Abstract
With the recognition of the threat posed by bacterial multi-drug resistance, the bacteriophage treatment concept has been revived as an alternative in the armamentarium. Over the last decade, research efforts on bacteriophage therapy have intensified, and stakeholders have called upon regulatory authorities in trying to define a bespoke licensing pathway for bacteriophages which would not adversely affect the standards required for quality, safety and efficacy. In this context, and in particular concerning the use of personalised phage cocktails, the concept of “hybrid licensing”, with patient-specific phage therapy selected from a local pre-authorised phage library, has recently been advanced. To date, however, and notwithstanding encouraging data, important knowledge gaps remain regarding the safe and effective administration of bacteriophages. Therefore, generation of further scientifically robust data concerning proposed bacteriophage therapies as well as extensive stakeholder consultation, including engagement with relevant competent authorities, would be important in facilitating bacteriophage therapeutic development and its successful introduction into the clinic.
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References
Briers Y, Walmagh M, Van Puyenbroeck V et al (2014) Engineered endolysin-based “Artilysins” to combat multidrug-resistant gram-negative pathogens. MBio 5:e01379–e01314. https://doi.org/10.1128/mBio.01379-14
Bruttin A, Brüssow H (2005) Human volunteers receiving Escherichia coli phage T4 orally: a safety test of phage therapy. Antimicrob Agents Chemother 49:2874–2878
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
Cooper CJ, Khan Mirzaei M, Nilsson AS (2016) Adapting drug approval pathways for bacteriophage-based therapeutics. Front Microbiol 7:1209. https://doi.org/10.3389/fmicb.2016.01209
Czaplewski L, Bax R, Clokie M et al (2016) Alternatives to antibiotics—a pipeline portfolio review. Lancet Infect Dis 16:239–251
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 25 Aug 2018
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 25 Aug 2018
Dufour N, Delattre R, Ricard J-D et al (2017) The lysis of pathogenic Escherichia coli by bacteriophages releases less endotoxin than by β-lactams. Clin Infect Dis 64:1582–1588
Eichler H-G, Baird LG, Barker R et al (2015) From adaptive licensing to adaptive pathways: delivering a flexible life-span approach to bring new drugs to patients. Clin Pharmacol Ther 97(3):234–246
European Medicines Agency (2015) Guideline on influenza vaccines – submission and procedural requirements. http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2015/07/WC500189035.pdf. Accessed 25 Aug 2018
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 25 Aug 2018
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 25 Aug 2018
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 25 Aug 2018
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
Fish R, Kutter E, Wheat G et al (2016) Bacteriophage treatment of intransigent diabetic toe ulcers: a case series. J Wound Care 25(Suppl 7):S27-33. https://doi.org/10.12968/jowc.2016.25.7.S27
Górski A, Dąbrowska K, Międzybrodzki R et al (2017) Phages and immunomodulation. Future Microbiol 12(10). https://doi.org/10.2217/fmb-2017-0049
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
Hong Y, Thimmapuram J, Zhang J et al (2016) The impact of orally administered phages on host immune response and surrounding microbial communities. Bacteriophage 6(3):e1211066. https://doi.org/10.1080/21597081.2016.1211066
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
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, Sarker SA, Barretto C et al (2013) Safety analysis of a Russian phage cocktail: from metagenomic analysis to oral application in healthy human subjects. Virology 443:187–196. https://doi.org/10.1016/j.virol.2013.05.022
Nilsson AS (2014) Phage therapy – constraints and possibilities. Ups J Med Sci 119:192–198
O’Flaherty S, Ross RP, Coffey A (2009) Bacteriophage and their lysins for elimination of infectious bacteria. FEMS Microbiol Rev 33:801–819
Parracho HMRT, 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
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
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
Reindel R, Fiore CR (2017) Phage therapy: considerations and challenges for development. Clin Infect Dis 64:1589–1590
Rhoads DD, Wolcott RD, Kuskowski MA et al (2009) Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial. J Wound Care 18:237–238, 240–243
Sarker SA, McCallin S, Barretto C et al (2012) Oral T4-like phage cocktail application to healthy adult volunteers from Bangladesh. Virology 434:222–232. https://doi.org/10.1016/j.virol.2012.09.002
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
Schuch R, Khan BK, Raz A et al (2017) Bacteriophage lysin CF-301, a potent antistaphylococcal biofilm agent. Antimicrob Agents Chemother 61(7):e02666–e02616. https://doi.org/10.1128/AAC.02666-16
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
Tetz G, Tetz V (2016) Bacteriophage infections of microbiota can lead to leaky gut in an experimental rodent model. Gut Pathog 8:33. https://doi.org/10.1186/s13099-016-0109-1
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. (2019). Developing Phages into Medicines for Europe. In: Górski, A., Międzybrodzki, R., Borysowski, J. (eds) Phage Therapy: A Practical Approach. Springer, Cham. https://doi.org/10.1007/978-3-030-26736-0_14
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