Abstract:  Many publications list advantages and disadvantages associated with phage therapy, which is the use of bacterial viruses to combat populations of nuisance or pathogenic bacteria. The goal of this commentary is to discuss many of those issues in a single location. In terms of "Pros," for example, phages can be bactericidal, can increase in number over the course of treatment, tend to only minimally disrupt normal flora, are equally effective against antibiotic-sensitive and antibiotic-resistant bacteria, often are easily discovered, seem to be capable of disrupting bacterial biofilms, and can have low inherent toxicities. In addition to these assets, we consider aspects of phage therapy that can contribute to its safety, economics, or convenience, but in ways that are perhaps less essential to the phage potential to combat bacteria. For example, autonomous phage transfer between animals during veterinary application could provide convenience or economic advantages by decreasing the need for repeated phage application, but is not necessarily crucial to therapeutic success. We also consider possible disadvantages to phage use as antibacterial agents. These "Cons," however, tend to be relatively minor.

, in addition to being suitable for most routes of administration , milk) as well as of downstream environments such as from sewage effluent , PFGE profiles of restriction digested genomes), etc , significant phage amplification via auto dosing that results in greater bacterial kiling , treatment courses that begin prior to the identification of the pathogens susceptibility to antibacterials such as to specific phages ,18 though the costs associated with exhaustive phage characterization prior to phage use can be prohibitive …but nonetheless are unusual 10 Phages similarly can release bacterial components while killing bacteria in situ, a property associated with lysis that also can result from the application of cell-wall disrupting antibiotics 10 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 10 Relatively low cost 10,14 By contrast, many chemical antibiotics, which tend to have broader spectrums of activity, are prone to inducing superinfections, such as antibioticassociated Clostridium difficile colitis or Candida albicans yeast infections 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 10,18 Phage characterization additionally can include virion morphology (via electron microscopy), protein profiles, or genotype characterization other than via full-genome sequencing (e 11,22,23 Capacity for low-dosage use 112 Bacteriophage Volume 1 Issue 2 Possible transfer of phages between subjects 14,16 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 15 Narrower potential for inducing resistance 18 Unlike antibiotics, which can be toxic,19 phages that display little or no toxicity can be isolated against most target bacteria 2 In reviews of phage therapy3 authors commonly list advantages of employing phages as antibacterials (for example, Pros and cons of phage therapy Catherine Loc-Carrillo1,2 and Stephen T 21 Additional Advantages of Phage Therapy The following advantages associated with the use of phages as antibacterials have possible safety-, economic-, or convenience- enhancing virtues but are not essential to phage antibacterial use 24 Since phages do not contribute Rapid discovery 27 While the cost of host growth varies depending upon bacterial species, the cost of phage purification appears to be coming down as technology improves 28 Generally these costs of phage production, per unit,9 are not out of line with the costs of pharmaceutical production while the costs of discovery (isolation) and characterization can be relatively low 3 Achieving efficacy following only a single dose, or far less frequent dosing, is an obvious convenience, though in many or most instances a single dosage of phages should not be expected, a priori, to be sufficient to achieve desired efficacy 3 Also less desirable for therapeutics are those phages that display poor pharmacokinetics, that is, poor absorption, distribution, and survival in situ 3 Application of phages in low doses may also improve product safety, since phages will only increase in density if they are actively killing bacteria and do not otherwise linger long within the body 3 Ideally phages should also display a low potential to transfer bacterial genes between bacteria (transduction) 3 Low environmental impact 3 Low inherent toxicity 3 Phages that do not adequately meet these criteria should in most circumstances not be employed as therapeutics 3,7,8 We call this auto dosing because the phages themselves contribute to establishing the phage dose 3,9,10 However, phages can interact with immune systems, at least potentially resulting in harmful immune responses, though there is little evidence that this actually is a concern during phage treatment 4) 4,25,26 In addition, there is concern about antibiotic contamination of foods (e 4,5,11,12 Nonetheless, it can be imperative for certain phage therapy protocols to use highly purified phage preparations8 to prevent anaphylactic responses to bacterial components, such as the endotoxins that can be found in crude phage lysates 4,5,9,12,18 Different phages furthermore can be mixed as cocktails to broaden their properties, typically resulting in a collectively greater antibacterial spectrum of activity 4,9,20 Biofilm clearance 4,9,20 Even broadly to antibiotic resistance, using phages to replace antibiotics could help extend the clinical utility of conventional antibiotics 5 In addition, some mutations to resistance negatively impact bacterial fitness or virulence due to loss of pathogenicity-related phage receptors 5 Often fewer units of phages therefore are required per treatment, though high multiplicities of phage adsorption to bacteria are still necessary to substantially reduce target bacterial densities 5 The historical bias towards developing only broader spectrum antibiotics, however, may be changing 5,6 Auto dosing 7 proteins, they are inherently nontoxic 7,8 Lack of cross-resistance with antibiotics 9 Avoiding phage application at higher doses for safety reasons, however, has utility only if phage application at higher doses is not safe, but there is little evidence suggesting that higher versus lower phage doses may be associated with increases in side effects, especially when using purified phage preparations 9,11 They are also versatile in application form, as liquids, creams, impregnated into solids, etc 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 A more comprehensive review of phage therapy is presented in this same issue while this commentary focuses expressly on the pros and cons of phage use as antibacterials see ref Applying phages in only a single dose7 takes advantage of the phage potential to replicate and thereby achieve active therapy, i As lists vary from author to author, it is useful to condense them into a coherent whole Bacteria that have been successfully infected by obligately lytic phages are unable to regain their viability Bactericidal agents Because phages infect and kill using mechanisms that differ from those of antibiotics, specific antibiotic resistance mechanisms do not translate into mechanisms of phage resistance Because they are composed predominantly of nucleic acids and proteins,3 and possess relatively narrow host ranges,13 discarded therapeutic phages, unlike broad-spectrum chemical antibiotics,24 will at worst have an impact on only a small subset of environmental bacteria Biofilms tend to be substantially more resistant to antibiotics than planktonic bacteria By contrast, certain antibiotics are bacteriostatic, such as tetracycline, and as a consequence may more readily permit bacterial evolution towards resistance Conclusion Phages, as antibacterial agents, have a number of properties that make them compelling alternatives to chemical antibiotics while most or perhaps all concerns associated with phage therapy should be manageable through a combination of proper phage selection, effective formulation, and greater clinician understanding of and familiarity with product application Do not distribute e e For example, many protein-based pharmaceuticals can stimulate immune systems, antibiotics that lyse bacteria will release bacterial toxins in situ, and liveattenuated vaccines both actively replicate and evolve including within the context of infecting body tissues Formulation and application versatility g g 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 Here we highlight the strengths and weaknesses of individual assertions However, as noted, the various phage oddities as drugs at least are not unique to them 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 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 In this section we consider those properties that, in our opinion, can contribute substantially to phage therapy utility 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 Introduced in the early 1900s,1 phage therapy is the application of bacteria-specific viruses (phages) to combat uncontrolled and undesired bacteria such as those associated with infectious disease Isolation can be more technically demanding, however, if host bacteria themselves are difficult to culture17 and bacteria may differ in terms of the number of phage types to which they are susceptible It therefore stands to reason that phage-based pharmaceuticals should not be disqualified for possessing similar attributes Major Advantages of Phage Therapy Advantages of phage therapy over the use of chemical antibiotics can be framed in terms of phage properties Minimal disruption of normal flora Minimally this should entail avoiding temperate phages and, ideally, full genome sequencing should be used to rule out virulencefactor carriage No antimicrobials displaying selective toxicity will affect all possible microbial targets Not all phages make for good therapeutics Owing to their host specificity which can range from an ability to infect only a few strains of a bacterial species to, more rarely, a capacity to infect more than one relatively closely related bacterial genus13 phages only minimally impact health-protecting normal flora bacteria Phages against many pathogenic bacteria are easily discovered, often from sewage and other waste materials that contain high bacterial concentrations Phages are natural products Phages are not antibiotics Phages are not unique pharmaceuticals… Phages as pharmaceuticals are protein-based, live-biological agents that can potentially interact with the bodys immune system, can actively replicate, and can even evolve during manufacture or use, but are far from unique in these regards Phages consequently can be readily employed to treat antibiotic-resistant infections5,9-12 such as against multi-drug-resistance Staphylococcus aureus Phages during the bacterial-killing process are capable of increasing in number specifically where hosts are located,5 though with some limitations such as dependence on relatively high bacterial densities Phages not adapted to degradative environmental factors, such as sunlight, desiccation, or temperature extremes, also can be rapidly inactivated Phages, however, have a demonstrated ability to clear at least some biofilms, perhaps owing to a potential to actively penetrate their way into biofilms by lysing one bacterial layer at a time, or due to the display of biofilm exopolymer-degrading depolymerases Phages, like antibiotics, can be versatile in terms of formulation development, such as being combined with certain antibiotics Protein-based drugs, chemical antibiotics, and whole vaccines have previously been approved for use despite these various properties Public resistance to laboratory-synthesized drugs or genetically modified organisms should not apply to non-engineered phage products as they are natural components of environments See references 4 and 5 for additional discussion Since phages consist mostly of nucleic acids and ©2011 Landes Bioscience Single-dose potential Single-hit kinetics So far, however, public resistance has not materialized, and it is perhaps fortunate that bacterial viruses are known, instead, as phages Such low virulence can be due to poor adsorption properties, low potential to evade bacterial defenses, or poor replication characteristics The ability of phages to increase in density in situ, given sufficient bacterial densities, could potentially reduce treatment costs by reducing phage doses required to achieve efficacy 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) The problem of narrow host range The production of phages predominately involves a combination of host growth and subsequent purification The relatively narrow host range exhibited by most phages13 limits the number of bacterial types with which selection for specific phage-resistance mechanisms can occur 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 The Western medical establishments unfamiliarity with phages, as antibacterial agents, may be phage therapys greatest challenge There are a number of non-essential uses of antibiotics that contribute to bacterial evolution of resistance: antibiotic treatment of animal or plant diseases, antibiotic use to increase food-animal growth rates, and over- or improper use of antibiotics to treat human diseases 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 These lists can be used as talking points of why, in this age of epidemic antibiotic resistance, phage therapy should not be overlooked This contrasts with the substantial fraction of bacteria that can be affected by most chemical antibiotics This could be useful in some agricultural applications This is essentially cross-infection of phages from treated subjects or environments to untreated subjects Typically the narrowness of phage host ranges a few strains, a few species, or much rarer, a few genera of bacteria13 will at a minimum place limitations on presumptive treatment, i Unlike chemical antibiotics, only a single phage is needed to kill a single bacterium We also consider possible limitations to phage use as antibacterials