Abstract
Interest in phage therapy continues to intensify, driven in part by the threat of global antimicrobial multidrug resistance. However, there is uncertainty whether the phage therapy approaches – mainly, industrial fixed cocktails or, alternatively, personalized tailor-made phage products – can be clinically safe and efficacious. The adoption of separate regulatory protocols in EU Member States, with subsequent treatment experience gained in selected patients, supports the need for collecting high-standard clinical trial data. Since regulatory oversight will be a crucial determinant for successful introduction of bacteriophages into clinical practice, the main regulatory prerequisites for phage therapeutic development are highlighted.
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References
Abedon ST, Thomas-Abedon C (2010) Phage therapy pharmacology. Curr Pharm Biotechnol 11(1):28–47
Abedon ST, Kuhl SJ, Blasdel BG et al (2011) Phage treatment of human infections. Bacteriophage 1(2):66–85
Borysowski J, Ehni H-J, Gorski A (2017) Ethics review in compassionate use. BMC Med 15:136
Breederveld RS (2019) Phage therapy 2.0. Where do we stand? Lancet Infect Dis 19(1):2–3
Castillo DE, Nanda S, Keri JE (2019) Propionibacterium (Cutibacterium) acnes bacteriophage therapy in acne: current evidence and future perspectives. Dermatol Ther (Heidelberg) 9(1):19–31
Chan BK, Abedon ST (2015) Bacteriophages and their enzymes in biofilm control. Curr Pharm Des 21:85–99
Chan BK, Turner PE, Kim S et al (2018) Phage treatment of an aortic graft infected with Pseudomonas aeruginosa. Evol Med Public Health 1:60–66. https://doi.org/10.1093/emph/eoy005
d’Herelle F (1919) Sur le rôle du microbe bactériophage dans la typhose aviaire. C R Acad Sci 169:932–934
Dąbrowska K (2019) Phage therapy: what factors shape phage pharmacokinetics and bioavailability? Systematic and critical review. Med Res Rev 39:2000–2025
Dedrick RM, Guerrero-Bustamante CA, Garlena RA, Russell DA et al (2019) Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus. Nat Med 25:730–733
Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EEC. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex%3A32001L0018. Accessed 07 Jan 2020
Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_83_cons2009/2001_83_cons2009_en.pdf. Accessed 07 Jan 2020
European Commission (2008) Annex 1: manufacture of sterile medicinal products. In: EudraLex – the rules governing medicinal products in the European Union, Volume 4: EU guidelines to good manufacturing practice, medicinal products for human and veterinary use. http://www.ec.europa.eu/health/files/eudralex/vol-4/2008_11_25_gmp-an1_en.pdf. Accessed 07 Jan 2020
European Medicines Agency (1998) International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use, Committee for Proprietary Medicinal Products (1998). CHMP/ICH Q5D note for guidance on quality of biotechnology products: derivation and characterisation of cell substrates used for production of biotechnological/biological products (CPMP/ICH/294/95). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003280.pdf. Accessed 07 Jan 2020
European Medicines Agency (2020) Human regulatory/research and development/scientific guidelines. https://www.ema.europa.eu/en/human-regulatory/research-development/scientific-guidelines. Accessed 07 Jan 2020
European Union (2004) Regulation (EC) No 726/2004 of the European Parliament and Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2004_726/reg_2004_726_en.pdf. Accessed 07 Jan 2020
European Union (2007) Regulation (EC) No 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004. https://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2007:324:0121:0137:en:PDF. Accessed 07 Jan 2020
European Union (2008) Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/reg_2008_1234_cons_2012-11-02/reg_2008_1234_cons_2012-11-02_en.pdf. Accessed 07 Jan 2020
European Union (2014) Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC. https://ec.europa.eu/health//sites/health/files/files/eudralex/vol-1/reg_2014_536/reg_2014_536_en.pdf. Accessed 07 Jan 2020
Fauconnier A (2017) Regulating phage therapy: the biological master file concept could help to overcome regulatory challenge of personalized medicines. EMBO Rep 18:198–200. https://doi.org/10.15252/embr.201643250
Fischetti VA (2018) Development of phage lysins as novel therapeutics: a historical perspective. Viruses 10:310. https://doi.org/10.3390/v10060310
Fischetti VA (2019) Lysin therapy offers new hope for fighting drug-resistant bacteria. Science News, February 1. https://www.rockefeller.edu/news/24920-lysin-therapy-offers-new-hope-fighting-drug-resistant-bacteria/. Accessed 07 Jan 2020
Gordillo Altamirano F, Barr JJ (2019) Phage therapy in the postantibiotic era. Clin Microbiol Rev 32:e00066–e00018
Górski A, Międzybrodzki R, Łobocka M et al (2018) Phage therapy: what have we learned ? Viruses 10(6):288. https://doi.org/10.3390/v10060288
Harper DR (2018) Criteria for selecting suitable infectious diseases for phage therapy. Viruses 10(4):177. https://doi.org/10.3390/v10040177
Harper DR, Parracho HMRT, Walker J et al (2014) Bacteriophages and biofilms. Antibiotics 3:270–284. https://doi.org/10.3390/antibiotics3030270
Hodyra-Stefaniak K, Miernikiewicz P, Drapała J et al (2015) Mammalian host-versus-phage immune response determines phage fate in vivo. Sci Rep 5:14802. https://doi.org/10.1038/srep14802
Imanishi I, Uchiyama J, Tsukui T et al (2019) Therapeutic potential of an endolysin derived from Kayvirus S25-3 for Staphyloccocal impetigo. Viruses 11(9):76
Jault P, Leclerc T, Jennes S et al (2019) Efficacy and tolerability of a cocktail of bacteriophages to treat burn wounds infected by Pseudomonas aeruginosa (Phagoburn): a randomised, controlled, double-blind phase 1/2 trial. Lancet Infect Dis 19(1):35–45
Jennes S, Merabishvili M, Soentjens P (2017) Use of bacteriophages in the treatment of colistin-only-sensitive Pseudomonas aeruginosa septicaemia in a patient with acute kidney injury – a case report. Crit Care 21:129. https://doi.org/10.1186/s13054-017-1709-y
Kutateladze M (2015) Experience of the Eliava institute in bacteriophage therapy. Virol Sin 30(1):80–81
Lehman SM, Mearns G, Rankin D et al (2019) Design and preclinical development for the treatment of antibiotic-resistant Staphylococcus aureus infections. Viruses 11(1):88
Leitner L, Sybesma W, Chanishvili N et al (2017) Bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: a randomized, placebo-controlled, double-blind clinical trial. BMC Urol 17:90. https://doi.org/10.1186/s12894-017-0283-6
Łusiak-Szelachowska M, Żaczek M, Weber-Dąbrowska B et al (2017) Antiphage activity of sera in patients during phage therapy in relation to its outcome. Future Microbiol 12:109–117
Marza JA, Soothill JS, Boydell P et al (2006) Multiplication of therapeutically administered bacteriophages in Pseudomonas aeruginosa infected patients. Burns 32:644–646
McCallin S, Sacher JC, Zheng J et al (2019) Current state of compassionate phage therapy. Viruses 11(4):343
Międzybrodzki R, Borysowski J, Weber-Dąbrowska B et al (2012) Clinical aspects of phage therapy. Adv Virus Res 83:73–121
Nir-Paz R, Gelman D, Khouri A et al (2019) Successful treatment of antibiotic-resistant, polymicrobial bone infection with bacteriophages and antibiotics combination. Clin Infect Dis 69(11):2015–2018
Oechslin F (2018) Resistance development to bacteriophages occurring during bacteriophage therapy. Viruses 10(7):351
Parfitt T (2005) Georgia: an unlikely stronghold for bacteriophage therapy. Lancet 365(9478):2166–2167
Parracho HM, Burrowes BH, Enright MC et al (2012) The role of regulated clinical trials in the development of bacteriophage therapeutics. J Mol Genet Med 6:279–286
Patey O, McCallin S, Mazure H et al (2019) Clinical indications and compassionate use of phage therapy: personal experience and literature review with a focus on osteoarticular infections. Viruses 11(1):18
Pelfrene E, Willebrand E, Cavaleiro Sanches A et al (2016) Bacteriophage therapy: a regulatory perspective. J Antimicrob Chemother 71:2071–2074. https://doi.org/10.1093/jac/dkw083
Pires DP, Cleto S, Sillankorva S et al (2016) Genetically engineered phages: a review of advances over the last decade. Microbiol Mol Biol Rev 80(3):523–543
Pirnay J-P, De Vos D, Verbeken G et al (2011) The phage therapy paradigm: Prêt-à-Porter or Sur-mesure? Pharm Res 28:934–937
Pirnay J-P, Verbeken G, Ceyssens PJ et al (2018) The magistral phage. Viruses 10:64. https://doi.org/10.3390/v10020064
Principi N, Silvestri E, Esposito S (2019) Advantages and limitations of bacteriophages for the treatment of bacterial infections. Front Pharmacol 10:513. https://doi.org/10.3389/fphar.2019.00513
Regnstrom J, Koenig F, Aronsson B et al (2010) Factors associated with success of market authorisation applications for pharmaceutical drugs submitted to the European Medicines Agency. Eur J Clin Pharmacol 66:39–48
Reindel R, Fiore CR (2017) Phage therapy: considerations and challenges for development. Clin Infect Dis 64:1589–1590
Roach DR, Debarbieux L (2017) Phage therapy: awakening of a sleeping giant. Emerg Top Life Sci 1(1):93–103
Rodríguez-Rubio L, Jofre J, Muniesa M (2017) Is genetic mobilization considered when using bacteriophages in antimicrobial therapy? Antibiotics 6:32. https://doi.org/10.3390/antibiotics6040032
Sarker SA, Sultana S, Reuteler G et al (2016) Oral phage therapy of acute bacterial diarrhea with two coliphages preparations: a randomized trial in children from Bangladesh. eBioMedicine 4:124–137. https://doi.org/10.1016/j.ebiom.2015.12.023
Schooley RT, Biswas B, Gill JJ et al (2017) Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant Acinetobacter baumannii infection. Antimicrob Agents Chemother 61(10):e00954–e00917. https://doi.org/10.1128/AAC.00954-17
Speck P, Smithyman A (2016) Safety and efficacy of phage therapy via the intravenous route. FEMS Microbiol Lett 363:fnv242. https://doi.org/10.1093/femsle/fnv242
Sulakvelidze A, Alavidze Z, Morris JG Jr (2001) Bacteriophage therapy. Antimicrob Agents Chemother 45:649–659. https://doi.org/10.1128/AAC.45.3.649-659.2001
Tan SY, Tatsumura Y (2015) Alexander Fleming: discoverer of penicillin. Singap Med J 56(7):366–367
Torres-Barceló C, Hochberg ME (2016) Evolutionary rationale for phages as complements of antibiotics. Trends Microbiol 24(4):249–256
Totté J, de Wit J, Pardo L et al (2017) Targeted anti-staphylococcal therapy with endolysins in atopic dermatitis and the effect on steroid use, disease severity and the microbiome: study protocol for a randomized controlled trial (MAAS trial). Trials 18:404. https://doi.org/10.1186/s13063-017-2118-x
Vandenheuvel D, Singh A, Vandersteegen K et al (2013) Feasibility of spray drying bacteriophages into respirable powders to combat pulmonary bacterial infections. Eur J Biopharm 84:578–582
Wienhold S-M, Lienau J, Witzenrath M (2019) Towards inhaled phage therapy in Western Europe. Viruses 11(3):295
Wittebole X, De Roock S, Opal SM (2014) A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens. Virulence 5:226–235
Wright A, Hawkins CH, Anggård EE et al (2009) A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin Otolaryngol 34:349–357
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Pelfrene, E., Sebris, Z., Cavaleri, M. (2021). Regulatory Aspects of the Therapeutic Use of Bacteriophages: Europe. In: Harper, D.R., Abedon, S.T., Burrowes, B.H., McConville, M.L. (eds) Bacteriophages. Springer, Cham. https://doi.org/10.1007/978-3-319-41986-2_51
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