Mark H.Adams's Book: Bacteriophages

I think it is useful to reread the MARK H.ADAMS' S book: BACTERIOPHAGES, a milestone in bacteriophage research.


From this book:

"Under certain conditions some bacteriophages can attack and kill susceptible bacteria with no evidence of bacterial lysis or of phage multiplication. In these circumstances the phage particle behaves as an antibiotic rather than as a virus."



"Lwoff (1953) lists the characteristic signs of lysogeny as follows:

1. In a lysogenic culture lysogenesis is a property of every cell
and every spore.

2. Bacteria of a lysogenic culture generally can adsorb the mature phage produced by the culture, but are not damaged by it.

3. Lysis of lysogenic bacteria by enzymes, by other phages, or by mechanical means does not liberate mature phage particles.The intracellular phage in lysogenic bacteria is noninfectious;it is prophage.

4. Infection of a susceptible bacterial culture by a temperate phage may result in the conversion of a considerable proportion of the bacterial cells to the lysogenic condition, potentially capable of liberating the same kind of phage that was used to infect them.

5. Lysogenic bacteria can multiply without liberating mature phage and can undergo many cell divisions in the absence of external phage without losing the lysogenic propensity.

6. Lysis of single lysogenic bacterial cells spontaneously or after a characteristic latent period following induction is accompanied by the release of many mature phage particles. Lysogeny is potentially lethal to the bacterial cell."

Frequency rate between Lytic phages and Lysogenic phages

The questions are:
Are there more Lytic phages or more Lysogenic phages for example in Acinetobacter baumannii or in Mycobacterium ulcerans or in other genera ?Are there Lytic Phages or are there not Lytic Phages for all genera?

What is the frequency rate between Lytic phages (%?) and Lysogenic phages (%?) capable to growth in each of these Bacteria ?


Lytic phages> Lysogenic phages ?
or
Lysogenic phages >Lytic phages ?
or
no Lytic phages but only Lysogenic phages ?


From the book " BACTERIOPHAGES" the probable answer: "Lysogenic bacteria are very common in nature and probably constitute the principal reservoir of bacteriophages."

The success of Phage therapy depends how we are able to give these answers.

Bacteriophage Plaque Morphology

A plaque is a (small) clearing in a lawn of bacteria grown on a plate. This plaque usually indicates the presence of a virus that infects the bacteria and uses it to reproduce (such viruses are called phages or bacteriophages). Although some may look similar, each phage forms a unique plaque. The way a plaque look is called its morphology.

Plaque morphologies tell us a lot about the type of phages that made them. For example if the plaques the phage makes are very clear (one could see clearly through them) the phage is highly lytic, whereas if the plaques are hazy or turbid (one could not see clearly when looking through them) the phage is probably lysogenic. In some cases plaques have clear centers and hazy rings, or halos.
No one is absolutely certain what causes these halos but one hypothesis is that the halos are rings of bacteria that are resistant to the phage. Larger plaques often mean more phage and smaller plaques, less phage.
Looking at plaque morphologies is a preliminary way (before electron microscopy) to tell if one has more than one phage on a plate. It is still unknown weather a phage’s plaque morphology is at all related to the phage’s morphology.

Differentiation of Bacteriophages on the basis of their Life Cycle

The differentiation between phages on the basis of their type of genetic material is a rather technical one. Another important differentiation can be made on the basis of the Phage Life Cycle.

Two main groups are distinguished there:

• Lysogenic or Temperate Phages• Lytic Phages

Lysogenic phages

The most important feature of lysogenic phages is the integration of their genome in the bacterial genome after infection.
This results in the so-called pro-phage stage.
Genes that control the lytic pathway are repressed by protein repressors which bind to specific DNA-regions. This prevents
transcription of genes whose products are involved in the lytic pathway. During this stage the bacteria grow and divide normally and the phage inside the bacteria can remain unnoticed.

Upon activation of the pro-phage, in many cases for as yet unknown reasons, the bacteriophages genetic material is transcribed and replicated inside the bacterium. This ultimately results in
the formation of new bacteriophage particles which, once released form the bacterium, are capable of infecting new bacteria and integration of their genetic material into the bacterial genome, thus closing the circle.
Prophages are released by excision. Sometimes excision is not precise and bacterial genes adjacent to the prophage are packaged into a phage particle. These bacterial genes then can be transferred into other percipient bacteria and during, the formation of the prophage stage, integrated into the chromosome.

This process is called Transduction and has not
only led to the exchange of bacterial DNA between bacteria but also to the transfer of bacterial DNA to the genome of certain phages.
A nice example of this is the presence of so-called ‘pathogenicity islands’ in the genome of CTX Phi phage of the Vibrio cholerae (cholera bacterium) which contains a bacterial toxin encoding gene.

Although highly interesting, lysogenic phages are (as yet) unpredictable in their properties and behaviour. Transition from the pro-phage stage to the lytic phage is uncontrollable and the exchange of genetic material unpredictable.
Lysogenic phages have been observed to transfer potentially harmful genes into their target bacteria (including genes encoding Shiga toxins of Shigatoxinogenic E. coli , the cholera toxin of toxinogenic Vibrio cholerae, and various antibiotic resistance genes.

Although many of the lysogenic phages are relatively well studied (e.g. Phage λ) and sometimes detailed knowledge is available about their genome and its regulation, because of their unpredictable behaviour, they are generally considered to be unsuitable of use in bacteriophage therapy.

Lytic phages

Lytic phages infect their host, replicate and then kill their host by cell lysis, thereby releasing progeny viruses into the environment.

Infection of the bacterial host is often based on specific recognition of particular components (receptors) on the pili or cell wall of the bacterium which is likely to determine the specific recognition. After initial infection it can be a matter of hours before cell lysis occurs.

Lytic phages are theoretically ideally suited as an alternative antibiotic in phage therapy:

• Most bacteriophages are very specific for their host bacterium.

• Upon successful infection they replicate exponentially.

• They kill their hosts quickly (often in hours).

• Upon bacterial lysis a large number of progeny phages are released into the environment.Each of those phages is capable of infecting other target bacteria. As an ‘antibiotic’ bacteriophages are ‘self multiplying’.

• Bacteriophages depend on their hosts and will disappear with the destruction of their target bacterium leaving no residues; ‘antibiotic’bacteriophages are ‘self eliminating’.

Bacteriophage Lytic Activity

Most phages elaborate at least two proteins, one of which is a murein hydrolase, or lysin, and the other is a membrane protein, which is given the designation holin.
The function of the holin is to create a lesion in the cytoplasmic membrane through which the murein hydrolase passes to gain access to the murein layer.


Lysis of bacterial cell wall is based on the action of two phage encoded enzymes: holins and lysins.

Lysins are phage-encoded murein hydrolases that act on the bacterial host cell wall at the terminal stage of the phage reproduction cycle to release progeny phage.

These enzymes are also known as phage lysozymes, endolysins, or muralytic/mureolytic enzymes. Their action is tightly regulated by holins, by membrane arrest, and by conversion from their inactive state. Their N-terminal catalytic domains are able to target almost every possible bond in the peptidoglycan network, and their corresponding C-terminal cell wall binding domains target the enzymes to their substrate.
Owing to their specificity and high activity, endolysins have been employed for various in vitro and in vivo aims, in food science, in microbial diagnostics, and for treatment of experimental infections.

Clearly, phage lysins represent great tools for use in molecular biology, biotechnology and in medicine, and we are just beginning to tap this potential.There are at least two distinct mechanisms by which phages destroy the cell wall.

Bacteriophages with large genomes use a holin-endolysin system, while bacteriophages with small genomes encode a single lysis protein. Some single protein lysis systems inhibit cell wall synthesis and are thus the phage analogs of antibiotics like penicillin. Sometimes also phage capsid proteins are responsible for lysis.

In gram-positive bacteria, (endo)lysins can also act as exolysins because the pepticoglycan layer of the bacterial cell wall is, in most cases, accessible from the outside. This is not the case for gram-negative bacteria, in which the presence of the outer membrane effectively prevents access by hydrophilic lytic enzymes.
However, when the lipopolysaccharide layer is disrupted (by EDTA,detergents, etc.) cells become sensitive to external murein hydrolases.

Lysin domains can be cloned into non-host bacteria and purified after expression and used for different applications.

Lysins have now been used successfully in animal models to control pathogenic antibiotic resistant bacteria found on mucosal surfaces and in blood. The advantage over antibiotics are their specificity for the pathogen without disturbing the normal flora, the low chance of bacterial resistance to lysins and their ability to kill colonizing pathogens on mucosal surfaces, capabilities that were previously unavailable. Thus, lysins could be an effective anti-infective in an age of mounting antibiotic resistance.
A potential concern in the use of lysins is the development of neutralizing antibodies. Unlike antibiotics, which are small molecules that are generally not immunogenic, enzymes are proteins that stimulate an immune response when delivered both mucosally or systemically. It was found that highly immune serum slows, but does not block, the killing of bacteria by lysins.

Similar to other proteins that are delivered intravenously to animals and humans, phage enzymes have a short half life (ca. 15 min.). However, the action of lysins for bacteria is so rapid, that this might be sufficient time to observe a therapeutic effect.

Because of the specific action of lysins, they offer a unique possibility for the biological control of unwanted bacteria without having any effect on other organisms. The most obvious approach to the use of lysins for the biocontrol of pathogens in food and feed is to directly add purified enzyme to the food or to the raw product. A more elegant and also less expensive alternative is the production and secretion of specific endolysins by fermenting. In this case the cell wall of the host bacterium must be insensitive to the produced lysin. By contrast, some applications aim to cause self-destruction, which is mediated by cells carrying endolysin genes that are able to degrade their own murein.

As bacteria get resistant to phages quite rapidly, they could also become resistant against lysins. However, repeated exposure of several bacteria grown on agar plates to low concentrations of lysins did not lead to the recovery of resistant strains. The cell wall receptor of lysins of S. pneumoniae is choline, a molecule that is essential for pneumococcal viability.
Although not yet proven, it is possible that during interaction of phage and bacteria over the millennia, to avoid becoming trapped inside the host, the binding domain of the lytic enzymes has evolved to target a unique and essential molecule in the cell wall, making resistance to these enzymes a rare event.

Stage of Drug Development

PHASE

Food and Drug Administration (FDA) categories (http://www.fda.gov/drugs/resourcesforyou/consumers/ucm143534.htm) for describing the clinical trial of a drug based on the study’s characteristics, such as the objective and number of participants. There are five phases:

Phase 0: Exploratory study involving very limited human exposure to the drug, with no therapeutic or diagnostic goals (for example, screening studies, microdose studies).

Phase 1: Studies that are usually conducted with healthy volunteers and that emphasize safety. The goal is to find out what the drug’s most frequent and serious adverse events are and, often, how the drug is metabolized and excreted.

Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition). For example, participants receiving the drug may be compared with similar participants receiving a different treatment, usually an inactive substance (called a placebo) or a different drug. Safety continues to be evaluated, and short-term adverse events are studied.

Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs.

Phase 4: Studies occurring after FDA has approved a drug for marketing. These including postmarket requirement and commitment studies that are required of or agreed to by the sponsor. These studies gather additional information about a drug’s safety, efficacy, or optimal use.

(See also Study Phase data element on our clinical trials partner site*.)

Got to Clinical trial for Phage therapy

A Prospective, Randomized, Double-Blind Controlled Study of WPP-201 for the Safety and Efficacy of Treatment of Venous Leg Ulcers. Phase I

Old post

Sunday, 12 July 2009

An interesting piece of news:

From:
Journal of Wound Care, Vol. 18, Iss. 6 , 01 Jun 2009, pp 237 - 243

D.D. Rhoads, R.D. Wolcott, M.A. Kuskowski, B.M. Wolcott, L.S. Ward, A. Sulakvelidze

Objective: This phase 1 trial set out to examine the safety of a bacteriophage based preparation for difficult to treat wounds.

Method: The intention to treat sample comprised 42 patients with chronic venous leg ulcers (VLUs); 39 patients completed the trial. The ulcers were treated for 12 weeks with either a saline control or bacteriophages targeted against Pseudomonas aeruginosa, Staphylococcus aureus and Escherichia coli. Follow-up continued until
week 24.Results: No adverse events were attributed to the study product. No significant difference (p>0.05) was determined between the test and control groups for frequency of adverse events, rate of healing, or frequency of healing.

Conclusion: This study found no safety concerns with the bacteriophage treatment. Efficacy of the preparation will need to be evaluated in a phase II efficacy study.

Declaration of interest: One of the authors (AS) holds an equity interest in Intralytix. The other authors do not have any interest in commercial activities.


From Clinical Trials.gov.:

"A Prospective, Randomized, Double-Blind Controlled Study of WPP-201 for the Safety and Efficacy of Treatment of Venous Leg Ulcers"

Sponsored by: Southwest Regional Wound Care Center
ClinicalTrials.gov- Identifier: NCT00663091

Phase I : completed (April 14, 2009 )

Drug: Bacteriophage
WPP-201 is a pH neutral, polyvalent phage preparation, which contains 8 bacteriophages ("component bacteriophages" or "component phages") lytic for P. aeruginosa, S. aureus, and (Table 1). The E. coli cocktail contains a concentration of approximately 1 x 10^9 PFU/ml of each of the component monophages. The phage component of WPP-201 is roughly estimated to be 0.5 ppm by weight and the remainder is phosphate-buffered saline containing < 1,000 ppm total organic carbon from the growth medium and biomass. All phages contained in the preparation have been originally isolated from the environment, and they have not been genetically manipulated in any way (i.e., the preparation is 100% natural). WPP-201 contains no preservatives and antioxidants.

Exclusion of Temperate Bacteriophages from the Host Strains

From:

"Bacteria, Phages and Septicemia

Aušra Gaidelyté 1, Martti Vaara 2, Dennis H.Bamford 1
1 Department of Biological and Environmental Sciences, Institute of Biotechnology, University of Helsinki, Helsinki, Finland, 2 Department of Clinical Microbiology, Helsinki University Hospital, Helsinki, Finland

We observed that the majority of the bacterial isolates from septicemia patients spontaneously secreted phages active against other isolates of the same bacterial strain, but not to the strain causing the disease.
Such phages were also detected in the initial blood cultures, indicating that phages are circulating in the blood at the onset of sepsis. The fact that most of the septicemic bacterial isolates carry functional prophages suggests an active role of phages in bacterial infections. Apparently, prophages present in sepsis causing bacterial clones play a role in clonal selection during bacterial invasion.”
1-For UV induction, bacteria were grown to 200 Klett units and collected by centrifugation for 10 min at 6,000 rpm using a Sorvall SS-34 rotor at 4°C. Bacteria were suspended in the same volume of M9 broth and transferred to a glass Petri dish.
The bacterial suspension was irradiated for 42 sec at A254 followed by dark storage on ice for 1 h. Cells were collected by centrifugation for
5 min at 13,000 rpm using a Heraeus Biofuge at 22°C. Bacteria were suspended in 3 volumes of LB and the number of plaques was determined after additional two h incubation at 37°C.

2a-For MitC (mitomycin C) induction experiments, cells were grown to 200 Klett units and induced with MitC at a final concentration of 5 mg/ml. Cells were incubated for 15 min at 37°C and the growth medium was then replaced with fresh LB. Plaques were determined after additional two h incubation at 37°C.

or

2b-To confirm the absence of temperate bacteriophages,originating from the bacterial hosts a standard technique for bacteriophage induction using the DNA-damaging antimicrobial agent mitomycin C was carried out, as described by Miller.
Bacterial cultures were aliquoted in 1 ml volumes in sterile eppendorf tubes, covered with aluminium foil thus protecting the bacteria from photoreactivation of drug-induced DNA damage. Mitomycin C (Sigma-Aldrich) was added to final concentrations of 1 or 5 mg/ml . A control tube without mitomycin C was added to evaluate the presence of ‘nondrug induced’ bacteriophages. The tubes were incubated for 3 h at 37°C. Subsequently, twenty ml of chloroform was added to the control tubes to lyse the bacteria. The lysates were centrifuged in order to separate the intact bacterial cells from the supernatant. The final titre of bacteriophages in the supernatant was determined using the double agar overlay method.

3-To test if antibiotics could induce phage production, the same procedure was used as in the previous paragraph with the following
modifications. Three different antibiotic concentrations were tested depending on the antibiotic used and bacterial strain employed.
For E. coli strains, 1, 10, and 30 mg/ml final concentrations of tobramycin (tomycin, Orion Pharma) and 0.03, 0.3, and 3 mg/ml of ciprofloxacin (Bayer) were used. For S. aureus strains, 1, 10, 20 mg/ml final concentrations of tobramycin and 1, 10, 30 mg/ml of ciprofloxacin were used.

Viable counts of cell suspensions were determined to evaluate the antibacterial activity of UV, MitC or antibiotic treatment.

Methods for Phage induction

Bacterial Virulence properties altered by Phages

From:Bacteriophage Control of Bacterial VirulencePatrick L. Wagner and Matthew K. Waldor

                             
 

“Lysis from within”, “Lysis from without”and Lysogenic bacteriophages

Bacteriophages that can only follow the lytic cycle are known as virulent bacteriophages. Lysis of the host bacterial cell can occur as a result of two possible mechanisms indicated below:

"Lysis from within”

In this case, lysis of the host cell occurs as a result of phage replication. The genetic material is the only component of the virion that enters into the host cell, which may occur through injection (bacteriophages with contractile tails) or following the enzymatic breakage of the cell wall. In both cases, the pore generated in the membrane will affect its electric potential, although this harm is easily repaired. Once inside the cell, the genetic material of the bacteriophage is replicated hundreds of times, the coat proteins are synthesized and new particles are assembled that will constitute the viral progeny (usually between several tens and a few hundreds per infected cell). Release of the progeny is the consequence of the collaborative action of the holin, a hydrophobic polypeptide that forms pores in the cell membrane, through which the lysin (a muramidase) reaches the cell wall, thus provoking the lysis of the host-cell.

"Lysis from without"

In this case, lysis of the host cell occurs in the absence of phage replication. This happens when a sufficiently high number of phages particles adhere to the cell, and lyse it through alteration of the membrane electric potential, and/or the activity of cell wall degrading enzymes.

Lysogenic bacteriophages

Some dsDNA bacteriophages, however, have the capacity to synthesize a repressor protein that silences most bacteriophage genes and results in abortion of the lytic cycle. Under these circumstances the bacteriophage DNA (the prophage) synchronizes its replication to that of the host to be inherited by its offspring.

In most cases this is brought about through integration of the bacteriophage DNA into the host genome via site-specific recombination. This alternative method of bacteriophage propagation is called the lysogenic cycle and the bacteriophages able to pursue it are known as temperate.

Is better a genetic modification of Phages or the alteration of the environmental conditions?

I have doubts about advantages regarding a modification by molecular biology or by chemical reactions of Phages for Phage Therapy. In these cases Phage Therapy would be impracticable in a hospital because it would become an artistic work. But at times these modifications may be one solution.

I prefer a genetic modification of Phages promoted by a drastic alteration of one environmental condition all through the replication cycle of Phages inside to their hosts.

Biofilms and Infectious Diseases

The Biofilm Lifecycle (video)


Looking for Chinks in the Armor of Bacterial Biofilms
by Don Monroe


Biofilm from Wikipedia


Interview with Dr. Randall Wolcott, bacterial biofilm wound specialist

Diversity of biofilms produced by quorum-sensing deficient clinical isolates of Pseudomonas aeruginosa
J. Andy Schaber, Adrienne Hammond, Nancy L. Carty,Simon C. Williams, Jane A. Colmer-Hamood, Ben H. Burrowes,Vijian Dhevan, John A. Griswold and Abdul N. Hamood.

A Synergistic DispersinBTM    and Bacteriophage Combo for Wound Healing
( On Sunday, 21 June 2009 was present)

Controlling clinically relevant biofilms using bacteriophages
(write biofilm and bacteriophages)

Quorum Sensing

Quorum sensing is best characterized as a means of communication within a bacterial species, whereas competitive or cooperative signaling can occur between groups of bacteria or between bacteria and the host ( Gram-Negative bacteria,Gram-Positive bacteria and Biofilm).

Quorum sensing can be divided into at least 4 steps:
(1) production of small biochemical signal molecules by the bacterial cell; (2) release of the signal molecules, either actively or passively,into the surrounding environment; and (3) recognition of the signal molecules by specific receptors once they exceed a threshold concentration, leading to (4) changes in gene regulation.

One common consequence of quorum sensing induction of gene expression is increased synthesis of the proteins involved in signal molecule production. Increased synthesis of the signal molecule creates a positive feedback loop, which is why quorum signals are commonly called autoinducers.
 
From:
Bench-to-bedside review: Quorum sensing and the role of
cell to cell communication during invasive bacterial infection

The Herxheimer Reaction

From the Net

The Herxheimer reaction (also known as Jarisch-Herxheimer or Herx) occurs when large quantities of toxins are released into the body as bacteria (typically Spirochetal bacteria) die, due to antibiotic treatment or rapid detoxification.

Typically the death of these bacteria and the associated release of endotoxins occurs faster than the body can remove the toxins via the natural detoxification process performed by the kidneys and liver. It is manifested by fever, chills, headache, myalgia (muscle pain), and exacerbation of skin lesions. Duration in syphilis is normally only a few hours but can be much longer, up to months or years, for other diseases. The intensity of the reaction reflects the intensity of inflammation present.

The Herxheimer reaction has shown an increase in inflammatory cytokines during the period of exacerbation, including tumor necrosis factor alpha, interleukin-6 and interleukin-8.


                                                 History
 Both Adolf Jarisch, an Austrian dermatologist, and Karl Herxheimer, a German dermatologist, are credited with the discovery of the Herxheimer reaction. Both Jarish and Herxheimer observed reactions in patients with syphilis treated with mercury. The reaction was first seen following treatment in early and later stages of syphilis treated with Salvarsan, mercury, or antibiotics. It is seen in 50% of patients with primary syphilis and about 90% of patients with secondary syphilis.

The reaction is also seen in other diseases, such as borreliosis (Lyme disease and tick-borne relapsing fever), bartonellosis, brucellosis, typhoid fever, and trichinellosis and Q fever.

Clinical Trials for phage therapy

LINK to Clinical Trials for phage therapy

 Hide Studies Not Seeking New Volunteers


RECRUITING

1Experimental Phage Therapy of Bacterial Infections

Condition(s): Bacterial Infections Last Updated: September 5, 2013Recruiting

  TERMINATED

3Antibacterial Treatment Against Diarrhea in Oral Rehydration Solution

Condition(s): Diarrhea Last Updated: November 12, 2013Terminated

NOT YET RECRUITING

2Evaluation of Phage Therapy for the Treatment of Escherichia Coli and Pseudomonas Aeruginosa Wound Infections in Burned Patients

Condition(s): Wound Infection Last Updated: April 14, 2014Not yet recruiting

 COMPLETED

4Bacteriophage Effects on Pseudomonas Aeruginosa

Condition(s): Cystic Fibrosis Last Updated: September 4, 2013Completed

5A Prospective, Randomized, Double-Blind Controlled Study of WPP-201 for the Safety and Efficacy of Treatment of Venous Leg Ulcers

Condition(s): Venous Leg Ulcers Last Updated: September 6, 2011Completed
Go to Post

10The Use of Bacteriophage Phi X174 to Assess the Immune Competence of HIV-Infected Patients In Vivo

Condition(s): HIV Infections Last Updated: March 3, 2008Completed

The therapeutic Phage Bank

From P.H.A.G.E

My idea of "Phages and Bacteria Bank"

For Mycobacterium ulcerans

 

P.H.A.G.E and Project PHAGOBURN

P.H.A.G.E    Presse Release

skin infections caused by Escherichia coli and Pseudomonas aeruginosa bacteria in burn patients

 

LINK 1

LINK 2

BioVet-PA and BioPhage-PA from Biocontrol Limited

Old post

Sunday, 11 July 2010

BioVet-PA and BioPhage-PA are the same mixture of six bacteriophages specific for Pseudomonas aeruginosa containing 1x10^5 pfu by original titration of each of the 6 therapeutic bacteriophages.

The six bacteriophage strains (which were deposited at the National Collection of Industrial and Marine Bacteria, 23 St Machar Drive, Aberdeen, AB24 3RY, Scotland, UK on 24 June 2003) :

 Reference NCIMB Deposit

1- BC-BP-01 NCIMB 41174
2- BC-BP-02 NCIMB 41175
3-BC-BP-03 NCIMB 41176
4- BC-BP-04 NCIMB 41177
5- BC-BP-05 NCIMB 41178 
6- BC-BP-06 NCIMB 41179

Veterinary Field Trial

A combined preparation of six bacteriophages was named BioVet-PA, and was authorized for trial in dogs with such infection by the Veterinary Medicines Directorate of the United Kingdom in November 2003.

Conduct of the Trial

BioVet-PA was stored at -80° C. Immediately prior to administration, the product was thawed and warmed in the hand 0.2 ml (containing 1x10^5 pfu by original titration of each of the 6 bacteriophages) was administered drop-wise using a sterile 1 ml capacity syringe into the ear. Ear condition and microbiology was assessed at 2 days post-administration.


Human Clinical Trial

This study investigated the efficacy and safety of BioPhage-PA, a mixture of six Pseudomonas aeruginosa bacteriophages of the same types as those tested as BioVet-PA in the veterinary field trial.

BIOPHAGE-PA