Phage therapy for severe bacterial infections: a narrative review

Petrovic Fabijan, Aleksandra; Khalid, Ali; Maddocks, Susan; Ho, Josephine; Gilbey, Timothy; Sandaradura, Indy; Lin, Ruby CY; Ben Zakour, Nouri; Venturini, Carola; Bowring, Bethany; Iredell, Jonathan R

doi:10.5694/mja2.50355

Topics

Infectious diseases

Summary

Bacteriophage (phage) therapy is re‐emerging a century after it began.
Activity against antibiotic‐resistant pathogens and a lack of serious side effects make phage therapy an attractive treatment option in refractory bacterial infections.
Phages are highly specific for their bacterial targets, but the relationship between in vitro activity and in vivo efficacy remains to be rigorously evaluated.
Pharmacokinetic and pharmacodynamic principles of phage therapy are generally based on the classic predator–prey relationship, but numerous other factors contribute to phage clearance and optimal dosing strategies remain unclear.
Combinations of fully characterised, exclusively lytic phages prepared under good manufacturing practice are limited in their availability.
Safety has been demonstrated but randomised controlled trials are needed to evaluate efficacy.

1 Centre for Infectious Diseases and Microbiology, Westmead Hospital, Sydney, NSW
2 Westmead Institute for Medical Research, Sydney, NSW
3 University of Sydney, Sydney, NSW
4 Westmead Hospital, Sydney, NSW
5 Wagga Wagga Base Hospital, Wagga Wagga, NSW

Correspondence: jonathan.iredell@sydney.edu.au

Acknowledgements:

This work is supported by grants (1104232 and 1107322) from the Australian National Health and Medical Research Council. AmpliPhi Biosciences Corporation partially contributed to the funding of a bacteriophage therapy investigator‐led clinical trial at Westmead Hospital and Westmead Institute for Medical Research.

Competing interests:

No relevant disclosures.

1. Hankin EH. L'action bactéricide des eaux de la Jumna et du Gange sur le vibrion du choléra. Ann Inst Pasteur (Paris) 1896; 10: 511–523.
2. Twort FW. An investigation on the nature of ultra‐microscopic viruses. Lancet 1915; 186: 1241–1243.
3. Keen EC. Phage therapy: concept to cure. Front Microbiol 2012; 3: 238.
4. d'Herelle F. Sur un microbe invisible antagoniste des bacilles dysentériques. Comptes Rendus Acad Sci Paris 1917; 165: 173–175.
5. d'Herelle F. Bacteriophage as a treatment in acute medical and surgical infections. Bull N Y Acad Med 1931; 7: 329–348.
6. Ruska H. Ergebnisse der Bakteriophagenforschung und ihre Deutung nach morphologischen Befunden. Ergeb Hyg Bakteriol Immunforsch Exp Ther 1943; 25: 437–498.
7. Simmonds P, Aiewsakun P. Virus classification — where do you draw the line? Arch Virol 2018; 163: 2037–2046.
8. Clokie MR, Millard AD, Letarov AV, Heaphy S. Phages in nature. Bacteriophage 2011; 1: 31–45.
9. Aslam B, Wang W, Arshad MI, et al. Antibiotic resistance: a rundown of a global crisis. Infect Drug Resist 2018; 11: 1645–1658.
10. Jault P, Leclerc T, Jennes S, et al. 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 2019; 19: 35–45.
11. Lin DM, Koskella B, Lin HC. Phage therapy: an alternative to antibiotics in the age of multi‐drug resistance. World J Gastrointest Pharmacol Ther 2017; 8: 162–173.
12. Chan BK, Abedon ST, Loc‐Carrillo C. Phage cocktails and the future of phage therapy. Future Microbiol 2013; 8: 769–783.
13. Debarbieux L, Pirnay JP, Verbeken G, et al. A bacteriophage journey at the European Medicines Agency. FEMS Microbiol Lett 2016; 363: fnv225.
14. Furfaro LL, Payne MS, Chang BJ. Bacteriophage therapy: clinical trials and regulatory hurdles. Front Cell Infect Microbiol 2018; 8: 376.
15. Pelfrene E, Willebrand E, Cavaleiro Sanches A, et al. Bacteriophage therapy: a regulatory perspective. J Antimicrob Chemother 2016; 71: 2071–2074.
16. Gorski A, Jonczyk‐Matysiak E, Lusiak‐Szelachowska M, et al. The potential of phage therapy in sepsis. Front Immunol 2017; 8: 1783.
17. Patey O, McCallin S, Mazure H, et al. Clinical indications and compassionate use of phage therapy: personal experience and literature review with a focus on osteoarticular infections. Viruses 2018; 11: E18.
18. Fish R, Kutter E, Wheat G, et al. Bacteriophage treatment of intransigent diabetic toe ulcers: a case series. J Wound Care 2016; 25: S27–S33.
19. Letkiewicz S, Międzybrodzki R, Fortuna W, et al. Eradication of Enterococcus faecalis by phage therapy in chronic bacterial prostatitis — case report. Folia Microbiol 2009; 54: 457–461.
20. Letkiewicz S, Międzybrodzki R, Kłak M, et al. Pathogen eradication by phage therapy in patients with chronic bacterial prostatitis. Eur Urol Suppl 2010; 9: 140.
21. Letkiewicz S, Międzybrodzki R, Kłak M, et al. The perspectives of the application of phage therapy in chronic bacterial prostatitis. Fems Immunol Med Mic 2010; 60: 99–112.
22. Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM. Phage treatment of human infections. Bacteriophage 2011; 1: 66–85.
23. Sulakvelidze A, Alavidze Z, Morris JG. Bacteriophage therapy. Antimicrob Agents Chemother 2001; 45: 649–659.
24. Chanishvili N. Phage therapy — history from Twort and d'Herelle through Soviet experience to current approaches. Adv Virus Res 2012; 83: 3–40.
25. Gordillo‐Altamarino FL, Barr JJ. Phage therapy in the postantibiotic era. Clin Microbiol Rev 2019; 32: e00066–18.
26. Monsur KA, Rahman MA, Huq F, et al. Effect of massive doses of bacteriophage on excretion of vibrios, duration of diarrhoea and output of stools in acute cases of cholera. Bull World Health Organ 1970; 42: 723–732.
27. Sarker SA, McCallin S, Barretto C, et al. Oral T4‐like phage cocktail application to healthy adult volunteers from Bangladesh. Virology 2012; 434: 222–232.
28. Wright A, Hawkins CH, Anggard EE, Harper DR. A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic‐resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clinical Otolaryngology 2009; 34: 349–357.
29. Sarker SA, Sultana S, Reuteler G, et al. Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: a randomized trial in children from Bangladesh. EBioMedicine 2016; 4: 124–137.
30. Rhoads DD, Wolcott RD, Kuskowski MA, et al. Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial. J Wound Care 2009; 18: 237–243.
31. Sime‐Ngando T. Environmental bacteriophages: viruses of microbes in aquatic ecosystems. Front Microbiol 2014; 5: 355.
32. Weinbauer MG. Ecology of prokaryotic viruses. FEMS Microbiol Rev 2004; 28: 127–181.
33. Petrovic A, Kostanjsek R, Rakhely G, Knezevic P. The first Siphoviridae family bacteriophages infecting Bordetella bronchiseptica isolated from environment. Microb Ecol 2017; 73: 368–377.
34. Schooley RT, Biswas B, Gill JJ, et al. 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.
35. Lehman SM, Mearns G, Rankin D, et al. Design and preclinical development of a phage product for the treatment of antibiotic‐resistant Staphylococcus aureus infections. Viruses 2019; 11: E88.
36. Iredell JR, Aslam S, Gilbey T, et al. Safety and efficacy of bacteriophage therapy. ID Week 2018, Infectious Diseases Society of America; San Francisco (USA): Oct 3–7; 2018. https://idsa.confex.com/idsa/2018/webprogram/Paper72613.html (viewed Sept 2019).
37. Levin BR, Bull JJ. Population and evolutionary dynamics of phage therapy. Nat Rev Microbiol 2004; 2: 166–173.
38. Abedon ST. Phage therapy: eco‐physiological pharmacology. Scientifica (Cairo) 2014; 2014: 581639.
39. Maslov S, Sneppen K. Population cycles and species diversity in dynamic Kill‐the‐Winner model of microbial ecosystem. Scientific Reports 2017; 7: 39642.
40. Abedon ST. Kinetics of phage‐mediated biocontrol of bacteria. Foodborne Pathog Dis 2009; 6: 807–815.
41. Abedon ST, Thomas‐Abedon C. Phage therapy pharmacology. Curr Pharm Biotechnol 2010; 11: 28–47.
42. Tsonos J, Vandenheuvel D, Briers Y, et al. Hurdles in bacteriophage therapy: deconstructing the parameters. Vet Microbiol 2014; 171: 460–469.
43. Brüssow H. Phage therapy: the Escherichia coli experience. Microbiology 2005; 151: 2133–2140.
44. Dąbrowska K. Phage therapy: what factors shape phage pharmacokinetics and bioavailability? Systematic and critical review. Med Res Rev 2019; 39: 2000–2025.
45. Tsonos J, Vandenheuvel D, Briers Y, et al. Hurdles in bacteriophage therapy: deconstructing the parameters. Vet Microbiol 2014; 171: 460–469.
46. Hodyra‐Stefaniak K, Miernikiewicz P, Drapała J, et al. Mammalian host‐versus‐phage immune response determines phage fate in vivo. Sci Rep 2015; 5: 14802.
47. Chan BK, Sistrom M, Wertz JE, et al. Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. Sci Rep 2016; 6: 26717.
48. Jung LS, Ding T, Ahn J. Evaluation of lytic bacteriophages for control of multidrug‐resistant Salmonella Typhimurium. Ann Clin Microbiol Antimicrob 2017; 16: 66.
49. Ginn AN, Hazelton B, Shoma S, et al. Quantitative multiplexed‐tandem PCR for direct detection of bacteraemia in critically ill patients. Pathology 2017; 49: 304–308.
50. Sieber M, Gudelj I. Do‐or‐die life cycles and diverse post‐infection resistance mechanisms limit the evolution of parasite host ranges. Ecol Lett 2014; 17: 491–498.
51. Khawaldeh A, Morales S, Dillon B, et al. Bacteriophage therapy for refractory Pseudomonas aeruginosa urinary tract infection. J Med Microbiol 2011; 60: 1697–1700.
52. Chan BK, Abedon ST. Chapter 1. Phage therapy pharmacology: phage cocktails. In: Laskin AI, Sariaslani S, Gadd GM, editors. Advances in applied microbiology; volume 78. Salt Lake City, UT: Academic Press, 2012; pp 1–23.
53. Nilsson AS. Phage therapy — constraints and possibilities. Ups J Med Sci 2014; 119: 192–198.
54. Payne RJH, Jansen VAA. Pharmacokinetic principles of bacteriophage therapy. Clin Pharmacokinet 2003; 42: 315–325.
55. Schultz I, Neva FA. Relationship between blood clearance and viruria after intravenous injection of mice and rats with bacteriophage and polioviruses. J Immunol 1965; 94: 833–841.
56. Nishikawa H, Yasuda M, Uchiyama J, et al. T‐even‐related bacteriophages as candidates for treatment of Escherichia coli urinary tract infections. Arch Virol 2008; 153: 507–515.
57. Ryan EM, Alkawareek MY, Donnelly RF, Gilmore BF. Synergistic phage‐antibiotic combinations for the control of Escherichia coli biofilms in vitro. FEMS Immunol Med Microbiol 2012; 65: 395–398.
58. Vidakovic L, Singh PK, Hartmann R, et al. Dynamic biofilm architecture confers individual and collective mechanisms of viral protection. Nat Microbiol 2018; 3: 26–31.
59. Górski A, Międzybrodzki R, Weber‐Dąbrowska B, et al. Phage therapy: combating infections with potential for evolving from merely a treatment for complications to targeting diseases. Front Microbiol 2016; 7: 1515.
60. Merabishvili M, Pirnay JP, Verbeken G, et al. Quality‐controlled small‐scale production of a well‐defined bacteriophage cocktail for use in human clinical trials. PloS One 2009; 4: e4944.
61. McCallin S, Alam Sarker S, Barretto C, et al. Safety analysis of a Russian phage cocktail: from metagenomic analysis to oral application in healthy human subjects. Virology 2013; 443: 187–196.
62. Fauconnier A. Guidelines for bacteriophage product certification. Methods Mol Biol 2018; 1693: 253–268.
63. Carlson K. Appendix: working with bacteriophages: common techniques and methodological approaches. In: Kutter E, Sulakvelidze A, editors. Bacteriophages: biology and applications. Boca Raton, FL: CRC Press, 2005.
64. Dedrick RM, Guerrero‐Bustamante CA, Garlena RA, et al. Engineered bacteriophages for treatment of a patient with a disseminated drug‐resistant Mycobacterium abscessus. Nat Med 2019; 25: 730–733.
65. Fauconnier A. Phage therapy regulation: from night to dawn. Viruses 2019; 11: 352.
66. Pirnay JP, Verbeken G, Ceyssens PJ, et al. The magistral phage. Viruses 2018; 10: 64.
67. Ooi ML, Drilling AJ, Morales S, et al. Safety and tolerability of bacteriophage therapy for chronic rhinosinusitis due to Staphylococcus aureus. JAMA Otolaryngol Head Neck Surg 2019. https://doi.org/10.1001/jamaoto.2019.1191. [Epub ahead of print]
68. Gilbey T, Ho J, Cooley L, et al. Adjunctive bacteriophage therapy for prosthetic valve endocarditis due to Staphylococcus aureus. Med J Aust 2019; 211: 142–143. https://www.mja.com.au/journal/2019/211/3/adjunctive-bacteriophage-therapy-prosthetic-valve-endocarditis-due
69. Petrovic Fabijan A, Lin RCY, Ho J, et al. Safety and tolerability of bacteriophage therapy in severe Staphylococcus aureus infection [preprint]. bioRxiv 619999. https://doi.org/10.1101/619999 (viewed Sept 2019).
70. Law N, Logan C, Yung G, et al. Successful adjunctive use of bacteriophage therapy for treatment of multidrug‐resistant Pseudomonas aeruginosa infection in a cystic fibrosis patient. Infection 2019; 47: 665–668.

Online responses are no longer available. Please refer to our instructions for authors page for more information.