapid rise and fall. Stanford University set up a laboratory to
determine whether phages could be used therapeutically. Eli Lilly,
Squibb & Sons, and Abbott Laboratories sold therapeutic bacte-
riophages and received positive reports on their efficacy – espe-
cially for staphylococcal infections and intestinal diseases.[3] In
the 1930s, however, reports of inactive commercial preparations
and deaths of treated patients began to surface. A review in 1934
concluded that there was no evidence of any therapeutic effect of
phages except in staphylococcal infections and cystitis.[4] The
discovery of antibacterials was the final undoing of research on
the therapeutic uses for phages, at least in the West.
2. Phage Therapy of Humans in Eastern Europe
In Eastern Europe, however, phage therapy remained an accept-
able field of study. At the Eliava Institute, co-founded by d’Herelle,
in Tblisi, Georgia, research was particularly active. Water from
the Kura River was used to isolate phages that were sent through-
out Russia. During World War II, Russian soldiers carried vials
of phage to treat wounds or dysentery. Phages were also used
therapeutically in Poland. In addition to our brief summary of this
body of work, we refer readers to an extensive review of the
Russian and Polish literature dealing with phage therapy.[5]
What could be considered the reintroduction of an awareness
of phage therapy in the West began in the 1980s. Between 1980
and 1985, English translation was made available of reports from
Polish scientists, led by Steven Slopek, using phage therapy on
550 patients, most of whom had failed antibacterial treatment.
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Duckworth & Gulig
The results are contained in a large review that documents the age
and sex of the patients, the type and severity of infection, and the
causative agent.[6] The infections treated were caused by Staphy-
lococcus, Klebsiella, Proteus, Escherichia, Shigella, Pseudomo-
nas, or Salmonella, and were located in several different sites in
the body. Treated diseases included the following: dysentery; sep-
ticaemia; blepharitis; otitis media; meningitis; inflammation of
the upper and lower respiratory tracts; pneumonia; ulcerative sto-
matitis; suppurative peritonitis; abscesses of the inner organs; sup-
purative infections of the urinary tract and vagina; furunculosis;
decubitus ulcer; pyogenic infections and arthritis. Wounds, burns,
fractures of facial bones and postoperative contusions of the brain
and brain stem were also subjected to phage therapy. The phages
came from an extensive collection maintained at the Bacterio-
phage Laboratory of the Institute of Immunology and Experimen-
tal Therapy in Wroclaw. Prior to their administration, the phages
were tested for induction of complete lysis of bacterial strains iso-
lated from patients. Bacteriophages were administered orally be-
fore meals, after neutralisation of gastric acid. Phages were also
used locally as moist applications to wounds and as eye, ear, and
nose drops. After oral administration, phages were readily found
in both blood and urine, indicating a widespread distribution
throughout the body. All of the studies were carried out in clinics
or hospitals, mostly surgery departments, and the clinical results
of phage therapy were evaluated by a ‘therapeutist’. The overall
success rate in this study ranged from 75 to 100% (92% overall)
as judged by improvements in health, healing of wounds, and the
disappearance of infecting bacteria. The rate of success depended
on the age of the patient, with older patients doing less well, and
severity of disease, as would be expected. The course of therapy
was sometimes as long as 14 weeks, but virtually no adverse effects
were encountered. Slopek and colleagues highly recommended
phage therapy, particularly for the following conditions: acute
infections of the alimentary tract (bacillary dysentery and diar-
rhoea); septicaemia irrespective of its origin; postoperative infec-
tions irrespective of location; suppurative skin diseases; diseases
of the subcutaneous tissue; furunculosis; infections of the urinary
tract; and suppurative infections of joints and bones. Although
extensive studies were done, there are weaknesses. Most impor-
tantly, there were no controls; the decision as to whether the phage
had been effective or not was subjective, and no quantification of
numbers of bacteria or phages, either before or after treatment,
was given. Thus, the work would not be considered as meeting
the stricter standards in the Western medical community. How-
ever, it is difficult to completely dismiss the far-reaching and
extensive results. Perhaps the fairest analysis would be to say that
the results suggest that phage therapy can have a useful role in
infectious disease and merits further, more controlled, analysis.
Biodrugs 2002; 16 (1)
Phage Therapy
Extensive clinical work was also carried out at the Phage
Institute in Tblisi, although much of that work is unpublished.
Visitors to Georgia after 1989, however, report that phage therapy
is part of the general standard of care and is used extensively in
paediatric, burn, and surgical settings. The problem of phage re-
sistance is overcome by using specially formulated mixtures of
phages with different receptor specificities. To treat burns and
other skin infections, a mixture of phages for several different
bacteria has been made. This phage cocktail has evolved into
PhageBioderm,1 a biodegradable nontoxic polymer composite
containing phage for covering wounds and burns. The Phage In-
stitute has also developed an Intestiphage preparation, which
includes 23 different phages able to kill a range of enteric bacte-
ria. Tblisi researchers found that phages used in conjunction with
antibacterials were generally more effective than phages used
alone, although the Polish group found the opposite – phages
alone were more effective than when combined with antibacteri-
als. This discrepancy could be because the Polish researchers
treated mainly antibacterial-resistant bacteria.
Other reports published in Russian and recently translated
include a study of 131 postoperative pseudomonal or staphylo-
coccal infections that were treated with phage with a success rate
of 82%.[7] The phage appeared to be particularly effective against
Pseudomonas. Another study of 236 antibacterial-resistant, sup-
purative infections reported a 92% cure rate with phage.[8] In a
study of 500 low-birthweight infants, Escherichia coli and Pro-
teus phage were mixed with Bifidobacterium and administered to
combat sepsis, with positive results in all patients.[9] In another
study involving children, Shigella phage were given to 3210 chil-
dren to prevent dysentery in kindergartens.[10] When phage-
treated children were compared with a control group of 3310
children, the group receiving the phage had a 2.5-fold lower in-
cidence of dysentery.
These reports have all been criticised, as indicated for
Slopek’s original review, for their lack of information on the iso-
lation and properties of the phage as well as for being anecdotal,
uncontrolled, and lacking scientific criteria for evaluation of
cures. Also troubling is the length of time it took in some cases
to effect a cure. The average time in the Polish studies was more
than 5 weeks, and in some cases treatment lasted for 14 weeks.
One would think that after this amount of time patients would
have mounted an antibody response to the phages, rendering them
ineffective. In addition, none of the reports approach the problem
from a mechanistic point of view, i.e. if the phages are working,
how so? However, taken together, one would have to conclude
1 Tradenames are for identification purposes only and do not imply
endorsement.
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59
that it appears that under the right conditions phages can be useful
therapeutically and that the likely mechanism is by killing the
infecting bacteria. Still, further definitive experimental studies
are needed.
3. Recent Animal Model Studies
To approach phage therapy more rigorously than is possible
with human studies, several groups began to experiment with
phages in animal models. In the 1980s, Smith and colleagues
[11-14] performed phage treatment experiments on mice, calves,
lambs, and piglets. These studies were followed in the 1990s by
Barrow and co-workers, who examined chickens and calves,
[15,16] and Soothill and co-workers, who worked with guinea-pigs
and mice.[17,18] These studies confirmed the potential use of bac-
teriophages in treating certain bacterial infections in animals.
Smith and Huggins [11] treated septicaemia and meningitis in
mice inoculated intramuscularly or intracerebrally with virulent
E. coli K1, followed by treatment with either a phage that attached
to the K1 capsule or with antibacterials. Phage treatment pre-
vented death and caused a rapid reduction in numbers of bacteria
in all tissues examined. Interestingly, phage treatment was more
effective than multiple doses of antibacterials. Phage were found
in all tissues examined (muscle, blood, spleen, liver, brain) within
5 minutes of their injection into muscle and their concentrations
in tissues actually increased, presumably because of replication
in the E. coli. The only phage-resistant bacterial mutants that
arose were K1– and thus were of low virulence. This result under-
scores the use of phages that utilise essential virulence factors of
the bacteria as their receptor and demonstrates a key aspect of de-
veloping phage research, i.e. an understanding of bacterial viru-
lence needs to be included in the rational design of phage therapy.
Smith and colleagues then examined phage therapy of diarrhoea
in calves and other farm animals caused by stable toxin-producing
E. coli.[13,14] Calves that responded to phage treatment had lower
numbers of the bacteria in their gastrointestinal tracts and contin-
ued to excrete phage until all of the infecting bacteria had disap-
peared. Similar results were obtained with piglets and lambs.
Since the phages used in these studies were not using essential
virulence factors as their receptors, Smith and Huggins employed
another attribute of phages to their benefit – the immense variety
of phages present in nature. Specifically, they used a phage that
was able to infect E. coli mutants that became resistant to the first
phage.[14] By mixing these phages together, resistant mutants aris-
ing in treated animals were killed by the second phage. In theory,
by isolating phages that recognise different receptors on host bac-
teria and by selecting for mutant phages in the laboratory that
have altered their receptor-binding activity, it should be possible
Biodrugs 2002; 16 (1)
60
to produce phages that will continue to be effective against spon-
taneously occurring phage-resistant bacteria. This is in contrast
to the slow identification and development of new antibacterials
required to fight antibacterial-resistant bacteria. In later experi-
ments using different phages, Smith et al. found that spraying the
bedding in barns with phage could prevent disease in calves,[13]
and they examined several factors that could adversely influence
the effectiveness of phage therapy in an agricultural setting.[12]
These included antibodies to the phage, which appeared after
phage therapy of an E. coli infection, acidity, and temperature of
the host animal. The results suggested that phage therapy would
not be as straightforward as initially hoped.
Berchieri et al. [16] reported success using phages to prevent
salmonellosis in poultry. The birds were inoculated orally with
Salmonella typhimurium followed by oral treatment with differ-
ent phages that were isolated from human sewage. Only some of
the phages provided protection, with death as the endpoint, and
high levels of phage were required to achieve protection. It should
be noted that phage treatment of salmonellosis could be problem-
atical because the bacteria reside within host cells where they
could be inaccessible to phage therapy. In a subsequent study,
Barrow et al. [15] used one of the E. coli K1-specific phages of
Smith and Huggins [11] to protect chickens and calves against E.
coli K1. Simultaneous infection with phage and bacteria afforded
protection from death, and phage administered to birds as early
as 2 days before infection also exhibited some protection, dem-
onstrating the prophylactic use of phage. Calves inoculated orally
with E. coli K1 and treated intramuscularly with phage experi-
enced a delay in onset of disease, but not full protection.
Soothill examined phages specific for Acinetobacter bau-
mannii or Pseudomonas aeruginosa to protect mice from death
by parenteral inoculation of these bacteria, which infect burn
wounds.[17] It appeared that relatively small numbers, in the order
of 102 of A. baumannii phage could protect against lethal infec-
tion with 107 to 108 colony forming units (cfu), while higher
numbers of phage [107 to 108 plaque forming units (pfu)] were
required to protect against 108 cfu of P. aeruginosa. Soothill [18]
later used the Pseudomonas-specific phage to protect guinea-pig
skin grafts from ‘failure to take’ by localised application of P.
aeruginosa. No quantitative bacteriology was performed in this
limited set of experiments. The sum of these initial rediscoveries
of phage therapy in animal models was the support of further
experimentation and the hope that phage therapy would withstand
the further scrutiny of controlled and probing analyses.
We have been studying the therapeutic effect of phages
against Vibrio vulnificus, an environmental bacterium able to
cause severe disease after ingestion of raw oysters or contamina-
tion of wounds with seawater or oyster material.[19] Phages iso-
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Duckworth & Gulig
lated were used against disease caused by V. vulnificus in a mouse
model of infection. In mice, V. vulnificus causes both skin infec-
tion (necrotising fasciitis) and septicaemia, mimicking diseases
of humans.[20] Mice were injected intraperitoneally with iron dex-
tran to mimic the predisposing condition of iron overload for V.
vulnificus septic shock in humans, followed by subcutaneous in-
jection of the bacteria. Phages were administered intravenously
at the time of bacterial inoculation or at various times thereafter.
When phages were injected simultaneously with, or within 3
hours of, bacterial injection, they could prevent disease as indi-
cated by subcutaneous lesion size, numbers of bacteria in the skin
and liver, and normal body temperature.[21] Two different phages
were effective against three different strains of V. vulnificus of
varying levels of pathogenicity, while a third phage that required
a medium containing sea-salts to grow was not effective in the
mice. These results demonstrate that bacteriophages have thera-
peutic potential against necrotising fasciitis and septicaemia
caused by V. vulnificus, but that care must be taken to assure that
the phages in question are able to reproduce in the infecting strain
of bacteria under physiological conditions in the infected animal.
In addition to the aforementioned studies of agricultural use
of phage treatment, there has also been success in using phages
to treat bacterial infections in aquacultured fish [22] and to prevent
bacterial infections in plants.[23] We are also extending our studies
of phage treatment in a mouse model for V. vulnificus disease to
treating V. vulnificus-contaminated oysters to render them safe for
human consumption.[24] Although still preliminary, these studies
suggest that phage treatment could have applications in the agri-
cultural sphere.
4. Limitations to Phage Therapy
Having discussed the numerous studies that demonstrate the
usefulness and efficacy of phage treatment of humans, animals,
and plants, we must also note that there are limitations to and
potential problems with phage therapy. Of primary concern for
any treatment of humans is safety. Although no harmful adverse
effects have ever been reported with phages themselves, the pu-
rity of the phages could be an issue. Since phages are released by
lysed bacteria, crude phage preparations can contain lipopolysac-
charide, peptidoglycan, or other inflammatory or toxic compo-
nents. However, phages are easily purified by several different
procedures, such as density gradient centrifugation and column
chromatography, and such methods have eliminated problems as-
sociated with impurities.[25]
There are several reasons why not all phages will be effective
in therapy. Our studies with V. vulnificus show that some phages
do not have activity against bacteria in the environment of a mam-
Biodrugs 2002; 16 (1)
Phage Therapy
malian host.[21] Either the bacteria do not express the phage re-
ceptor in the animal or the biochemical conditions for phage bind-
ing are not optimal. A major drawback of phages is their speci-
ficity. It is unlikely that any single phage will be sufficient to treat
all strains of a particular pathogen, so banks of phages would be
needed to cover clones or strains of the given pathogen. Addition-
ally, as opposed to the case for antibacterials, in which some broad-
spectrum agents might provide coverage for all bacterial patho-
gens causing a particular disease, different phages would be
required for each bacterial aetiological agent. However, this host
specificity of phages is also of benefit, since phages will not upset
the normal flora. In contrast, this is a common occurrence with
antibacterials and can lead to secondary diseases.
It is possible that an immune response generated as a result
of exposure to the phage would neutralise the phage and inhibit
its usefulness. However, phage therapy is usually complete before
specific immunity has had a chance to develop. A more relevant
concern is that subsequent use of the same phage may be hindered
by immune reactions to the first use. However, phages would
most probably be used in restricted situations, for example, infec-
tion with a fully antibacterial-resistant strain where no alternative
treatment exists. In such a scenario, the possibility of a sub-
sequent infection requiring identical phage therapy would not be
of prime concern. However, even in such a case, it is not out of
the realm of possibility that an alternative phage therapy could be
reserved, in which the second set of phages does not immunolog-
ically cross-react with the first set of phages. A potential safety
problem related to immune responses to phages is formation of
antibody-antigen complexes; however, this has never been de-
scribed in clinical or animal treatments. Another issue involving
phage-host defence interactions recently addressed by Merril et
al. [26] was the clearance of phages by nonspecific defences of the
host. They selected in mice for mutant phages that were cleared
less effectively by the mice because of point mutations in phage
coat proteins. Whether clearing by nonspecific defences will be
a real problem in phage therapy is yet to be determined. However,
the study by Merril et al. [26] underscores the power of using
genetic selection to isolate phages that have acquired beneficial
phenotypes.
There are two additional potential problems with the thera-
peutic use of phages. Some phages are able to transfer genetic
information between bacterial cells by generalised or specialised
transduction. The possibility thus exists that use of such phages
could contribute to the spreading of antibacterial resistance or
virulence genes among bacterial populations. Therefore, thera-
peutic phages should not have transducing potential. However,
this is easily tested in the laboratory, and mutants that lack trans-
ducing ability could be isolated for therapeutic use. Another po-
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61
tential problem inherent in some phages is that they can code for
bacterial virulence factors and confer virulence by lysogenic con-
version. The best-known examples are cholera toxin, botulism
toxin, diphtheria toxin, and certain streptococcal toxins.[27] There-
fore, sequencing the genomes of potentially therapeutic phages
should be done.
5. Conclusion
An abundance of evidence indicates that phages can be used
successfully in humans, animals, and plants to treat bacterial in-
fections. In humans and controlled animal studies, phages have
been shown to work very effectively in both the prevention and
cure of a wide variety of diseases . Success rates are high, usually
in the 80 to 90% range. Phages can prevent or treat diarrhoea,
dysentery, septicaemia, and wound and burn infections in humans,
as well as intestinal and systemic diseases in animals. Anecdotal
reports indicate the effectiveness of phage therapy in a variety of
other human ailments. Phages can be administered orally, topi-
cally, intramuscularly, or intravenously. After administration,
phages can be found in virtually every tissue of the body exam-
ined, as well as being excreted in urine and faeces.
It is unlikely that phages will take the place of antibacterials
except in very limited situations. First, certain types of infections
will be more amenable to phage therapy than others. These would
include infections where the bacteria remain outside of host cells
and within fluids or organs that are easily accessible, such as the
digestive or respiratory tracts. Some of the most promising areas
of use would be for the treatment of wounds and burns where the
phages could be applied locally or for intestinal diseases where
they can be ingested. However, phages have been found to be
effective when administered parenterally as well.
We are entering a time in which basic and clinical research
on phage therapy will increase tremendously, and we are hopeful
that the vast experience of the Eastern Europeans will be con-
firmed with further experimentation and that the ongoing animal
studies will lead to new clinical applications. However, there are
several hurdles that need to be overcome before phage therapy
can be implemented in the West. Still, there is comfort in knowing
that when or if antibacterials cease to be effective, phages, how-
ever imperfect, will be ready to go to work.
Acknowledgements
Our studies of phage therapy have been supported by funds from a Johnson
and Johnson, Inc. Focused Giving Award and National Oceanographic and
Atmospheric Administration SeaGrant GMO-99-1.
Biodrugs 2002; 16 (1)
62
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Correspondence and offprints: Professor Paul A. Gulig, Department of Mo-
lecular Genetics and Microbiology, University of Florida College of Medi-
cine, Box 100266, Gainesville, FL 32610-0266 , USA.
E-mail: gulig@ufl.edu
Biodrugs 2002; 16 (1)