This perspective paper follows up on earlier communications on bacteriophage therapy that we wrote as a multidisciplinary and intercontinental expert-panel when we first met at a bacteriophage conference hosted by the Eliava Institute in Tbilisi, Georgia in 2015. In the context of a society that is confronted with an ever-increasing number of antibiotic-resistant bacteria, we build on the previously made recommendations and specifically address how the Nagoya Protocol might impact the further development of bacteriophage therapy. By reviewing a number of recently conducted case studies with bacteriophages involving patients with bacterial infections that could no longer be successfully treated by regular antibiotic therapy, we again stress the urgency and significance of the development of international guidelines and frameworks that might facilitate the legal and effective application of bacteriophage therapy by physicians and the receiving patients. Additionally, we list and comment on several recently started and ongoing clinical studies, including highly desired double-blind placebo-controlled randomized clinical trials. We conclude with an outlook on how recently developed DNA editing technologies are expected to further control and enhance the efficient application of bacteriophages.

Department of Biological Sciences Cork Institute of Technology Bishopstown Cork T12 P928 UK

Department of Experimental Biology Faculty of Science Masaryk University Brno 611 37 Czech Republic

Department of Fundamental Microbiology University of Lausanne CH 1015 Lausanne Switzerland

Department of Neuro Urology Balgrist University Hospital University of Zürich CH 8008 Zürich Switzerland

Eliava Institute of Bacteriophage Microbiology and Virology Tbilisi 0160 Georgia

GeneCology Research Centre and the Faculty of Science Health Education and Engineering University of the Sunshine Coast Maroochydore DC QLD 4558 Australia

Laboratory for Molecular and Cellular Technology Queen Astrid Military Hospital B 1120 Brussels Belgium

Leibniz Institute DSMZ German Collection of Microorganisms and Cell Cultures D 38124 Braunschweig Germany

Nestlé Research Center Nestec Ltd Vers chez les Blanc CH 1000 Lausanne Switzerland

School of Medicine and Dentistry University of Aberdeen Aberdeen AB25 2ZD UK

School of Pharmacy and Biomolecular Sciences and School of Environment and Technology University of Brighton Brighton BN2 4GJ UK

Zobrazit více v PubMed

Aminov R. History of antimicrobial drug discovery: Major classes and health impact. Biochem. Pharmacol. 2017;133:4–19. doi: 10.1016/j.bcp.2016.10.001. PubMed DOI

Aminov R.I. A brief history of the antibiotic era: Lessons learned and challenges for the future. Front. Microbiol. 2010;1:134. doi: 10.3389/fmicb.2010.00134. PubMed DOI PMC

Centers for Disease Control and Prevention . Antibiotic Resistance Threats in the United States, 2013. Centers for Disease Control and Prevention; Atlanta, GA, USA: 2013.

European Centre for Disease Prevention and Control. European Food Safety Authority. European Medicines Agency Ecdc/efsa/ema second joint report on the integrated analysis of the consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from humans and food-producing animals. EFSA J. 2017;15:e04872. doi: 10.2903/j.efsa.2017.4872. PubMed DOI PMC

Organization W.H. Global Action Plan on Antimicrobial Resistance. WHO; Geneva, Switzerland: 2015.

O’Neill J. Tackling Drug–Resistant Infections Globally: Final Report and Recommendations. [(accessed on 18 April 2018)]; Available online: http://www.iica.int/en/press/news/tackling-drug-resistant-infections-globally-final-report-and-recommendations.

Expert round-table on acceptance and re–implementation of bacteriophage therapy Silk route to the acceptance and re-implementation of bacteriophage therapy. Biotechnol. J. 2016;11:595–600. PubMed

Servick K. Beleaguered phage therapy trial presses on. Science. 2016;352:1506. doi: 10.1126/science.352.6293.1506. PubMed DOI

PhagoBurn Evaluation of Phage Therapy for the Treatment of Escherichia coli and Pseudomonas aeruginosa Burn Wound Infections. [(accessed on 18 April 2018)]; Available online: http://www.phagoburn.eu/

Sarker S.A., Sultana S., Reuteler G., Moine D., Descombes P., Charton F., Bourdin G., McCallin S., Ngom-Bru C., Neville T. Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: A randomized trial in children from bangladesh. EBioMedicine. 2016;4:124–137. doi: 10.1016/j.ebiom.2015.12.023. PubMed DOI PMC

Międzybrodzki R., Borysowski J., Weber-Dąbrowska B., Fortuna W., Letkiewicz S., Szufnarowski K., Pawełczyk Z., Rogóż P., Kłak M., Wojtasik E. Chapter 3–Clinical aspects of phage therapy. In: Łobocka M., Szybalski W., editors. Advances in Virus Research. Volume 83. Academic Press; Cambridge, MA, USA: 2012. pp. 73–121. PubMed

Abedon S.T., García P., Mullany P., Aminov R. Editorial: Phage therapy: past, present and future. Front. Microbiol. 2017;8:981. doi: 10.3389/fmicb.2017.00981. PubMed DOI PMC

McCallin S., Alam Sarker S., Barretto C., Sultana S., Berger B., Huq S., Krause L., Bibiloni R., Schmitt B., Reuteler G. Safety analysis of a russian phage cocktail: From metagenomic analysis to oral application in healthy human subjects. Virology. 2013;443:187–196. doi: 10.1016/j.virol.2013.05.022. PubMed DOI

Leitner L., Sybesma W., Chanishvili N., Goderdzishvili M., Chkhotua A., Ujmajuridze A., Schneider M.P., Sartori A., Mehnert U., Bachmann L.M. Bacteriophages for treating urinary tract infections in patients undergoing transurethral resection of the prostate: A randomized, placebo-controlled, double-blind clinical trial. BMC Urol. 2017;17:90. doi: 10.1186/s12894-017-0283-6. PubMed DOI PMC

Ujmajuridze A., Chanishvili N., Goderdzishvili M., Leitner L., Mehnert U., Chkhotua A., Kessler T., Sybesma W. Adapted bacteriophages for treating urinary tract infections. 2018 Submitted for publication. PubMed PMC

Górski A., Międzybrodzki R., Weber-Dąbrowska B., Fortuna W., Letkiewicz S., Rogóż P., Jończyk-Matysiak E., Dąbrowska K., Majewska J., Borysowski J. Phage therapy: Combating infections with potential for evolving from merely a treatment for complications to targeting diseases. Front. Microbiol. 2016;7:1515. doi: 10.3389/fmicb.2016.01515. PubMed DOI PMC

Saussereau E., Vachier I., Chiron R., Godbert B., Sermet I., Dufour N., Pirnay J.P., De Vos D., Carrié F., Molinari N. Effectiveness of bacteriophages in the sputum of cystic fibrosis patients. Clin. Microbiol. Infect. 2014;20:O983–O990. doi: 10.1111/1469-0691.12712. PubMed DOI

Bernstein L.J., Ochs H.D., Wedgwood R.J., Rubinstein A. Defective humoral immunity in pediatric acquired immune deficiency syndrome. J. Pediatr. 1985;107:352–357. doi: 10.1016/S0022-3476(85)80505-9. PubMed DOI

Rhoads D.D., Wolcott R.D., Kuskowski M.A., Wolcott B.M., Ward L.S., Sulakvelidze A. Bacteriophage therapy of venous leg ulcers in humans: Results of a phase i safety trial. J. Wound Care. 2009;18:237–243. doi: 10.12968/jowc.2009.18.6.42801. PubMed DOI

Duplessis C., Biswas B., Hanisch B., Perkins M., Henry M., Quinones J., Wolfe D., Estrella L., Hamilton T. Refractory pseudomonas bacteremia in a 2-year-old sterilized by bacteriophage therapy. J. Pediatr. Infect. Dis. Soc. 2017 doi: 10.1093/jpids/pix056. PubMed DOI

Schooley R.T., Biswas B., Gill J.J., Hernandez-Morales A., Lancaster J., Lessor L., Barr J.J., Reed S.L., Rohwer F., Benler S. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with a disseminated resistant acinetobacter baumannii infection. Antimicrob. Agents Chemother. 2017;61:e00954-17. doi: 10.1128/AAC.00954-17. PubMed DOI PMC

Zhvania P., Hoyle N.S., Nadareishvili L., Nizharadze D., Kutateladze M. Phage therapy in a 16-year-old boy with netherton syndrome. Front. Med. 2017;4:94. doi: 10.3389/fmed.2017.00094. PubMed DOI PMC

Jennes S., Merabishvili M., Soentjens P., Pang K.W., Rose T., Keersebilck E., Soete O., François P.-M., Teodorescu S., Verween G. 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. 2017;21:129. doi: 10.1186/s13054-017-1709-y. PubMed DOI PMC

Fish R., Kutter E., Wheat G., Blasdel B., Kutateladze M., Kuhl S. Bacteriophage treatment of intransigent diabetic toe ulcers: A case series. J. Wound Care. 2016;25:S27–S33. doi: 10.12968/jowc.2016.25.Sup7.S27. PubMed DOI

Soothill J. Use of bacteriophages in the treatment of pseudomonas aeruginosa infections. Expert Rev. Anti-Infect. Ther. 2013;11:909–915. doi: 10.1586/14787210.2013.826990. PubMed DOI

Khawaldeh A., Morales S., Dillon B., Alavidze Z., Ginn A.N., Thomas L., Chapman S.J., Dublanchet A., Smithyman A., Iredell J.R. Bacteriophage therapy for refractory pseudomonas aeruginosa urinary tract infection. J. Med. Microbiol. 2011;60:1697–1700. doi: 10.1099/jmm.0.029744-0. PubMed DOI

Letkiewicz S., Międzybrodzki R., Fortuna W., Weber-Dąbrowska B., Górski A. Eradication of enterococcus faecalis by phage therapy in chronic bacterial prostatitis—Case report. Folia Microbiol. 2009;54:457–461. doi: 10.1007/s12223-009-0064-z. PubMed DOI

Fadlallah A., Chelala E., Legeais J.-M. Corneal infection therapy with topical bacteriophage administration. Open Ophthalmol. J. 2015;9:167–168. doi: 10.2174/1874364101509010167. PubMed DOI PMC

Jikia D., Chkhaidze N., Imedashvili E., Mgaloblishvili I., Tsitlanadze G., Katsarava R., Glenn Morris J., Sulakvelidze A. The use of a novel biodegradable preparation capable of the sustained release of bacteriophages and ciprofloxacin, in the complex treatment of multidrug-resistant staphylococcus aureus-infected local radiation injuries caused by exposure to sr90. Clin. Exp. Dermatol. 2005;30:23–26. doi: 10.1111/j.1365-2230.2004.01600.x. PubMed DOI

Leszczyński P., Weber-Dabrowska B., Kohutnicka M., Łuczak M., Górecki A., Górski A. Successful eradication of methicillin-resistantstaphylococcus aureus (MRSA) intestinal carrier status in a healthcare worker—Case report. Folia Microbiol. 2006;51:236–238. doi: 10.1007/BF02932128. PubMed DOI

Fevre C., Ferry T., Petitjean C., Leboucher C., L’hostis G., Laurent F., Regulski K. Phages-sur-Yvette. Gif-sur-Yvette; Essonne, France: 2017. Phage therapy: Compassionate use in france in 2017.

Verbeken G., Pirnay J.P., De Vos D., Jennes S., Zizi M., Lavigne R., Casteels M., Huys I. Optimizing the european regulatory framework for sustainable bacteriophage therapy in human medicine. Arch. Immunol. Ther. Exp. 2012;60:161–172. doi: 10.1007/s00005-012-0175-0. PubMed DOI

Pirnay J.-P., Verbeken G., Ceyssens P.-J., Huys I., De Vos D., Ameloot C., Fauconnier A. The magistral phage. Viruses. 2018;10:64. doi: 10.3390/v10020064. PubMed DOI PMC

Young R., Gill J.J. Microbiology. Phage therapy redux–What is to be done? Science. 2015;350:1163–1164. doi: 10.1126/science.aad6791. PubMed DOI PMC

Debarbieux L., Pirnay J.-P., Verbeken G., De Vos D., Merabishvili M., Huys I., Patey O., Schoonjans D., Vaneechoutte M., Zizi M. A bacteriophage journey at the european medicines agency. FEMS Microbiol. Lett. 2015;363 doi: 10.1093/femsle/fnv225. PubMed DOI PMC

Nagel T.E., Chan B.K., De Vos D., El-Shibiny A., Kang’ethe E.K., Makumi A., Pirnay J.-P. The developing world urgently needs phages to combat pathogenic bacteria. Front. Microbiol. 2016;7:882. doi: 10.3389/fmicb.2016.00882. PubMed DOI PMC

Van Zimmeren E., Vanneste S., Matthijs G., Vanhaverbeke W., Van Overwalle G. Patent pools and clearinghouses in the life sciences. Trends Biotechnol. 2011;29:569–576. doi: 10.1016/j.tibtech.2011.06.002. PubMed DOI PMC

Inoue M., Minghui R. Antimicrobial resistance: Translating political commitment into national action. Bull. World Health Organ. 2017;95 doi: 10.2471/blt.17.191890. PubMed DOI PMC

Johansen E. Future access and improvement of industrial lactic acid bacteria cultures. Microb. Cell Fact. 2017;16:230. doi: 10.1186/s12934-017-0851-1. PubMed DOI PMC

Overmann J., Scholz A.H. Microbiological research under the nagoya protocol: Facts and fiction. Trends Microbiol. 2017;25:85–88. doi: 10.1016/j.tim.2016.11.001. PubMed DOI

Smith D., da Silva M., Jackson J., Lyal C. Explanation of the nagoya protocol on access and benefit sharing and its implication for microbiology. Microbiology. 2017;163:289–296. doi: 10.1099/mic.0.000425. PubMed DOI

McCluskey K., Barker K.B., Barton H.A., Boundy-Mills K., Brown D.R., Coddington J.A., Cook K., Desmeth P., Geiser D., Glaeser J.A. The U.S. Culture collection network responding to the requirements of the nagoya protocol on access and benefit sharing. mBio. 2017;8 doi: 10.1128/mBio.00982-17. PubMed DOI PMC

Kiro R., Shitrit D., Qimron U. Efficient engineering of a bacteriophage genome using the type i-e crispr-cas system. RNA Biol. 2014;11:42–44. doi: 10.4161/rna.27766. PubMed DOI PMC

Bari S.M.N., Walker F.C., Cater K., Aslan B., Hatoum-Aslan A. Strategies for editing virulent staphylococcal phages using crispr-cas10. ACS Synth. Biol. 2017;6:2316–2325. doi: 10.1021/acssynbio.7b00240. PubMed DOI PMC

Pouillot F., Blois H., Iris F. Genetically engineered virulent phage banks in the detection and control of emergent pathogenic bacteria. Biosecur. Bioterror. 2010;8:155–169. doi: 10.1089/bsp.2009.0057. PubMed DOI PMC

Oślizło A., Miernikiewicz P., Piotrowicz A., Owczarek B., Kopciuch A., Figura G., Dąbrowska K. Purification of phage display-modified bacteriophage T4 by affinity chromatography. BMC Biotechnol. 2011;11:59. doi: 10.1186/1472-6750-11-59. PubMed DOI PMC

Vitiello C.L., Merril C.R., Adhya S. An amino acid substitution in a capsid protein enhances phage survival in mouse circulatory system more than a 1000-fold. Virus Res. 2005;114:101–103. doi: 10.1016/j.virusres.2005.05.014. PubMed DOI

Fagen J.R., Collias D., Singh A.K., Beisel C.L. Advancing the design and delivery of crispr antimicrobials. Curr. Opin. Biomed. Eng. 2017;4:57–64. doi: 10.1016/j.cobme.2017.10.001. DOI

Cross A. Endotoxin: Back to the future. Crit. Care Med. 2016;44:450–451. doi: 10.1097/CCM.0000000000001440. PubMed DOI PMC

Martel B., Moineau S. Crispr-cas: An efficient tool for genome engineering of virulent bacteriophages. Nucleic Acids Res. 2014;42:9504–9513. doi: 10.1093/nar/gku628. PubMed DOI PMC

Box A.M., McGuffie M.J., O’Hara B.J., Seed K.D. Functional analysis of bacteriophage immunity through a type i-e crispr-cas system in vibrio cholerae and its application in bacteriophage genome engineering. J. Bacteriol. 2016;198:578–590. doi: 10.1128/JB.00747-15. PubMed DOI PMC

Lemay M.-L., Tremblay D.M., Moineau S. Genome engineering of virulent lactococcal phages using crispr-cas9. ACS Synth. Biol. 2017;6:1351–1358. doi: 10.1021/acssynbio.6b00388. PubMed DOI

Tao P., Wu X., Tang W.-C., Zhu J., Rao V. Engineering of bacteriophage t4 genome using crispr-cas9. ACS Synth. Biol. 2017;6:1952–1961. doi: 10.1021/acssynbio.7b00179. PubMed DOI PMC

Luo M.L., Leenay R.T., Beisel C.L. Current and future prospects for crispr-based tools in bacteria. Biotechnol. Bioeng. 2016;113:930–943. doi: 10.1002/bit.25851. PubMed DOI PMC

Bardy P., Pantucek R., Benesik M., Doskar J. Genetically modified bacteriophages in applied microbiology. J. Appl. Microbiol. 2016;121:618–633. doi: 10.1111/jam.13207. PubMed DOI

Golan T., Milella M., Ackerstein A., Berger R. The changing face of clinical trials in the personalized medicine and immuno-oncology era: Report from The International Congress on Clinical Trials in Oncology & Hemato–Oncology (Icto 2017) J. Exp. Clin. Cancer Res. 2017;36:192. PubMed PMC