Biological
Sciences/Microbiology
Dr.Aleshkin A.V., Dr. Lakhtin V.M., Dr. Prof.
Afanasiev S.S.,
Dr. Lakhtin M.V., Dr.Prof. Aleshkin V.A.
Bacteriophage practice antimicrobial potential. The
review
Abstract:
In the review scientific and commercial potential
of bacteriophage applications as probiotic factors in different spheres of
microecological biocontrol and safety of microbial contaminations and
decontamination, bioprocessing and stabilization of foods, prevention of
eukaryotic organism diseases induced by microbial infections, phage therapy are
analyzed. The historic aspects are also under consideration.
Keywords: Bacteriophages, microbiocenoses, antimicrobials.
Bacteriophages
(BP) are viruses possessing capability to selective infection of bacterial
cells of strain or antigenic homological strains of specie or genus [1].
According to majority of publications, BP may be used as natural antimicrobial
agents for fight to bacterial infections of human, animal and other
agricultural origin [2-4]. Investigators combine all spectra of such
therapeutic actions in term “phage therapy” [5]. A number of authors consider
the possibility of practical application of BP within sanitary-hygienic actions
in food industry, sphere of social alimentary, children and army contingents,
and therapy-prophylaxis organizations [6-11]. Investigations of problems which
are closed to BP are considered as strategical perspectives including synergism
of antimicrobials, nanotechniques, etc. [12-14]. Combining all possibilities of
such BP applications as biocontrol ones, specialists mean use of BP for both
human (goods like peroral food additives, tooth pastes, creams, deodorants; as
well as for bioprocessings of medical tools and foods, diagnostics of
infections, etc.) and agricultural plants and animals (bioprocessings for
decreasing levels of potentially relative pathogenic microorganisms) [15, 16].
This overview is firstly devoted to problems of safety and effective
application of BP as food additives – agents of decontamination of foods (at
all stages of their production) and probiotic biologically active additives to
alimentary which serve additional sources of BP for human organism. In the latter,
the presence of BP among human normal microflora allows decreasing risk of
highly contagious food infections like escherichiosis, salmonellosis, diarrhea,
etc.
Bacterial viruses were
discovered in 1915 year by Frederick Twort, however era of BP is
begun since publication by Felix d’Herelle who 95 years ago for the first time demonstrated the
presence of BP in normal microflora of human and animals [17]. A lot of later
investigations support the presence of BP in human and animal fecal, urine and
salivary in both normal and pathological conditions in concentrations up to 106
PFU/ml [18-27]. In addition, it was shown that bacterial viruses are presented
all over objects of environment (water and soil, plants, etc.) in quantities which are higher than billions of
particles in unit of substrate (for example, in drop of sea water) [28]. Thus, the problem of BP using as the part of
food ration may be considered as close to quantitative aspect (according to
content of viral particles in the food product) but not to qualitative aspect
(as in the case of chemical antibacterial agents). A number of authors consider
BP action like probiotic one that underlines biological nature of BP and their
action according to determination by the World Health Organization (WHO):
“Probiotics are alive microorganisms which are useful for the host organism
when applied in adequate quantities” [29-31]. Principally, the specificity of
interaction of BP particles to indicator bacterial culture limits the
possibility of the direct negative action of BP in respect of human organism
(cells) that is the basis of BP safe application for decontamination of foods
and prevention bacterial carriers. However from theoretical points of view, it
could be expected some side effects which can be realized by the following
ways:
* Infection of bacteria of the human normal microflora
following by development of yatrogenic
dysbacteriosis takes place in the case of application of other antimicrobials.
Selection of industrial BP strains used for prophylactic aims allows to choice
viral particles possessing maximally narrow diapasons of specific lytic
activity limited within specie or even strain of the bacterial host [32, 33].
Coctails of BP are able to change biotope bacterial and eukaryotic
microbiocenoses towards more healthy state [34-35]. Mean time according to
literature and our own data, inclusion of non-wanted viruses in the BP cocktail
(some BP as danger for probiotic bifidobacteria and lactobacilli) used for
decreasing risk of food infections is not detected [28, 36; our unpublished
data for in vitro and in vivo conditions].
More than 50-years experience of application of mono- and polyvalent
prescriptions of drug agents in therapy of acute intestinal diseases and
decompensated forms of dysbacteriosis in Russian Federation (former Soviet
Union) and Poland also supports non-possibility of realization of non-specific
lytic BP activity in respect of normal human microflora [37-40].
* By stimulation of the human immune reactions. As the result
of clinical investigations, it was shown that BP influence different functions
of the immune system cell populations involving forming innate and adaptive
immunity: cytokine production, T-cell proliferation, antibody synthesis,
phagocytosis and phagocyte respiratory bursts [40, 41]. In the same time in the
process of local and system phage therapy, it was not registered significant
anaphylactic reactions with exclusion of endotoxic reaction which was the
result of both the quality of the used phage composition (see below) and the
bacteriolysis reactions of Yarish-Gerkmeister in situ [42]. Upon prophylactic using BP, by minimizing
concentration of phage particles like the titers of BP from the human organism
(103-106 PFU/ml), it was possible to decrease quantity of
the endotoxin simultaneously formed at bacteriolysis [42]. Poland investigators
accent their attention on modulated BP influence on some immune reactions
induced by pathogenic bacteria and viruses that may be positively revealed as
synergistic BP effects (antibacterial and immune modulation) [40,
41].
* By modulated virulence of bacterial
host. Prevention of such BP action on human organism is also directly coupled
to the directed industrial strain selection resulted in inclusion of
exclusively virulent phages (non-producing resistant lysogens in bacterial
culture in any conditions) into composition [43-45]. Thus, it is possible to
avoid the direct modification of bacterial phenotype at the expense of
attachment of prophage genome to the host DNA as well as transduction (from
lysogenic toxigenic bacterial cultures to non-pathogenic ones) genes coding
toxins, and also to decrease possibility of horizontal transfer of antibiotic
resistance genes between microorganisms and appearance of lysogenic bacterial
cultures of resistance to BP [29].
* By spontaneous transduction of non-temperate (virulent) BP.
The danger of such phenomenon is transfer of the known pathogenic loci that may
be in BP genome. Using PCR-typing toxin-coding strains or complete sequencing
BP genome, it is maximally possible to safe BP application in respect of human [15, 46].
* By introduction of bacterial host toxins (which are
presented in sterile filtrate upon phage-induced lysis) into human organism.
The quality of the ready phage cocktail is obligatory controlled in respect of
the contents of endo- and exotoxins [47]. Exotoxin concentration may be reached
to zero using non-pathogenic cultures (for example, E. coli K-12 and Listeria
innocua) for increasing BP biomass [48]. Content of endotoxin (which is
determined after additional purification of sterile filtrate upon phage-induced
lysis) in composition is established as units of endotoxin in ml, according
regulating rules of the country - producer (according to European Food Safety
Authority [EFSA] – 50 ÅU/ml)
[43]. Quantity of endotoxin secreted in
situ is not controlled sharp but may be regulated using variation of doses
and number of times of administration of BP coctail.
Thus, negative specific BP
action on human health was not revealed during more than 80-years study of BP
and their interaction to eukaryotic cells (also animal and human) [5].
Upon considering the
problem of the BP usefulness for the host organism, or the problem of BP
effectiveness of application to human, it should be noted that more than 40
years in Soviet Union (beginning on the base of Tbilissi Institute for vaccines
and sera after G Eliava, and Ufa Institute for vaccines and sera after II
Mechnikov, and later in Russian Federation in branches of plants like “SIO
Microgen” (in Nizhny Novgorod, Perm and Ufa), more than 10 denominations of
therapeutic agents on the basis of separated species of BP or their
combinations for therapy and prophylaxis of acute intestinal infections and
decompensated forms of dysbacteriosis, and also against pathogens of a number
of pus-inflammation infections were developed [37, 49]. These are liquid and tablet forms of therapeutic
monovalent preparations of BP against dyarrhea, typhoid fever, staphylococci,
streptococci, E. coli, Klebsiella ssp.,
Salmonella ssp., Proteus ssp. and
Pseudomonas aeruginosa; and also
combined predescriptions containing few phages: coli-proteus, pyo-BP (against
staphylococci, streptococci, Klebsiella
ssp., Proteus ssp., P. aeruginosa and E.
coli), intesti-BP (against Shigella
ssp., Salmonella ssp., staphylococci, enterococci, Proteus ssp., E. coli and P.
aeruginosa) and others [50] (see detailed examples also in the tables 1, 2). Therapeutic preparations represent sterile filtrates of
BP-induced lysates which can be used intra and locally as: irrigation of wounds
and mucus envelopes, introduction into cavity of uterus, urinary bladder, ear,
sinuse’s paranasales, conjunctiva of eye, and also in draining cavities – abdominal,
pleural, cavity of abscesses after elimination of pus (table 1). In the last years BP in Russian Federation found their
application as therapeutic agents in dentist and dermatologic practice. On the
basis of BP, tooth-pastes and creams are prepared [51].
The world practice of phage
therapy is significantly inferior to Russian Federation (exclusion may be in
cases of Poland and Georgian ones). On the background of thousands of patients
taking BP in accordance to therapeutists in Russian Federation (this
quantitatively is in accordance to the size of sales of therapeutic
preparations based on BP on the data of annual retail audit which was performed
by the Companies IMS Health, DSM, RM BC and PharmExpert), in the frame of branched plant standard of medical help:
“Dysbacteriosis of the intestine. Protocol of conducting patients» [52], not
numerous modern comments of the West colleagues: within 40-years of the last
100 years mass production of BP was made by the Companies L’Oreal in France (5 denominations
of BP preparations) and Eli Lilly in USA (6 variants of mono- and polyvalent
phage-containing agents) about performed in the beginning stages of clinical
trials in USA, Great Britain and Belgium look like more than modesty [17] (table 2). However experience of
application of phages in complex of sanitary-epidemiologic procedures in
countries of Åuropean
Economic Cooperation (EEC), USA and Canada are represented in scientific
literature as extended enough [9, 15, 16]. These arrangements include 4 spheres
of action: (1) BP-îïîñðåäîâàííûé biocontrol – application of phages for the fight with bacteria of
danger for agricultural plants (vegetables, fruits, etc., before harvest
gathering) and animals (meat and dairy cattle, poultry, etc. before killing) at
the stage before their delivery to respective plants; (2) phage bioprocessing –
BP application for decontamination of vegetables, fruits, meat, fish, etc. In
process of their production before packing foods reading to eat or further
consuming; (3) prophylactic taking BP by peoples as probiotic biologically
active additives to diet for decreasing risk of development of sporadic cases
and epidemiologic out-breaks of food infections.
As
example of phage-directed biocontrol, may serve registered in December of 2005
year by the Agency of Protection of Environment USA (US EPA) biopesticide AgriPhage containing cocktail
of virulent phages lysing Xanthomonas
campestris pv. vesicatoria and
Pseudomonas syringae pv. tomato which strike tomato and pepper (so called
“black bacterial spotty”) [44]. Originally, BP (as components of biopesticide)
were isolated from fruits and vegetables infected with bacteria. For example,
the effectiveness of the BP using in respect of culture of hot-house pepper in
comparison to chemical pesticides is significantly higher [53]. 1 litre of
phage cocktail (produced by American company OmniLytics) contains at least 4,1
× 1012 viral particles (4,1×109 PFU/ml). 1 or
2 pints of AgriPhage diluted in 100 gallons of water are enough for sprinkle of 1 acre of vegetable plantations [53].
In 2006-2007 years OmniLytics received from Department of Agriculture of USA (US DA) the certificate for using composition on the base of BP against E.coli O157:H7 and Salmonella ssp. (BacWash) for bioprocessing fells of agricultural cattle, and also for all ecological locations (enclosures, transport containers, etc.) of possible infection of animals before their killing [40]. Similar investifations are listed In the table 3 which argue high BP effectiveness in the sphere of biocontrol of plants and animals used as foods for human.As example of phage bioprocessing, it may be presented registered in 2006 year Food and Drug Administration of USA (US FDA) phage-containing food additive (auxiliary technical agent – processing aid) on the basis of polyvalent listerial cocktail – ListShield (LMP-102, producer Intralytix, USA) – «Listeria monocytogenes Specific Phage Preparation» which includes 6 different phages possessing sensitivity to 170 strains of L. monocytogenes and allowing processing ready to eating meat of animals and poultry (so called “RTE products”). This food additive is applied directly before packing at meat and poultry plants for decomintation of semifabricates, sausages, meat slices by aerosol treatment of their surfaces in the dose not more than 1 ml on 500 cm2 of area of food products [10, 45]. The effectiveness of this BP cocktail was also demonstrated for processing fruits [54, 55].
In the same year FDA recognized that food additive Listex (producer - Micreos, The Netherlands) on the basis of strain of listerial BP P100 can be attributed to the class (of food additives) GRAS – Generally Recognized as a Safety – which are safe as a rule that means non-needing additional studies supporting safety of their application in the food industry, and can be used in production of cheese and (later, in 2007 year) other foods (EFSA gave a certificate to use Listex for decontamination of raw fish in 2012 year) [15, 43, 46, 56]. There are a lot of examples of successful using this food additive on the basis of listeria BP in bioprocessing different food semifabricates [48, 57]. It should be noted that BP effective concentrations are different in dependence on the product of decontamination. Thus in liquid foods (milk and cheese brine), the distribution of phage particles reveal uniform and free character. In cases of food products having improved flat solid surface (hot-dogs, leaves of salad, etc.), general surface area and its capability to absorb liquid of phage suspension are key critical parameters. From point of view of phage bioprocessing, the most complicated food products have non-flat surface possessing large area (fish, meat and sea products), that physically limited delivery of phage particles to all bacterial cell targets. It was experimentally found universal (from point of view of reaching maximal effect of decontamination of food products) concentration of suspension listeria BP – at least 108 PFU/(ml or cm2) [57]. In 2011 year Intralytics presented for examination in US FDA cocktail (EcoShield or ECP-100) of 3 virulent BP (family Myoviridae, originally isolated from fresh and sea water, active in respect of 111 strains of E. coli O157:H7, 76 strains of E. coli other serotypes and 20 strains of other bacterial species) received resolution (Food Contact Notification) to be used in the processing of raw meat and stuffing [15, 58]. Authors showed high effectiveness (quantity of E. coli was eliminated by 95% during 24 hours) of the developed food additive upon decontamination of permitted class of semifabricates [58].
In the same year The
Netherlands Medical Expert Council gave Micreos temporary certificate to use
food additive on the basis of salmonella BP (Salmonelex) for the large-scale
trials on the basis of one of the European largest poultry plants [56]. Later,
in 2012 year Intralytics presented for examination in US FDA with the aim of
posterior permission in respect of food additive of category GRAS
SalmoFresh – cocktail of lytic BP which are
specific active against highly
pathogenic Salmonella strains of such
serotypes as Typhimurium, Enteritidis, Heidelberg, Newport, Hadar, Kentucky and
Thompson (BP which was specially developed for decontamination of the raw meat
and poultry before cut of bulks [59]. In experimental studies upon artificial
infection of chicken skin by S.
enteritidis and S. typhimurium,
chicken legs and sausages of chicken meat, independent investigators
demonstrated effectiveness of BP cocktail which decreased contamination of semifabricates by 2 lg [9, 15, 16].
Processing by BP cocktail ÐÑ1 (containing phage Felix 01) possessing broad spectrum of lytic
activity, in the case of swine skin infected with S. typhimurium, allowed significant decrease of the density of
bacterial sowing, and in case of application of concentrations of phage particles
of 10 and more times higher compared to artificial bacterial density, it was
possible to reach 99% decontamination of skin surface [60].
The third sphere of sanitar-epidemiological BP using that
allows significantly to decrease the risk of appearance of out-break and
sporadic case of food infections is completely reflected in the developed by
the Company Intralytics probiotic biologically active additive ShigActive on
the basis of shigella BP (“phage-based
probiotic dietary supplement”- the
citation according to description of the BP preparation). At present, the third
phase of the project supposing large scale using this biologically active
additive in USA Army is taken place [59, 61]. The idea of prophylactic taking
dyarrheal and other types of BP (against salmonellesis, typhoid fever, etc.) is
not new and was used in army and other
closed collectives åùå
in the period of Soviet Union [7, 32, 62]. However until bacterial BP
preparations were used in the forms of therapeutic agents. The idea of their
administration into food ration (without therapeutist’s permission) belongs to
American scientists (Sulakvelidze and Kutter) [29-31].
Among prospects, it is of interest to use latent viruses of
probiotic bacterial strains and other microbial strains of consortia. Bacterial
genomes contain a lot of prophage sequences as it is known in case of
lactobacilli. In addition, lactobacilli can be classified (taxonomically or
not) in accordance ot their phage sequences [13]. The latter indicates key role
of probiotic bacterial phages in the metabolism of probiotic strains of
microorganisms. Phage lysins which lyse lactic acid bacteria (Lactococcus lactis and Leuconostoc ssp.) include minimal
evolutionary conservative three-domain composition of co-functionong
peptidoglycan-binding (adhesion or lectin-like); Cys, His-independent
bifunctional amidase/peptidase activity, and glycoside hydrolase activity [63].
As lactic acid bacteria (LAB) contain important for microbe survival prophage
sequences, it of especial interest to
identify the varying mosaic distribution of the aforementioned above activities
along phage nucleic acids. As a result, BP can be used as specific
adhesion—lysis cofunction nanorobotic supramolecular ensembles instead of (or
in addition to) antibiotics, other antimicrobials, etc.. For example, BP are
successfully applied combination containing lactic acid (as sprays) or
antifungal metabolites of lactobacilli, and polysaccharide components of LAB
regulate processes of inreactions between bacteria and phages [64, 65]. It is
of significance (one of the mechanism of BP selectivity) that usually lytic BP
act significantly less on low metabolizing probiotic bacterial strain compared
to high metabolizing non-probiotic microorganisms like pathogens.
It seems, like some probiotics, some BÐ are able to act against viral
pathogens (antitumor indirect final action influencing key cell metabolome
cascades, delivery of associated or integrated therapeutic effectors in
biotope, etc.) in complex conditions of biotopes in organisms. In this respect
it can be of importance to conserve or stabilize BP, for example, by adding
selective carbohydrate(s) of polysaccharide(s) [66]. In the latter cases such
BP—carbohydrates system may reveal additional useful properties. For example,
adding trehalose and thiosulfate resulted in increasing cryoprotective
properties of lactobacilli and induction of the host therapeutic proteins [67].
In addition, carbohydrate itself can be involved in antiviral action as in case
of trehalose possessing antitumor action against sarcoma 180 [68]. It is likely
that glycoconjugates (oligo/polysaccharide-containing, glycosaminoglycan
derivatives, glycoproteins, glycolipids, etc.) also influence BP behavior
through interaction to such lectins and lectin-like targets and effectors as
symbiotic (probiotic) bacterial lectins [69-72]. It should be expected
synergism of antimicrobial action of BP and lectins of probiotic bacteria of
human origin.
In conclusion, it should be noted that at present time in the
world there are some more than 10 companies as producers of therapeutic
preparations, veterinary agents and food additives based on BP action (table 4). The growth of
antibiotic-resistant strains of staphylococci, Pseudomonas aeruginosa, Campilobacter ssp., Clostridium ssp., Acinetobacter
ssp. and many others serves continuous stimulus for creating by
aforementioned above companies’ new phage preparations which are active in
respect of pathogenic microorganisms. Investigations of synergistic actions of
BP and other antimicrobials are perspective. The contingent (as one of the
largest groups in the world) of Russian scientists and clinicians successfully
investigate new developments in the field of BP that allows our country to
support frontier positions in this field of medicine.
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Table 1. Experience of clinical
application of BP in Russia and Soviet Union
|
Authors |
Ref |
Etiologic factor |
Nosology |
Number of patients |
Denominations,
prescription, Description of BP
preparations |
Effectivenes of BP
therapy |
Other details |
|
Akimkin et al. |
6, 73 |
Salmonella spp. |
Nosocomminal salmonellosis |
459 patients and 2500 coworkers |
Against Salmonella spp. |
The absence of facts of exclusion of bacteria within 12 months after
sanation |
Dose: 2-4 tablets 3 times a
day for 5-7 days; it is described the phenomenon of “itself-recovery” upon the presence of own phage strains
in organism of patients |
|
Anpilov et al. |
7 |
Shigella flexneri |
Dyarrhea |
3000 peoples |
Dyarrheal polyvalent, in tablets having acid-resistant cover |
Effective prophylactic agent against
out-breaks in closed collectives |
Dose: 2 tablets for 1 time during each 3days within June-October in
different geographic zones of USSR |
|
Babalova et
al. |
74 |
S. flexneri, S.sonne, E. coli |
Dysenteria |
30 769 children in age from 0,5 up to 7 years |
Dysenterial, in tablets |
The number of illness people in 3.8 times less compared to control group |
|
|
Voroshilova et al. |
75 |
Eeromonas aerogenes, E. cloacae, E. agglomerans |
Intestinal infections, Septic diseases of infants, Urologic infections, Surgery infections |
110 children 26 children 50 cases 20 cases |
“Enterobacter” polyvalent purified |
As more (20-40%) effective
than traditional antibiotic therapy |
|
|
Zhukov-Verezhnikov et al. |
76 |
Staphylococci, Streptococci, E. coli, Proteus ssp., Pseudomonas aerugenosa |
Surgery pus infections |
60 cases |
Individually adapted and industrial BP strains against all type
of etiological factors |
BP application was highly effective |
Individual adaptive strains as more effective compared to industrial
ones |
|
Zakharova et al. |
50 |
E. coli, Streptococcus pyogenes, Staphylococcus aureus, Êlebsiella
pneumoniae |
Infection of urogenital tract (IUGT) |
65 pregnant women |
BP: Coli, staphylococcal,
streptococcal |
The use of BP in
case of pregnant women (with IUGT) allowed to prevent beginning and development complications of
pregnancy and childbirth, hard
pus-septic çdiseases both from mother and
infant sides; to decrease mother and children mortality |
Dose: per os on 20,0 ml of preparation for 2-3 times a day before
eating, and in parallel 5-10,0 ml 2
times a day (for 40-60 min.) intra vagina using tampons, Course – 7-10 days |
|
Litvinova et al. |
77 |
E. coli, Proteus spp. |
Sepsis of infants |
500 prematurely born children |
BP against Coli-Proteus |
Application pf BP allowed significantly to decrease mortality |
A day does: 4 ml/kg as 2 times during 3 days within 2 courses and
breaks for 3-4 days |
|
Milyutina |
78 |
Salmonella typhimurium, S. enteritidis, S. flexneri |
Salmonellesis, dyarrhea |
45 children before age of 1, 67 children after age of 1 |
BP against Salmonella, dyarrhea |
Sanation effect of salmonella
BP (81,8-85,4%) or dyarrheal BP ( 90,9%) |
Observed synergism of phage therapy and antibiotic therapy |
|
Nilova |
79 |
S. aureus, E. coli, Klebsiella ssp., Proteus
ssp., P. aeruginosa, Enterococcus
faecalis |
Dysbacteriosis |
80 children before age of 1, 47 children îò 1 äî 3 ëåò |
BP: staphylococcal, Proteus, Coli, Aaeruginosa, Coli-Proteus,
Klebsiella pneumoniae, Klebsiella
polyvalent, pyopoly, sexta, intesti |
Phage therapy as perspective
method of correction of dysbacteriosis of
large intestine |
It was performed preliminary testing sensitivity of relatively
pathogenic microorganisms to preparations from different producers (filials of “SIO Microgen”) |
|
Pogorelskaya |
32 |
Enteric pathogenic E. coli, Poteus vulgaris, Pr. Mirabilis, S. flexneri |
Acute intestinal diseases |
3547 children of creche age |
Coli-Proteus BP, Dyarrheal BP |
Phage prophylaxis during epidemic season decreased morbidity by intestinal infections |
Multitimes and regular
administration of BP (16-20 times a year) |
Table 2. Foreign experience of
clinical use of BP
|
Authors |
Ref |
Nosology |
No of pathients |
Preparation, description |
Effectiveness of phage
therapy |
Other details |
|
Markoishvili et al. |
80 |
Skin ulcer on the background of the vein stagnation |
100 |
PhageBioDerm |
Complete cicatrizing ulcers in 70% cases |
Combination preparation of prolonged action on the base of polymer impregnated with BP and
antibiotics |
|
Slopek et al. |
81 |
Varicosis of vein with ulceration and inflammation Furunculesis and inflammation of connective tissue and lymphatic
vessels Pus infection Pus pericardit Methicillin-resistant staphylococcal infection Pyogenic arthritis and myosit
Pyogenic osteomielit Diseases of abdominal-intestinal tract (food infections and others) Diseases of respiratory system Conjunctivitis, Blefaro-conjunctivitis and middle otitis Diseases of urogenital tract Sepsis of blood |
36 162 370 7 550 adults and 90 children 19 40 48 180 16 42 98 |
Individually selected phage
strains |
Positive effects in 75% cases Rehabilitation - 95% Positive effects in 92,4% cases Effectiveness - 100% Ýôôåêòèâíîñòü - 93% Effectiveness - 95,5% Positive effects in 89,5% and 90% cases, respectively Effectiveness - up to 100% Positive effects in 86,7% cases Effectiveness - 93,8% Positive dynamics in 92,9%
cases Rehabilitation -88,8% |
|
|
Weber-Dabrowska
et al. |
82 |
Septic infection |
94 |
Individually selected phage
strains |
80 patients – complete rehabilitation, 14 – only decreasing
temperature |
|
|
Cislo et al. |
83 |
Chronic pustular infection of skin |
31 |
Individually sekected phage
strains |
25 patients with improvement |
Phages were administrated per os and locally |
|
Abdul-Hassan
et al. |
84 |
Wound burn infection, âûçâàâøàÿ
antibiotic-resistant sepsis (P.
aeruginosa) |
30 |
BP strains against P. aeruginosa
were preliminary isolated from wound |
24 patients with improvement
(granulation, etc.) |
3 times a day for exchange bandages impregnated by BP in the titre 1010PFU/ml |
|
Merabishvili et al. |
33 |
Wound burn infection, induced by S.
aureus, P. aeruginosa |
8 |
BFC-1 |
No side effects |
Aerosol application on wound surface |
|
Lang
et al. |
85 |
Septic complications of orthopedic operations |
7 |
|
Effecteveness in 6 cases |
|
|
Wright et al. |
86 |
Chronic otitis induced by P. aeruginosa |
24 |
Biophage-PA |
Complete reabilitation – 25%, improving – 92% cases |
|
Table 3. Examples of BP-based biocontrol of plants and animals used in production of foods
Host type |
Infection controlled |
Bacterial host for BP used |
Ref |
Cultural fungi |
Bacterial spotty |
Pseudomonas tolaasii |
87 |
Tomato |
Bacterial spotty |
Xanthomonas campestris pv. vesicatoria |
88 |
Apples |
Bacterial burn |
Erwinia amzlovara |
89 |
Stone fruits |
Bacterial spotty of plum |
X. campestris pv. pruni |
90 |
Legume seedlings |
Contamination of seeds |
Salmonella enteritidis |
91 |
Fish |
Disease of the red fin |
Aeromonas hydrophila |
92 |
|
Hemorrhagic ascites |
Pseudomonas piecoglossicida |
93 |
Chicken |
Salmonellesis of caecum |
Salmonella enteritidis |
94 |
|
Letal infection |
Salmonella typhimurium |
95 |
|
Respiratore infection |
Eschirichia coli |
96 |
Beef cattle |
Bacterial secretion |
E. coli O157:H7 |
97 |
Dairy cattle |
Mastitis |
Staphylococcus aureus |
9 |
Pigs |
Salmonellesis of tonsils and caecum |
Salmonella typhimurium |
98 |
Table 4. Some producers and localizations of BP-containing agents
|
Company or Firm |
Country |
Key competence |
Site address |
|
Biochimpharm or Biopharm Pharmaceuticals |
Georgia |
Production on the basis of Institute after G. Eliava (mono- and
polyvalent phages: staphylococcal BP, Streptococcal BP, Coli-phage,
Intesti-phage, Pyo-phage and others) |
|
|
AmpliPhi Biosciences (ðàíåå Biocontrol è Targeted Genetics) |
USA, Great Britain |
Clinical trials of BP against
P. aeruginosa (BioPhage-PA)
(bioprocessing otitis) and BioPhage-RA (cystic fibrosis) |
|
|
Biophage Pharma Inc. |
Canada |
Clinical trials on pigs and birds infected with E. coli and S. typhimurium [99] |
|
|
GangaGen Biotechnologies |
USA, India |
Development of preparations based on phages against MRSA strains of S. aureus and P. aeruginosa |
|
|
SIA Microgen |
Russia |
Serial production on the basis of
3 plants (mono- and polyvalent phages against staphylococci,
streptococci, P. aeruginosa, Proteus
ssp., E. coli; also Intesti-phage,
Pyo-combinated phage, Sexta-phage, others) |
|
|
Intralytix |
USA |
Probiotic biologically active additive on the basis of shigella BP –
ShigActive, polyvalent listeria coctail – ListShield for bioprocessing ready for using
foods, EcoShield – polyvalent ecsherichia coctail for processing raw
meat and
stuffing, SalmoFresh –
cocktail of lytic salmonella BP for bioprocessing raw meat and poultry |
|
|
Micreos |
The Netherlands |
Listex -
polyvalent listeria phage Ð100 for bioprocessing any semifabricates, Salmonelex - salmonella BP for bioprocessing
raw meat and poultry |
|
|
OmniLytics |
USA |
Biopesticide AgriPhage containg cocktail of virulent BP lysing Xanthomonas campestris pv. vesicatoria and Pseudomonas syringae pv. tomato
which are of danger for tomato and
pepper (so-called “black bacterial spotty”) |
|
|
Novolytics |
Great Britain |
Development of BP on the basis of gel against MRSA strains of S. aureus for local application and bioprocessing catheters and
other administrated into organism medical constructions |
|
|
Phage Biotech |
Israel |
Clinical trials of eye and ear droplets on the basis of BP against P. aeruginosa |
|
|
Special Phage Services |
Australia |
Clinical trials of MediPhage – BP against staphylococci (MRSA
strains), and also development of cocktails against polyresistant P. aeruginosa (VRPA strains) and vanñomycin-resistant enterococci (VRE
strains) |
|
|
Viridax |
USA |
Development of BP against S. àureus and other species of Staphylococcus |