Phage therapy: An alternative to antibiotics in the age of multi-drug resistance

The practice of phage therapy, which uses bacterial viruses (phages) to treat bacterial infections, has been around for almost a century. The universal decline in the effectiveness of antibiotics has generated renewed interest in revisiting this practice. Conventionally, phage therapy relies on the use of naturally-occurring phages to infect and lyse bacteria at the site of infection. Biotechnological advances have further expanded the repertoire of potential phage therapeutics to include novel strategies using bioengineered phages and purified phage lytic proteins. Current research on the use of phages and their lytic proteins, specifically against multidrug-resistant bacterial infections, suggests phage therapy has the potential to be used as either an alternative or a supplement to antibiotic treatments. Antibacterial therapies, whether phage- or antibiotic-based, each have relative advantages and disadvantages; accordingly, many considerations must be taken into account when designing novel therapeutic approaches for preventing and treating bacterial infections. Although much is still unknown about the interactions between phage, bacteria, and human host, the time to take phage therapy seriously seems to be rapidly approaching.

[1]  S. Opal,et al.  A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens , 2013, Virulence.

[2]  F. Bushman,et al.  The human gut virome: inter-individual variation and dynamic response to diet. , 2011, Genome research.

[3]  Chad W. Euler,et al.  Using a Novel Lysin To Help Control Clostridium difficile Infections , 2015, Antimicrobial Agents and Chemotherapy.

[4]  R. Goel,et al.  Biofilm control with natural and genetically-modified phages , 2016, World journal of microbiology & biotechnology.

[5]  Chad W. Euler,et al.  Novel Bacteriophage Lysin with Broad Lytic Activity Protects against Mixed Infection by Streptococcus pyogenes and Methicillin-Resistant Staphylococcus aureus , 2013, Antimicrobial Agents and Chemotherapy.

[6]  C. Hill,et al.  Characterization of a Bacteriophage-Derived Murein Peptidase for Elimination of Antibiotic-Resistant Staphylococcus aureus. , 2016, Current protein & peptide science.

[7]  K. Allin,et al.  Effect of antibiotics on gut microbiota, glucose metabolism and body weight regulation: a review of the literature , 2016, Diabetes, obesity & metabolism.

[8]  M. Blaser,et al.  Antibiotics in early life and obesity , 2015, Nature Reviews Endocrinology.

[9]  H. Boucher,et al.  Past, Present, and Future of Antibacterial Economics: Increasing Bacterial Resistance, Limited Antibiotic Pipeline, and Societal Implications , 2017, Pharmacotherapy.

[10]  Michael Bell,et al.  Vital Signs: Carbapenem-Resistant Enterobacteriaceae , 2013, MMWR. Morbidity and mortality weekly report.

[11]  M. Weinbauer Ecology of prokaryotic viruses. , 2004, FEMS microbiology reviews.

[12]  M. Muniesa,et al.  Persistence of naturally occurring antibiotic resistance genes in the bacteria and bacteriophage fractions of wastewater. , 2016, Water research.

[13]  Clayton K. Collings,et al.  The impact of orally administered phages on host immune response and surrounding microbial communities , 2016, Bacteriophage.

[14]  R. Nannapaneni,et al.  Use of Bacteriophages to Remove Biofilms of Listeria monocytogenes and other Foodborne Bacterial Pathogens in the Food Environment , 2015 .

[15]  Junbo Hu,et al.  Use of bacteriophage in the treatment of experimental animal bacteremia from imipenem-resistant Pseudomonas aeruginosa. , 2006, International journal of molecular medicine.

[16]  T. G. Gabisoniya,et al.  Effects of bacteriophages on biofilm formation by strains of Pseudomonas aeruginosa , 2016, Applied Biochemistry and Microbiology.

[17]  R. P. Ross,et al.  Phage therapy in the food industry. , 2014, Annual review of food science and technology.

[18]  M. Delbrück,et al.  THE GROWTH OF BACTERIOPHAGE AND LYSIS OF THE HOST , 1940, The Journal of general physiology.

[19]  R. Carlton,et al.  Phage therapy: past history and future prospects. , 1999, Archivum immunologiae et therapiae experimentalis.

[20]  C. Merril,et al.  Bacteriophage Therapy Rescues Mice Bacteremic from a Clinical Isolate of Vancomycin-Resistant Enterococcus faecium , 2002, Infection and Immunity.

[21]  J. Treatment of experimental infections of mice with bacteriophages , 2008 .

[22]  N. Suttorp,et al.  Systemic use of the endolysin Cpl-1 rescues mice with fatal pneumococcal pneumonia* , 2009, Critical care medicine.

[23]  J. Jofre,et al.  Antibiotic Resistance Genes in the Bacteriophage DNA Fraction of Human Fecal Samples , 2013, Antimicrobial Agents and Chemotherapy.

[24]  U. Qimron,et al.  Temperate and lytic bacteriophages programmed to sensitize and kill antibiotic-resistant bacteria , 2015, Proceedings of the National Academy of Sciences.

[25]  Nicole J. Crane,et al.  Personalized Therapeutic Cocktail of Wild Environmental Phages Rescues Mice from Acinetobacter baumannii Wound Infections , 2016, Antimicrobial Agents and Chemotherapy.

[26]  C. Suttle Marine viruses — major players in the global ecosystem , 2007, Nature Reviews Microbiology.

[27]  A. Górski,et al.  Bacteriophage therapy of bacterial infections: an update of our institute's experience. , 2000, Archivum immunologiae et therapiae experimentalis.

[28]  B. Berger,et al.  Oral Phage Therapy of Acute Bacterial Diarrhea With Two Coliphage Preparations: A Randomized Trial in Children From Bangladesh , 2016, EBioMedicine.

[29]  S. Schrag,et al.  US outpatient antibiotic prescribing variation according to geography, patient population, and provider specialty in 2011. , 2015, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[30]  V. Ong,et al.  Antibiotic Treatment , 2018, Atlas of Ulcers in Systemic Sclerosis.

[31]  A. Górski,et al.  Bacteriophage translocation. , 2006, FEMS immunology and medical microbiology.

[32]  Chad W. Euler,et al.  A novel chimeric phage lysin with high in vitro and in vivo bactericidal activity against Streptococcus pneumoniae. , 2015, The Journal of antimicrobial chemotherapy.

[33]  M. Kutateladze,et al.  Phage therapy experience at the Eliava Institute. , 2008, Medecine et maladies infectieuses.

[34]  I. Sutherland,et al.  Biofilm susceptibility to bacteriophage attack: the role of phage-borne polysaccharide depolymerase. , 1998, Microbiology.

[35]  B. Blasdel,et al.  Bacteriophage treatment of intransigent diabetic toe ulcers: a case series. , 2016, Journal of wound care.

[36]  G. Volckaert,et al.  Engineered Endolysin-Based “Artilysins” To Combat Multidrug-Resistant Gram-Negative Pathogens , 2014, mBio.

[37]  J. Costerton,et al.  Dynamic interactions of biofilms of mucoid Pseudomonas aeruginosa with tobramycin and piperacillin , 1992, Antimicrobial Agents and Chemotherapy.

[38]  D. Donovan,et al.  Antimicrobial bacteriophage-derived proteins and therapeutic applications , 2015, Bacteriophage.

[39]  M. Drab,et al.  Mammalian Host-Versus-Phage immune response determines phage fate in vivo , 2015, Scientific Reports.

[40]  P. Singh,et al.  Intravitreal Injection of the Chimeric Phage Endolysin Ply187 Protects Mice from Staphylococcus aureus Endophthalmitis , 2014, Antimicrobial Agents and Chemotherapy.

[41]  M. Clokie,et al.  Bacteriophage Combinations Significantly Reduce Clostridium difficile Growth In Vitro and Proliferation In Vivo , 2015, Antimicrobial Agents and Chemotherapy.

[42]  L. Krause,et al.  Safety analysis of a Russian phage cocktail: from metagenomic analysis to oral application in healthy human subjects. , 2013, Virology.

[43]  T. Wood,et al.  Cryptic prophages as targets for drug development. , 2016, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[44]  Tetsuya Matsumoto,et al.  Efficacy of Bacteriophage Therapy against Gut-Derived Sepsis Caused by Pseudomonas aeruginosa in Mice , 2006, Antimicrobial Agents and Chemotherapy.

[45]  S. Chhibber,et al.  Potential of combination therapy of endolysin MR-10 and minocycline in treating MRSA induced systemic and localized burn wound infections in mice. , 2016, International journal of medical microbiology : IJMM.

[46]  Zhi-ping Zhang,et al.  Existence of Separate Domains in Lysin PlyG for Recognizing Bacillus anthracis Spores and Vegetative Cells , 2012, Antimicrobial Agents and Chemotherapy.

[47]  S. Virtanen,et al.  Prenatal and Post-natal Exposure to Antibiotics and Risk of Asthma in Childhood , 2015, Pediatrics.

[48]  Arjun Srinivasan,et al.  Emergency department visits for antibiotic-associated adverse events. , 2008, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[49]  J. Fralick,et al.  Prevention of Clostridium difficile -induced ileocecitis with Bacteriophage , 1999 .

[50]  S. Sillankorva,et al.  Bacteriophage Therapy , 2018, Methods in Molecular Biology.

[51]  Chad W. Euler,et al.  Novel Phage Lysin Capable of Killing the Multidrug-Resistant Gram-Negative Bacterium Acinetobacter baumannii in a Mouse Bacteremia Model , 2015, Antimicrobial Agents and Chemotherapy.

[52]  J. Bartlett,et al.  Bad bugs, no drugs: no ESKAPE! An update from the Infectious Diseases Society of America. , 2009, Clinical infectious diseases : an official publication of the Infectious Diseases Society of America.

[53]  K. Servick DRUG DEVELOPMENT. Beleaguered phage therapy trial presses on. , 2016, Science.

[54]  G. Tetz,et al.  Bacteriophage infections of microbiota can lead to leaky gut in an experimental rodent model , 2016, Gut Pathogens.

[55]  M. Wittekind,et al.  Combination Therapy With Lysin CF-301 and Antibiotic Is Superior to Antibiotic Alone for Treating Methicillin-Resistant Staphylococcus aureus–Induced Murine Bacteremia , 2013, The Journal of infectious diseases.

[56]  H. Horz,et al.  The Janus-Face of Bacteriophages across Human Body Habitats , 2016, PLoS pathogens.

[57]  Sylvain Moineau,et al.  Bacteriophage resistance mechanisms , 2010, Nature Reviews Microbiology.

[58]  Harris H. Wang,et al.  Manipulating Bacterial Communities by in situ Microbiome Engineering. , 2016, Trends in genetics : TIG.

[59]  J. Costerton,et al.  Introduction to biofilm. , 1999, International journal of antimicrobial agents.

[60]  E. Dey,et al.  Bacteriophage receptors, mechanisms of phage adsorption and penetration into host cell. , 2010, Polish journal of microbiology.

[61]  J. Moult,et al.  A bacteriophage endolysin that eliminates intracellular streptococci , 2016, eLife.

[62]  J. Leiva,et al.  Antibiotic susceptibility assay for Staphylococcus aureus in biofilms developed in vitro. , 1999, The Journal of antimicrobial chemotherapy.

[63]  Tong Zhang,et al.  Antibiotic resistance genes in water environment , 2009, Applied Microbiology and Biotechnology.

[64]  S. Abedon Ecology of Anti-Biofilm Agents I: Antibiotics versus Bacteriophages , 2015, Pharmaceuticals.

[65]  S. Sillankorva,et al.  Structural and Enzymatic Characterization of ABgp46, a Novel Phage Endolysin with Broad Anti-Gram-Negative Bacterial Activity , 2016, Front. Microbiol..

[66]  B. Rouveix Antibiotic safety assessment. , 2003, International journal of antimicrobial agents.

[67]  H. Myung,et al.  Observation of inflammatory responses in mice orally fed with bacteriophage T7 , 2014, Journal of applied microbiology.

[68]  J. Jofre,et al.  Antibiotic Resistance Genes in the Bacteriophage DNA Fraction of Environmental Samples , 2011, PloS one.

[69]  S. Datta,et al.  Strain Specific Phage Treatment for Staphylococcus aureus Infection Is Influenced by Host Immunity and Site of Infection , 2015, PloS one.

[70]  S. Abedon,et al.  Phage cocktails and the future of phage therapy. , 2013, Future microbiology.

[71]  M. Wittekind,et al.  Cell wall hydrolases and antibiotics: exploiting synergy to create efficacious new antimicrobial treatments. , 2016, Current opinion in microbiology.

[72]  H. Brüssow,et al.  Human Volunteers Receiving Escherichia coli Phage T4 Orally: a Safety Test of Phage Therapy , 2005, Antimicrobial Agents and Chemotherapy.

[73]  N. Chanishvili,et al.  Bacteriophage therapy: experience from the Eliava Institute, Georgia , 2008 .

[74]  J. Borysowski,et al.  Is phage therapy acceptable in the immunocompromised host? , 2008, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases.

[75]  E. Änggård,et al.  A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic‐resistant Pseudomonas aeruginosa; a preliminary report of efficacy , 2009, Clinical otolaryngology : official journal of ENT-UK ; official journal of Netherlands Society for Oto-Rhino-Laryngology & Cervico-Facial Surgery.

[76]  Nuria Quiles-Puchalt,et al.  Bacteriophage-mediated spread of bacterial virulence genes. , 2015, Current opinion in microbiology.

[77]  M. Kutateladze,et al.  Bacteriophages as potential new therapeutics to replace or supplement antibiotics. , 2010, Trends in biotechnology.

[78]  N. Chanishvili Phage therapy--history from Twort and d'Herelle through Soviet experience to current approaches. , 2012, Advances in virus research.

[79]  H. Arachchi,et al.  Bacteriophages to reduce gut carriage of antibiotic resistant uropathogens with low impact on microbiota composition. , 2016, Environmental microbiology.

[80]  E. Bingen,et al.  Efficacy of Bacteriophage Therapy in Experimental Sepsis and Meningitis Caused by a Clone O25b:H4-ST131 Escherichia coli Strain Producing CTX-M-15 , 2012, Antimicrobial Agents and Chemotherapy.

[81]  H. Freund,et al.  Historical overview. , 2021, Advances in neurology.

[82]  G. Volckaert,et al.  Quality-Controlled Small-Scale Production of a Well-Defined Bacteriophage Cocktail for Use in Human Clinical Trials , 2009, PloS one.

[83]  B. Koskella,et al.  Bacteria–phage coevolution as a driver of ecological and evolutionary processes in microbial communities , 2014, FEMS microbiology reviews.

[84]  D. Tao,et al.  Therapeutic effectiveness of bacteriophages in the rescue of mice with extended spectrum beta-lactamase-producing Escherichia coli bacteremia. , 2006, International journal of molecular medicine.

[85]  C. Rm Phage therapy: past history and future prospects. , 1999 .

[86]  B. Koskella Bacteria-Phage Interactions across Time and Space: Merging Local Adaptation and Time-Shift Experiments to Understand Phage Evolution* , 2014, The American Naturalist.

[87]  Forest Rohwer,et al.  Viruses in the fecal microbiota of monozygotic twins and their mothers , 2010, Nature.

[88]  V. Mai,et al.  Bacteriophage administration significantly reduces Shigella colonization and shedding by Shigella-challenged mice without deleterious side effects and distortions in the gut microbiota , 2015, Bacteriophage.

[89]  J. Siby,et al.  Antibiotic resistance a global threat , 2012 .

[90]  K. Kurokawa,et al.  Diversification of Escherichia coli genomes: are bacteriophages the major contributors? , 2001, Trends in microbiology.

[91]  K. Stanford,et al.  Host range and lytic capability of four bacteriophages against bovine and clinical human isolates of Shiga toxin‐producing Escherichia coli O157:H7 , 2009, Journal of applied microbiology.

[92]  H. Goossens,et al.  Antibiotic resistance—the need for global solutions , 2013, BDJ.

[93]  Mark J. Sistrom,et al.  Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa , 2016, Scientific Reports.

[94]  R. B.,et al.  The United Nations , 1947, Nature.

[95]  J. Collins,et al.  Antibiotic Treatment Expands the Resistance Reservoir and Ecological Network of the Phage Metagenome , 2013, Nature.

[96]  Yun Zhang,et al.  Novel Chimeric Lysin with High-Level Antimicrobial Activity against Methicillin-Resistant Staphylococcus aureus In Vitro and In Vivo , 2013, Antimicrobial Agents and Chemotherapy.

[97]  T. Dinan,et al.  The microbiome: A key regulator of stress and neuroinflammation , 2016, Neurobiology of Stress.

[98]  Graham F Hatfull,et al.  Bacteriophages and their genomes. , 2011, Current opinion in virology.

[99]  H. Ackermann The first phage electron micrographs , 2011, Bacteriophage.

[100]  C. Rees,et al.  Bacteriophage applications: where are we now? , 2010, Letters in applied microbiology.

[101]  J. Jun,et al.  Bacteriophage Therapy of a Vibrio parahaemolyticus Infection Caused by a Multiple-Antibiotic–Resistant O3:K6 Pandemic Clinical Strain , 2014, The Journal of infectious diseases.

[102]  H. Horz,et al.  Preliminary survey of local bacteriophages with lytic activity against multi‐drug resistant bacteria , 2016, Journal of basic microbiology.

[103]  G. Stewart,et al.  Bacillus anthracis diagnostic detection and rapid antibiotic susceptibility determination using 'bioluminescent' reporter phage. , 2013, Journal of microbiological methods.

[104]  M. Loessner,et al.  Evolutionarily distinct bacteriophage endolysins featuring conserved peptidoglycan cleavage sites protect mice from MRSA infection. , 2015, The Journal of antimicrobial chemotherapy.

[105]  R. Donlan Preventing biofilms of clinically relevant organisms using bacteriophage. , 2009, Trends in microbiology.

[106]  T. Yoshikawa Antimicrobial Resistance and Aging: Beginning of the End of the Antibiotic Era? , 2002, Journal of the American Geriatrics Society.

[107]  J. Soothill Treatment of experimental infections of mice with bacteriophages. , 1992, Journal of medical microbiology.

[108]  Eric V Granowitz,et al.  Antibiotic adverse reactions and drug interactions. , 2008, Critical care clinics.

[109]  S. Sarker,et al.  Coverage of diarrhoea-associated Escherichia coli isolates from different origins with two types of phage cocktails , 2014, Microbial biotechnology.

[110]  J. Soothill,et al.  Experimental Bacteriophage Protection against Staphylococcus aureus Abscesses in a Rabbit Model , 2005, Antimicrobial Agents and Chemotherapy.

[111]  B. Koskella,et al.  Understanding Bacteriophage Specificity in Natural Microbial Communities , 2013, Viruses.