Phage Therapy - Reviews

1.

2010 -

Phage Therapy in Clinical Practice: Treatment of Human Infections - Kutter et al.

**“The Republic of Georgia is the one place in the world where phage therapy is a component of standard

medical practice, routinely used in a number of hospitals and clinics for both prophylactic and treatment purposes. Much of the phage availability both presently and historically has been associated with the Eliava Institute.”**

Abstract: Phage therapy is the application of bacteria-specific viruses with the goal of reducing or eliminating pathogenic or nuisance bacteria. While phage therapy has become a broadly relevant technology, including veterinary, agricultural, and food microbiology applications, it is for the treatment or prevention of human infections that phage therapy first caught the world’s imagination see, especially, Arrowsmith by Sinclair Lewis (1925) and which today is the primary motivator of the field. Nonetheless, though the first human phage therapy took place in the 1920s, by the 1940s the field, was in steep decline despite early promise. The causes were at least three-fold: insufficient understanding among researchers of basic phage biology; over exuberance, which led, along with ignorance, to carelessness; and the advent of antibiotics, an easier to handle as well as highly powerful category of antibacterials. The decline in phage therapy was neither uniform nor complete, especially in the former Soviet Republic of Georgia, where phage therapy traditions and practice continue to this day. In this review we strive toward three goals: 1. To provide an overview of the potential of phage therapy as a means of treating or preventing human diseases; 2. To explore the phage therapy state of the art as currently practiced by physicians in various pockets of phage therapy activity around the world, including in terms of potential commercialization; and 3. To avert a recapitulation of phage therapy’s early decline by outlining good practices in phage therapy practice, experimentation, and, ultimately, commercialization.

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2. 2011 review -

Pros and cons of phage therapy

Catherine Loc-Carrilloand Stephen T. Abedon

Potential Disadvantages

Concerns about using phages as antibacterial agents can be distinguished into four categories: (1) phage selection, (2) phage host-range limitations, (3) the uniqueness of phages as pharmaceuticals, and (4) unfamiliarity with phages. See references 4 and 5 for additional discussion.

Not all phages make for good therapeutics.

Good therapeutic phages should have a high potential to reach and then kill bacteria in combination with a low potential to otherwise negatively modify the environments to which they are applied. These characteristics can be reasonably assured so long as phages are obligately lytic, stable under typical storage conditions and temperatures, subject to appropriate efficacy and safety studies, and, ideally, fully sequenced to confirm the absence of undesirable genes such as toxins.10,18 Note that a phage that is obligately lytic we define as not temperate and released from infected cells via lysis, that is, unable to display lysogeny and not released chronically. The use of temperate phages as therapeutics is problematic due to a combination of display of superinfection immunity,13 which converts phage-sensitive bacteria into insensitive ones, and the encoding of bacterial virulence factors, including bacterial toxins.810,18,27,29

In addition to avoiding temperate or toxin-carrying phages, the aim of phage characterization is to exclude as therapeutics those phages that display poor killing potential against target bacteria. Such low virulence can be due to poor adsorption properties, low potential to evade bacterial defenses, or poor replication characteristics.3 Also less desirable for therapeutics are those phages that display poor pharmacokinetics, that is, poor absorption, distribution, and survival in situ.3 Ideally phages should also display a low potential to transfer bacterial genes between bacteria (transduction).10,18

Phage characterization additionally can include virion morphology (via electron microscopy), protein profiles, or genotype characterization other than via full-genome sequencing (e.g., PFGE profiles of restriction digested genomes), etc.,18 though the costs associated with exhaustive phage characterization prior to phage use can be prohibitive. The general aim, therefore, should be to identify those phages that display good primary pharmacodynamics (that is, antibacterial virulence), minimal secondary pharmacodynamics (low potential to do harm to patients), and good pharmacokinetics (an ability to reach target bacteria in situ).3 Phages that do not adequately meet these criteria should in most circumstances not be employed as therapeutics. Minimally this should entail avoiding temperate phages and, ideally, full genome sequencing should be used to rule out virulence-factor carriage.

The problem of narrow host range.

No antimicrobials displaying selective toxicity will affect all possible microbial targets. Typically the narrowness of phage host rangesa few strains, a few species, or much rarer, a few genera of bacteria13will at a minimum place limitations on presumptive treatment, i.e., treatment courses that begin prior to the identification of the pathogen’s susceptibility to antibacterials such as to specific phages. However, as phages can often be employed in combination with other antibacterial agents, including other phages (so-called phage cocktails), the lytic spectrum of phage products can be much broader than the spectrum of activity of individual phage types.4,9,20 Even broadly acting phage cocktails are normally more selective in their spectrum of activity than typical narrow-spectrum antibiotics, a property that can be viewed as an additional advantage of phage therapy.

Phages are not unique pharmaceuticals

Phages as pharmaceuticals are protein-based, live-biological agents that can potentially interact with the body’s immune system, can actively replicate, and can even evolve during manufacture or use, but are far from unique in these regards. For example, many protein-based pharmaceuticals can stimulate immune systems, antibiotics that lyse bacteria will release bacterial toxins in situ, and live-attenuated vaccines both actively replicate and evolve including within the context of infecting body tissues. Protein-based drugs, chemical antibiotics, and whole vaccines have previously been approved for use despite these various properties. It therefore stands to reason that phage- based pharmaceuticals should not be disqualified for possessing similar attributes.

but nonetheless are unusual.

The Western medical establishment’s unfamiliarity with phages, as antibacterial agents, may be phage therapy’s greatest challenge. However, as noted, the various phage oddities as drugs at least are not unique to them. Indeed, a few phage products have now passed regulatory standards, having been classified by the FDA as GRAS (Generally Regarded As Safe), registered by the EPA, or approved for use by the USDA.9,26 Nevertheless, phages as viruses could be misinterpreted by the general public as being in some manner equivalent to viral pathogens that cause human disease. So far, however, public resistance has not materialized, and it is perhaps fortunate that bacterial viruses are known, instead, as phages.

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3. 2012 review in Iranian journal -

Bacteriophage: Time to Re-Evaluate the Potential of Phage Therapy as a Promising Agent to Control Multidrug-Resistant Bacteria

Masoud Sabouri Ghannad, Avid Mohammadi

Nowadays the most difficult problem in treatment of bacterial infections is the appearance of resistant bacteria to the antimicrobial agents so that the attention is being drawn to other potential targets. In view of the positive findings of phage therapy, many advantages have been mentioned which utilizes phage therapy over chemotherapy and it seems to be a promising agent to replace the antibiotics. This review focuses on an understanding of phages for the treatment of bacterial infectious diseases as a new alternative treatment of infections caused by multiple antibiotic resistant bacteria. Therefore, utilizing bacteriophage may be accounted as an alternative therapy. It is appropriate time to re-evaluate the potential of phage therapy as an effective bactericidal and a promising agent to control multidrug-resistant bacteria.

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4.

Learning from Bacteriophages - Advantages and Limitations of Phage and Phage- Encoded Protein Applications

The emergence of bacteria resistance to most of the currently available antibiotics has become a critical therapeutic problem. The bacteria causing both hospital and community-acquired infections are most often multidrug resistant. In view of the alarming level of antibiotic resistance between bacterial species and difficulties with treatment, alternative or supportive antibacterial cure has to be developed. The presented review focuses on the major characteristics of bacteriophages and phage-encoded proteins affecting their usefulness as antimicrobial agents. We discuss several issues such as mode of action, pharmacodynamics, pharmacokinetics, resistance and manufacturing aspects of bacteriophages and phage-encoded proteins application.

1.?INTRODUCTION

The idea of using bacteriophages to treat infections has been well known since bacterial viruses were discovered by Frederick Twort [1] and Felix dHrelle [2] at the beginning of the 20th century. A few years later, Alexander Fleming revealed an antibacterial activity of Penicillium notatum mould and the antibiotics era was began. A large-scale introduction and success of antibiotics resulted in decreased interest in phage research/applications as a potential antimicrobial tool for controlling bacterial infections. At that time, the broad application of antibiotics resulted in an extensive bacterial resistance to these drugs, which shows that alternative methods are needed for eradication of pathogens. A renaissance of research on the biology of lytic bacteriophages appears to be a promising approach as a treatment for bacterial infections, especially those caused by multidrug resistant. A phage cocktail has been commonly applied as alternative or as supportive treatment simultaneously with antibiotics, particularly in Eastern Europe. For many years experiments were conducted only on a small scale in several centers, including Wroclaw and Georgia [3-11]. The most detailed historical publications documenting phage therapy come from Polish work done in Hirszfeld Institute by Stefan Slopek’s group [12-14]. Positive results were indicated by the eradication of Escherichia, Pseudomonas, Proteus, Klebsiella and Staphylococcus clinical strains of various infections among both humans and animal models [12, 13, 15-17]. Nowadays, phages have been proposed as natural antimicrobial agents to fight bacterial infections in humans, inanimals or in crops of agricultural importance. Moreover, phage encoded proteins such as endolysins, exopolysaccharidases, and holins proved their ability as a promising alternative antibacterial products [18-21]. In this review, we concentrate on both advantages and limitations of antibiotics, bacteriophages and phage proteins as useful tools for bacteria eradication.

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5.

2001 review -

Bacteriophage Therapy - ALEXANDER SULAKVELIDZE, ZEMPHIRA ALAVIDZE AND J. GLENN MORRIS, JR

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6.

2012 review -

Phage therapyconstraints and possibilities

The rise of antibiotic-resistant bacterial strains, causing intractable infections, has resulted in an increased interest in phage therapy. Phage therapy preceded antibiotic treatment against bacterial infections and involves the use of bacteriophages, bacterial viruses, to fight bacteria. Virulent phages are abundant and have proven to be very effective in vitro, where they in most cases lyse any bacteria within the hour. Clinical trials on animals and humans show promising results but also that the treatments are not completely effective. This is partly due to the studies being carried out with few phages, and with limited experimental groups, but also the fact that phage therapy has limitations in vivo. Phages are large compared with small antibiotic molecules, and each phage can only infect one or a few bacterial strains. A very large number of different phages are needed to treat infections as these are caused by genetically different strains of bacteria. Phages are effective only if enough of them can reach the bacteria and increase in number in situ. Taken together, this entails high demands on resources for the construction of phage libraries and the testing of individual phages. The effectiveness and host range must be characterized, and immunological risks must be assessed for every single phage.

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