The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform
Laurent Debarbieux - One of the best experts on this subject based on the ideXlab platform.
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The Gut Microbiota Facilitates Drifts in the Genetic Diversity and Infectivity of Bacterial Viruses
Cell Host and Microbe, 2017Co-Authors: Luisa De Sordi, Varun Khanna, Laurent DebarbieuxAbstract:The intestinal microbiota and human health are intimately linked, but interactions between bacteria and Bacteriophages in the context of the mammalian intestine remain largely unexplored. We used comparative population genomics to study a tripartite network consisting of a virulent Bacteriophage, its bacterial host, and a phage-insensitive bacterial strain both in vitro and within the murine gut. The Bacteriophage adapted to infect the insensitive strain when the three partners co-existed in the gut of conventional mice, but not in dixenic mice or in planktonic cultures. The molecular changes associated with modifications in the Bacteriophage host spectrum included single amino acid substitutions and an unusual homologous intragenomic recombination event within the genome of the Bacteriophage. An intermediate bacterial host isolated from the murine microbiota mediated Bacteriophage adaptation. Our data indicate that by offering access to new hosts, the microbiota shifts the genetic diversity of Bacteriophages, thereby promoting long-term persistence of Bacteriophage populations.
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intestinal colonization by enteroaggregative escherichia coli supports long term Bacteriophage replication in mice
Environmental Microbiology, 2012Co-Authors: Damien Maura, Chantal Le Bouguénec, Eric Morello, Laurence Du Merle, Perrine Bomme, Laurent DebarbieuxAbstract:Bacteriophages have been known to be present in the gut for many years, but studies of relationships between these viruses and their hosts in the intestine are still in their infancy. We isolated three Bacteriophages specific for an enteroaggregative O104:H4 Escherichia coli (EAEC) strain responsible for diarrhoeal diseases in humans. We studied the replication of these Bacteriophages in vitro and in vivo in a mouse model of gut colonization. Each Bacteriophage was able to replicate in vitro in both aerobic and anaerobic conditions. Each Bacteriophage individually reduced biofilms formed on plastic pegs and a cocktail of the three Bacteriophages was found to be more efficient. The cocktail was also able to infect bacterial aggregates formed on the surface of epithelial cells. In the mouse intestine, Bacteriophages replicated for at least 3 weeks, provided the host was present, with no change in host levels in the faeces. This model of stable and continuous viral replication provides opportunities for studying the long-term coevolution of virulent Bacteriophages with their hosts within a mammalian polymicrobial ecosystem.
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Virulent Bacteriophages Can Target O104:H4 Enteroaggregative Escherichia coli in the Mouse Intestine
Antimicrobial Agents and Chemotherapy, 2012Co-Authors: Damien Maura, Matthieu Galtier, Chantal Le Bouguénec, Laurent DebarbieuxAbstract:In vivo Bacteriophage targeting of enteroaggregative Escherichia coli (EAEC) was assessed using a mouse intestinal model of colonization with the O104:H4 55989Str strain and a cocktail of three virulent Bacteriophages. The colonization model was shown to mimic asymptomatic intestinal carriage found in humans. The addition of the cocktail to drinking water for 24 h strongly decreased ileal and weakly decreased fecal 55989Str concentrations in a dose-dependent manner. These decreases in ileal and fecal bacterial concentrations were only transient, since 55989Str concentrations returned to their original levels 3 days later. These transient decreases were independent of the mouse microbiota, as similar results were obtained with axenic mice. We studied the infectivity of each Bacteriophage in the ileal and fecal environments and found that 55989Str bacteria in the mouse ileum were permissive to all three Bacteriophages, whereas those in the feces were permissive to only one Bacteriophage. Our results provide the first demonstration that bacterial permissivity to infection with virulent Bacteriophages is not uniform throughout the gut; this highlights the need for a detailed characterization of the interactions between bacteria and Bacteriophages in vivo for the further development of phage therapy targeting intestinal pathogens found in the gut of asymptomatic human carriers.
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Pulmonary Bacteriophage therapy on pseudomonas aeruginosa cystic fibrosis strains: First steps towards treatment and prevention
PLoS ONE, 2011Co-Authors: Eric Morello, Emilie Saussereau, Damien Maura, Michel Huerre, Lhousseine Touqui, Laurent DebarbieuxAbstract:Multidrug-resistant bacteria are the cause of an increasing number of deadly pulmonary infections. Because there is currently a paucity of novel antibiotics, phage therapy--the use of specific viruses that infect bacteria--is now more frequently being considered as a potential treatment for bacterial infections. Using a mouse lung-infection model caused by a multidrug resistant Pseudomonas aeruginosa mucoid strain isolated from a cystic fibrosis patient, we evaluated Bacteriophage treatments. New Bacteriophages were isolated from environmental samples and characterized. Bacteria and Bacteriophages were applied intranasally to the immunocompetent mice. Survival was monitored and bronchoalveolar fluids were analysed. Quantification of bacteria, Bacteriophages, pro-inflammatory and cytotoxicity markers, as well as histology and immunohistochemistry analyses were performed. A curative treatment (one single dose) administrated 2 h after the onset of the infection allowed over 95% survival. A four-day preventive treatment (one single dose) resulted in a 100% survival. All of the parameters measured correlated with the efficacy of both curative and preventive Bacteriophage treatments. We also showed that in vitro optimization of a Bacteriophage towards a clinical strain improved both its efficacy on in vivo treatments and its host range on a panel of 20 P. aeruginosa cystic fibrosis strains. This work provides an incentive to develop clinical studies on pulmonary Bacteriophage therapy to combat multidrug-resistant lung infections.
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Bacteriophages Can Treat and Prevent Pseudomonas aeruginosa Lung Infections
The Journal of Infectious Diseases, 2010Co-Authors: Laurent Debarbieux, Olivier Grossi, Viviane Balloy, Damien Maura, Alexis Criscuolo, Eric Morello, Dominique Leduc, Lhousseine TouquiAbstract:Antibiotic-resistant bacteria threaten life worldwide. Although new antibiotics are scarce, the use of Bacteriophages, viruses that infect bacteria, is rarely proposed as a means of offsetting this shortage. Doubt also remains widespread about the efficacy of phage therapy despite recent encouraging results. Using a bioluminescent Pseudomonas aeruginosa strain, we monitored and quantified the efficacy of a Bacteriophage treatment in mice during acute lung infection. Bacteriophage treatment not only was effective in saving animals from lethal infection, but also was able to prevent lung infection when given 24 h before bacterial infection, thereby extending the potential use of Bacteriophages as therapeutic agents to combat bacterial lung infection.
Roberto Bastías - One of the best experts on this subject based on the ideXlab platform.
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Bacteriophage Production Models: An Overview.
Frontiers in microbiology, 2019Co-Authors: Rodrigo García, Simone Latz, Jaime Romero, Gastón Higuera, Katherine García, Roberto BastíasAbstract:The use of Bacteriophages has been proposed as an alternative method to control pathogenic bacteria. During recent years several reports have been published about the successful use of Bacteriophages in different fields such as food safety, agriculture, aquaculture and even human health. Several companies are now commercializing Bacteriophages or Bacteriophage-based products for therapeutic purposes. However, this technology is still in development and there are challenges to overcome before Bacteriophages can be widely used to control pathogenic bacteria. One big hurdle is the development of efficient methods for Bacteriophage production. To date, several models for Bacteriophage production have been reported, some of them evaluated experimentally. This mini-review offers an overview of different models and methods for Bacteriophage production, contrasting their principal differences.
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Virulence reduction in Bacteriophage resistant bacteria
Frontiers in Microbiology, 2015Co-Authors: Marcela León, Roberto BastíasAbstract:Bacteriophages can influence the abundance, diversity, and evolution of bacterial communities. Several Bacteriophages have been reported to add virulence factors to their host and to increase bacterial virulence. However, lytic Bacteriophages can also exert a selective pressure allowing the proliferation of strains with reduced virulence. This reduction can be explained because Bacteriophages use structures present on the bacterial surface as receptors, which can be virulence factors in different bacterial species. Therefore, strains with modifications in these receptors will be resistant to Bacteriophage infection and may also exhibit reduced virulence. This mini-review summarizes the reports on Bacteriophage-resistant strains with reductions in virulence, and it discusses the potential consequences in phage therapy and in the use of Bacteriophages to select attenuated strains for vaccines.
Damien Maura - One of the best experts on this subject based on the ideXlab platform.
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intestinal colonization by enteroaggregative escherichia coli supports long term Bacteriophage replication in mice
Environmental Microbiology, 2012Co-Authors: Damien Maura, Chantal Le Bouguénec, Eric Morello, Laurence Du Merle, Perrine Bomme, Laurent DebarbieuxAbstract:Bacteriophages have been known to be present in the gut for many years, but studies of relationships between these viruses and their hosts in the intestine are still in their infancy. We isolated three Bacteriophages specific for an enteroaggregative O104:H4 Escherichia coli (EAEC) strain responsible for diarrhoeal diseases in humans. We studied the replication of these Bacteriophages in vitro and in vivo in a mouse model of gut colonization. Each Bacteriophage was able to replicate in vitro in both aerobic and anaerobic conditions. Each Bacteriophage individually reduced biofilms formed on plastic pegs and a cocktail of the three Bacteriophages was found to be more efficient. The cocktail was also able to infect bacterial aggregates formed on the surface of epithelial cells. In the mouse intestine, Bacteriophages replicated for at least 3 weeks, provided the host was present, with no change in host levels in the faeces. This model of stable and continuous viral replication provides opportunities for studying the long-term coevolution of virulent Bacteriophages with their hosts within a mammalian polymicrobial ecosystem.
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Virulent Bacteriophages Can Target O104:H4 Enteroaggregative Escherichia coli in the Mouse Intestine
Antimicrobial Agents and Chemotherapy, 2012Co-Authors: Damien Maura, Matthieu Galtier, Chantal Le Bouguénec, Laurent DebarbieuxAbstract:In vivo Bacteriophage targeting of enteroaggregative Escherichia coli (EAEC) was assessed using a mouse intestinal model of colonization with the O104:H4 55989Str strain and a cocktail of three virulent Bacteriophages. The colonization model was shown to mimic asymptomatic intestinal carriage found in humans. The addition of the cocktail to drinking water for 24 h strongly decreased ileal and weakly decreased fecal 55989Str concentrations in a dose-dependent manner. These decreases in ileal and fecal bacterial concentrations were only transient, since 55989Str concentrations returned to their original levels 3 days later. These transient decreases were independent of the mouse microbiota, as similar results were obtained with axenic mice. We studied the infectivity of each Bacteriophage in the ileal and fecal environments and found that 55989Str bacteria in the mouse ileum were permissive to all three Bacteriophages, whereas those in the feces were permissive to only one Bacteriophage. Our results provide the first demonstration that bacterial permissivity to infection with virulent Bacteriophages is not uniform throughout the gut; this highlights the need for a detailed characterization of the interactions between bacteria and Bacteriophages in vivo for the further development of phage therapy targeting intestinal pathogens found in the gut of asymptomatic human carriers.
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Pulmonary Bacteriophage therapy on pseudomonas aeruginosa cystic fibrosis strains: First steps towards treatment and prevention
PLoS ONE, 2011Co-Authors: Eric Morello, Emilie Saussereau, Damien Maura, Michel Huerre, Lhousseine Touqui, Laurent DebarbieuxAbstract:Multidrug-resistant bacteria are the cause of an increasing number of deadly pulmonary infections. Because there is currently a paucity of novel antibiotics, phage therapy--the use of specific viruses that infect bacteria--is now more frequently being considered as a potential treatment for bacterial infections. Using a mouse lung-infection model caused by a multidrug resistant Pseudomonas aeruginosa mucoid strain isolated from a cystic fibrosis patient, we evaluated Bacteriophage treatments. New Bacteriophages were isolated from environmental samples and characterized. Bacteria and Bacteriophages were applied intranasally to the immunocompetent mice. Survival was monitored and bronchoalveolar fluids were analysed. Quantification of bacteria, Bacteriophages, pro-inflammatory and cytotoxicity markers, as well as histology and immunohistochemistry analyses were performed. A curative treatment (one single dose) administrated 2 h after the onset of the infection allowed over 95% survival. A four-day preventive treatment (one single dose) resulted in a 100% survival. All of the parameters measured correlated with the efficacy of both curative and preventive Bacteriophage treatments. We also showed that in vitro optimization of a Bacteriophage towards a clinical strain improved both its efficacy on in vivo treatments and its host range on a panel of 20 P. aeruginosa cystic fibrosis strains. This work provides an incentive to develop clinical studies on pulmonary Bacteriophage therapy to combat multidrug-resistant lung infections.
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Bacteriophages Can Treat and Prevent Pseudomonas aeruginosa Lung Infections
The Journal of Infectious Diseases, 2010Co-Authors: Laurent Debarbieux, Olivier Grossi, Viviane Balloy, Damien Maura, Alexis Criscuolo, Eric Morello, Dominique Leduc, Lhousseine TouquiAbstract:Antibiotic-resistant bacteria threaten life worldwide. Although new antibiotics are scarce, the use of Bacteriophages, viruses that infect bacteria, is rarely proposed as a means of offsetting this shortage. Doubt also remains widespread about the efficacy of phage therapy despite recent encouraging results. Using a bioluminescent Pseudomonas aeruginosa strain, we monitored and quantified the efficacy of a Bacteriophage treatment in mice during acute lung infection. Bacteriophage treatment not only was effective in saving animals from lethal infection, but also was able to prevent lung infection when given 24 h before bacterial infection, thereby extending the potential use of Bacteriophages as therapeutic agents to combat bacterial lung infection.
Jean-paul Pirnay - One of the best experts on this subject based on the ideXlab platform.
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Guidelines to Compose an Ideal Bacteriophage Cocktail
Methods in molecular biology (Clifton N.J.), 2017Co-Authors: Maya Merabishvili, Jean-paul Pirnay, Daniel De VosAbstract:Correctly designed Bacteriophage therapeutics are the cornerstone for a successful outcome of Bacteriophage therapy. Here we overview strategies on how to choose Bacteriophages and their bacterial hosts at different steps of a Bacteriophage cocktail development in order to comply with all quality and safety requirements based on the already existing essentially empirical experience in Bacteriophage therapy and current accomplishments in modern biomedical sciences. A modification of the classic Appelmans' method (1922) to assess stability of Bacteriophage activity in liquid media is presented in order to improve the overall performance of therapeutic Bacteriophages individually and collectively in the cocktail.
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Effectiveness of Bacteriophages in the sputum of cystic fibrosis patients.
Clinical Microbiology and Infection, 2014Co-Authors: Emilie Saussereau, Daniel De Vos, Jean-paul Pirnay, Isabelle Vachier, Raphaël Chiron, Benoit Godbert, Isabelle Sermet, Nicolas Dufour, Frédérique Carrié, Nicolas MolinariAbstract:Bacteriophages have been shown to be effective for treating acute infections of the respiratory tract caused by antibiotic-resistant bacteria in animal models, but no evidence has yet been presented of their activity against pathogens in complex biological samples from chronically infected patients. We assessed the efficacy of a cocktail of ten Bacteriophages infecting Pseudomonas aeruginosa following its addition to 58 sputum samples from cystic fibrosis (CF) patients collected at three different hospitals. Ten samples that did not contain P. aeruginosa were not analysed further. In the remaining 48 samples, the addition of Bacteriophages led to a significant decrease in the levels of P. aeruginosa strains, as shown by comparison with controls, taking two variables (time and Bacteriophages) into account (p = 0.024). In 45.8% of these samples, this decrease was accompanied by an increase in the number of Bacteriophages. We also tested each of the ten Bacteriophages individually against 20 colonies from each of these 48 samples and detected Bacteriophage-susceptible bacteria in 64.6% of the samples. An analysis of the clinical data revealed no correlation between patient age, sex, duration of P. aeruginosa colonization, antibiotic treatment, FEV1 (forced expiratory volume in the first second) and the efficacy of Bacteriophages. The demonstration that Bacteriophages infect their bacterial hosts in the sputum environment, regardless of the clinical characteristics of the patients, represents a major step towards the development of Bacteriophage therapy to treat chronic lung infections.
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Call for a dedicated European legal framework for Bacteriophage therapy
Archivum Immunologiae et Therapiae Experimentalis, 2014Co-Authors: Gilbert Verbeken, Daniel De Vos, Rob Lavigne, Minne Casteels, Serge Jennes, Jean-paul Pirnay, Isabelle HuysAbstract:The worldwide emergence of antibiotic resistances and the drying up of the antibiotic pipeline have spurred a search for alternative or complementary antibacterial therapies. Bacteriophages are bacterial viruses that have been used for almost a century to combat bacterial infections, particularly in Poland and the former Soviet Union. The antibiotic crisis has triggered a renewed clinical and agricultural interest in Bacteriophages. This, combined with new scientific insights, has pushed Bacteriophages to the forefront of the search for new approaches to fighting bacterial infections. But before Bacteriophage therapy can be introduced into clinical practice in the European Union, several challenges must be overcome. One of these is the conceptualization and classification of Bacteriophage therapy itself and the extent to which it constitutes a human medicinal product regulated under the European Human Code for Medicines (Directive 2001/83/EC). Can therapeutic products containing natural Bacteriophages be categorized under the current European regulatory framework, or should this framework be adapted? Various actors in the field have discussed the need for an adapted (or entirely new) regulatory framework for the reintroduction of Bacteriophage therapy in Europe. This led to the identification of several characteristics specific to natural Bacteriophages that should be taken into consideration by regulators when evaluating Bacteriophage therapy. One important consideration is whether Bacteriophage therapy development occurs on an industrial scale or a hospital-based, patient-specific scale. More suitable regulatory standards may create opportunities to improve insights into this promising therapeutic approach. In light of this, we argue for the creation of a new, dedicated European regulatory framework for Bacteriophage therapy.
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Optimizing the European regulatory framework for sustainable Bacteriophage therapy in human medicine
Archivum Immunologiae et Therapiae Experimentalis, 2012Co-Authors: Gilbert Verbeken, Daniel De Vos, Martin Zizi, Rob Lavigne, Minne Casteels, Serge Jennes, Jean-paul Pirnay, Isabelle HuysAbstract:For practitioners at hospitals seeking to use natural (not genetically modified, as appearing in nature) Bacteriophages for treatment of antibiotic-resistant bacterial infections (Bacteriophage therapy), Europe's current regulatory framework for medicinal products hinders more than it facilitates. Although many experts consider Bacteriophage therapy to be a promising complementary (or alternative) treatment to antibiotic therapy, no Bacteriophage-specific framework for documentation exists to date. Decades worth of historical clinical data on Bacteriophage therapy (from Eastern Europe, particularly Poland, and the former Soviet republics, particularly Georgia and Russia, as well as from today's 27 EU member states and the US) have not been taken into account by European regulators because these data have not been validated under current Western regulatory standards. Consequently, applicants carrying out standard clinical trials on Bacteriophages in Europe are obliged to initiate clinical work from scratch. This paper argues for a reduced documentation threshold for Phase 1 clinical trials of Bacteriophages and maintains that Bacteriophages should not be categorized as classical medicinal products for at least two reasons: (1) such a categorization is scientifically inappropriate for this specific therapy and (2) such a categorization limits the marketing authorization process to industry, the only stakeholder with sufficient financial resources to prepare a complete dossier for the competent authorities. This paper reflects on the current regulatory framework for medicines in Europe and assesses possible regulatory pathways for the (re-)introduction of Bacteriophage therapy in a way that maintains its effectiveness and safety as well as its inherent characteristics of sustainability and in situ self-amplification and limitation.
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Quality-controlled small-scale production of a well-defined Bacteriophage cocktail for use in human clinical trials
PLoS ONE, 2009Co-Authors: Maya Merabishvili, Thea Glonti, Nino Lashkhi, Marina Tediashvili, Victor N. Krylov, Jan Mast, Jean-paul Pirnay, Gilbert Verbeken, Nina Chanishvili, Luc Van ParysAbstract:We describe the small-scale, laboratory-based, production and quality control of a cocktail, consisting of exclusively lytic Bacteriophages, designed for the treatment of Pseudomonas aeruginosa and Staphylococcus aureus infections in burn wound patients. Based on successive selection rounds three Bacteriophages were retained from an initial pool of 82 P. aeruginosa and 8 S. aureus Bacteriophages, specific for prevalent P. aeruginosa and S. aureus strains in the Burn Centre of the Queen Astrid Military Hospital in Brussels, Belgium. This cocktail, consisting of P. aeruginosa phages 14/1 (Myoviridae) and PNM (Podoviridae) and S. aureus phage ISP (Myoviridae) was produced and purified of endotoxin. Quality control included Stability (shelf life), determination of pyrogenicity, sterility and cytotoxicity, confirmation of the absence of temperate Bacteriophages and transmission electron microscopy-based confirmation of the presence of the expected virion morphologic particles as well as of their specific interaction with the target bacteria. Bacteriophage genome and proteome analysis confirmed the lytic nature of the Bacteriophages, the absence of toxin-coding genes and showed that the selected phages 14/1, PNM and ISP are close relatives of respectively F8, phiKMV and phage G1. The Bacteriophage cocktail is currently being evaluated in a pilot clinical study cleared by a leading Medical Ethical Committee.
Teagan L. Brown - One of the best experts on this subject based on the ideXlab platform.
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The varying effects of a range of preservatives on Myoviridae and Siphoviridae Bacteriophages formulated in a semi‐solid cream preparation
Letters in applied microbiology, 2020Co-Authors: Teagan L. Brown, George Mnatzaganian, Mwila Kabwe, Steve Petrovski, Michael J. Angove, Joseph TucciAbstract:Bacteriophages may be formulated into semi-solid bases for therapeutic delivery. This work investigated the effects of a range of preservatives on the viability of Myoviridae and Siphoviridae Bacteriophages when these were formulated into a standard semi-solid cream base. The six preservatives tested included: benzoic acid (0·1%), chlorocresol (0·1%), combination hydroxybenzoates (propyl 4-hydroxybenzoates with methyl 4-hydroxybenzoates) (0·1%), methyl 4-hydroxybenzoate (0·08%), 2-phenoxyethanol (1%) and propyl 4-hydroxybenzoate (0·02%). These were each formulated into cetomacrogol cream aqueous to generate six individual semi-solid bases into which Myoviridae and Siphoviridae Bacteriophages were added and tested for stability. Optimal Bacteriophage stability was seen when the preservative chlorocresol was used. Bacteriophage in the acidic benzoic acid were the least stable, resulting in complete loss of viability after 4-5 weeks. Of the Bacteriophages tested, the Myoviridae KOX1 was significantly more stable than the Siphoviridae PAC1 after 91 days in formulations with each of the preservatives. Our results suggest the need for individual testing of specific Bacteriophages in pharmaceutical formulations, as their efficacy when exposed to preservatives and excipients in these delivery forms may vary. SIGNIFICANCE AND IMPACT OF THE STUDY: Bacteriophages are being increasingly investigated as alternatives to antibiotics. While Bacteriophages can be formulated in diverse ways for therapeutic delivery, there has been scant work on how excipients and preservatives in these formulations affect stability of different Bacteriophages. We demonstrate that the nature of preservatives in formulations will affect Bacteriophage stability, and that in these formulations, viability of Bacteriophage differs according to their morphology. Our work highlights the need for individual testing of specific Bacteriophages in pharmaceutical formulations, as efficacy when exposed to preservatives and excipients in these delivery forms may vary.
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the varying effects of a range of preservatives on myoviridae and siphoviridae Bacteriophages formulated in a semi solid cream preparation
Letters in Applied Microbiology, 2020Co-Authors: Heng Ku, George Mnatzaganian, Mwila Kabwe, Steve Petrovski, Teagan L. Brown, Michael J. Angove, Joseph TucciAbstract:: Bacteriophages may be formulated into semi-solid bases for therapeutic delivery. This work investigated the effects of a range of preservatives on the viability of Myoviridae and Siphoviridae Bacteriophages when these were formulated into a standard semi-solid cream base. The six preservatives tested included: benzoic acid (0.1%), chlorocresol (0.1%), combination hydroxybenzoates (propyl 4-hydroxybenzoates with methyl 4-hydroxybenzoates) (0.1%), methyl 4-hydroxybenzoate (0.08%), 2-phenoxyethanol (1%), and propyl 4-hydroxybenzoate (0.02%). These were each formulated into cetomacrogol cream aqueous to generate six individual semi-solid bases into which Myoviridae and Siphoviridae Bacteriophages were added and tested for stability. Optimal Bacteriophage stability was seen when the preservative chlorocresol was used. Bacteriophage in the acidic benzoic acid were the least stable, resulting in complete loss of viability after four to five weeks. Of the Bacteriophages tested, the Myoviridae KOX1 was significantly more stable than the Siphoviridae PAC1 after 91 days in formulations with each of the preservatives. Our results suggest the need for individual testing of specific Bacteriophages in pharmaceutical formulations, as their efficacy when exposed to preservatives and excipients in these delivery forms may vary.
