Skip to main content
Log in

Bacteriophages as Therapeutic Preparations: What Restricts Their Application in Medicine

  • REVIEW
  • Published:
Biochemistry (Moscow) Aims and scope Submit manuscript

Abstract

The increasing prevalence of bacterial pathogens with multiple antibiotic resistance requires development of new approaches to control infections. Phage therapy is one of the most promising approaches. In recent years, research organizations and a number of pharmaceutical companies have intensified investigations aimed at developing bacteriophage-based therapeutics. In the United States and European countries, special centers have been established that experimentally apply phage therapy to treat patients who do not respond to antibiotic therapy. This review describes the features of bacteriophages as therapeutic tools, critically discusses the results of clinical trials of bacteriophage preparations, and assesses the prospects for using phage therapy to treat certain types of infectious diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

REFERENCES

  1. D’Herrelle, F. (1935) Bakteriofag i fenomen vyzdorovleniya (The Bacteriophage and the Phenomenon of Cure), Tiflis Gos. Univ., Tiflis.

  2. Chanishvili, N. (2012) Phage therapy – history from Twort and d’Herelle through soviet experience to current approaches, Adv. Virus Res., 83, 4-40.

    Google Scholar 

  3. Pokrovskaya, M. P., Kaganova, L. S., Morozenko, M. A., Bulgakova, A. G., and Skatsenko, E. E. (1941) Lechenie ran bakteriofagami (Treatment of Wounds with Bacteriophages) Medgiz, Moscow, Leningrad.

  4. Tsulukidze, A. P. (1941) Revisiting bacteriophage application techniques in surgical practice, Vest. Khirurga, 6, 679-685.

    Google Scholar 

  5. Kokin, G. A. (1941) The use of bacteriophages in surgery, Sov. Meditsina, 9, 15-18.

    Google Scholar 

  6. Sapir, I. B. (1939) Nablyudeniya i zamechaniya po povodu lecheniya dizenterii bakteriofagom (Observations and Remarks on the Treatment of Dysentery with Bacteriophage) Mosk. Obl. Inst. Infekts. Bolezn., Moscow.

  7. Belikova, M. A. (1941) Experience in using phages to prevent dysentery in the infants and young children of Stalingrad, Zh. Mikrobiol. Epidemiol. Immunol., 5-6, 168-183.

    Google Scholar 

  8. Ermol’eva, Z. V. (1942) Kholera (Cholera), Medgiz, Moscow.

  9. Zhukov-Verezhnikov, N. N., Permitina, L. D., Berillo, E. A., Komissarov, V. P., Bardymov, V. M., Khvoles, A. G., and Ugryumov, L. B. (1978) Study of the therapeutic effect of bacteriophage preparations in the complex treatment of purulent surgical diseases, Sov. Meditsina, 12, 64-66.

    Google Scholar 

  10. Kochetkova, V. A., Mamontov, A. S., Moskovtseva, R. L., Erastova, E. I., Trofimov, E. I., Popov, M. I., and Dzhubalieva, S. K. (1989) Phage therapy of postoperative pyoinflammatory complications in cancer patients, Sov. Meditsina, 6, 23-26.

    Google Scholar 

  11. Bryusov, P. G., Zubritskii, V. F., Islamov, R. N., Nizovoi, A. V., and Fominykh, V. M. (2011) Phage prophylaxis and phage therapy of surgical infections, Voen. -Med. Zhurn., 4, 34-39.

    Google Scholar 

  12. Khairullin, I. N., Pozdeev, O. K., and Shaimardanov, R. Sh. (2002) Efficacy of specific bacteriophages in the treatment and prevention of surgical and postoperative infections, Kazan. Med. Zhurn., 83, 258-261.

    Google Scholar 

  13. Morozova, V. V., Kozlova, Y. N., Ganichev, D. A., and Tikunova, N. V. (2018) Bacteriophage treatment of infected diabetic foot ulcers, Methods Mol. Biol., 1693, 151-158, doi: https://doi.org/10.1007/978-1-4939-7395-8_13.

    Article  CAS  PubMed  Google Scholar 

  14. Schooley, R. T., Biswas, B., Gill, J. J., Hernandez-Morales, A., and Lancaster, J. (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, e00954-17, doi: https://doi.org/10.1128/AAC.00954-17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Chan, B. K., Turner, P. E., Kim, S., Mojibian, H. R., Elefteriades, J. A., and Narayan, D. (2018) Phage treatment of an aortic graft infected with Pseudomonas aeruginosa, Evol. Med. Public Health., 1, 60-66, doi: https://doi.org/10.1093/emph/eoy005.

    Article  Google Scholar 

  16. Onsea, J., Soentjens, P., Djebara, S., Merabishvili, M., Depypere, M., et al. (2019) Bacteriophage application for difficult-to-treat musculoskeletal infections: development of a standardized multidisciplinary treatment protocol, Viruses, 11, 891, doi: https://doi.org/10.3390/v11100891.

    Article  CAS  PubMed Central  Google Scholar 

  17. Dedrick, R. M., Guerrero-Bustamante, C. A., Garlena, R. A., Russell, D. A., Ford, K., et al. (2019) Engineered bacteriophages for treatment of a patient with a disseminated drug-resistant Mycobacterium abscessus, Nat. Med., 25, 730-733, doi: https://doi.org/10.1038/s41591-019-0437-z.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dutilh, B. E., Cassman, N., McNair, K., Sanchez, S. E., Silva, G. G., et al. (2014) A highly abundant bacteriophage discovered in the unknown sequences of human faecal metagenomes, Nat. Commun., 5, 4498, doi: https://doi.org/10.1038/ncomms5498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sausset, R., Petit, M. A., Gaboriau-Routhiau, V., and De Paepe, M. (2020) New insights into intestinal phages, Mucosal Immunol., 13, 205-215, doi: https://doi.org/10.1038/s41385-019-0250-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Górski, A., Wazna, E., Dąbrowska, B. W., Dąbrowska, K., SwitałaJeleń, K., and Miedzybrodzki, R. (2006) Bacteriophage translocation, FEMS Immunol. Med. Microbiol., 46, 313-319, doi: https://doi.org/10.1111/j.1574-695X.2006.00044.x.

    Article  CAS  PubMed  Google Scholar 

  21. Nguyen, S., Baker, K., Padman, B. S., Patwa, R., Dunstan, R. A., et al. (2017) Bacteriophage transcytosis provides a mechanism to cross epithelial cell layers, mBio., 8, e01874-17, doi: https://doi.org/10.1128/mBio.01874-17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Fish, R., Kutter, E., Bryan, D., Wheat, G., and Kuhl, S. (2018) Resolving digital Staphylococcal osteomyelitis using bacteriophage – a case report, Antibiotics (Basel), 7, 87, doi: https://doi.org/10.3390/antibiotics7040087.

    Article  Google Scholar 

  23. Huh, H., Wong, S., St Jean, J., and Slavcev, R. (2019) Bacteriophage interactions with mammalian tissue: therapeutic applications, Adv. Drug Deliv. Rev., 145, 4-17, doi: https://doi.org/10.1016/j.addr.2019.01.003.

    Article  CAS  PubMed  Google Scholar 

  24. Akturk, E., Oliveira, H., Santos, S. B., Costa, S., Kuyumcu, S., Melo, L. D. R., and Azeredo, J. (2019) Synergistic action of phage and antibiotics: parameters to enhance the killing efficacy against mono and dual-species biofilms, Antibiotics (Basel), 8, 103, doi: https://doi.org/10.3390/antibiotics8030103.

    Article  CAS  Google Scholar 

  25. Lin, Y., Chang, R., Britton, W. J., Morales, S., Kutter, E., and Chan, H. K. (2018) Synergy of nebulized phage PEV20 and ciprofloxacin combination against Pseudomonas aeruginosa, Int. J. Pharm., 551, 158-165, doi: https://doi.org/10.1016/j.ijpharm.2018.09.024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Samson, J. E., Magadán, A. H., Sabri, M., and Moineau, S. (2013) Revenge of the phages: defeating bacterial defences, Nat. Rev. Microbiol., 11, 675-687, doi: https://doi.org/10.1038/nrmicro3096.

    Article  CAS  PubMed  Google Scholar 

  27. Basu, S., Agarwal, M., Bhartiya, S. K., Nath, G., and Shukla, V. (2015) An in vivo wound model utilizing bacteriophage therapy of Pseudomonas aeruginosa biofilms, Ostomy Wound Manage., 61, 16-23.

    PubMed  Google Scholar 

  28. Fong, S. A., Drilling, A., Morales, S., Cornet, M. E., Woodworth, B. A., et al. (2017) Activity of bacteriophages in removing biofilms of Pseudomonas aeruginosa isolates from chronic rhinosinusitis patients, Front. Cell. Infect. Microbiol., 7, 418, doi: https://doi.org/10.3389/fcimb.2017.00418.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chan, B. K., Abedon, S. T., and Loc-Carrillo, C. (2013) Phage cocktails and the future of phage therapy, Future Microbiol., 8, 769-783, doi: https://doi.org/10.2217/fmb.13.47.

    Article  CAS  PubMed  Google Scholar 

  30. Yuan, Y., Wang, L., Li, X., Tan, D., Cong, C., and Xu, Y. (2019) Efficacy of a phage cocktail in controlling phage resistance development in multidrug resistant Acinetobacter baumannii, Virus Res., 272, 197734, doi: https://doi.org/10.1016/j.virusres.2019.197734.

    Article  CAS  PubMed  Google Scholar 

  31. Górski, A., Międzybrodzki, R., Łobocka, M., Głowacka-Rutkowska, A., Bednarek, A., et al. (2018) Phage therapy: what have we learned? Viruses, 10, 288, doi: https://doi.org/10.3390/v10060288.

    Article  PubMed Central  Google Scholar 

  32. Łusiak-Szelachowska, M., Zaczek, M., and Weber-Dąbrowska, B. (2014) Phage neutralization by sera of patients receiving phage therapy, Viral Immunol., 27, 295-304, doi: https://doi.org/10.1089/vim.2013.0128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Majewska, J., Beta, W., Lecion, D., Hodyra-Stefaniak, K., Kłopot, A., et al. (2015) Oral application of T4 phage induces weak antibody production in the gut and in the blood, Viruses, 7, 4783-99, doi: https://doi.org/10.3390/v7082845.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hodyra-Stefaniak, K., Miernikiewicz, P., Drapała, J., Drab, M., Jończyk-Matysiak, E. J., et al. (2015) Mammalian host-versus-phage immune response determines phage fate in vivo, Sci. Rep., 5, 14802, doi: https://doi.org/10.1038/srep14802.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Górski, A., Międzybrodzki, R., Borysowski, J., Dąbrowska, K., Wierzbicki, P., et al. (2012) Phage as a modulator of immune responses: practical implications for phage therapy, Adv. Virus Res., 83, 41-71, doi: https://doi.org/10.1016/B978-0-12-394438-2.00002-5.

    Article  CAS  PubMed  Google Scholar 

  36. Górski, A., Międzybrodzki, R., Jończyk-Matysiak, E., Żaczek, M., and Borysowski, J. (2019) Phage-specific diverse effects of bacterial viruses on the immune system, Future Microbiol., 14, 1171-1174, doi: https://doi.org/10.2217/fmb-2019-0222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sinha, A., and Maurice, C. F. (2019) Bacteriophages: uncharacterized and dynamic regulators of the immune system, Mediators Inflamm., 2019, 3730519, doi: https://doi.org/10.1155/2019/3730519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Van Belleghem, J. D., Dąbrowska, K., Vaneechoutte, M., Barr, J., and Bollyky, P. (2018) Interactions between bacteriophage, bacteria, and the mammalian immune system, Viruses, 11, 10, doi: https://doi.org/10.3390/v11010010.

    Article  CAS  PubMed Central  Google Scholar 

  39. Dąbrowska, K., Miernikiewicz, P., Piotrowicz, A., Hodyra, K., Owczarek, B., et al. (2014) Immunogenicity studies of proteins forming the T4 phage head surface, J. Virol., 88, 12551-12557, doi: https://doi.org/10.1128/JVI.02043-14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zaczek, M., Łusiak-Szelachowska, M., Jończyk-Matysiak, E., Weber-Dąbrowska, B., Miedzybrodzki, R., et al. (2016) Antibody production in response to staphylococcal MS-1 phage cocktail in patients undergoing phage therapy, Front. Microbiol., 7, 1-14, doi: https://doi.org/10.3389/fmicb.2016.01681.

    Article  Google Scholar 

  41. Dąbrowska, K. (2019) Phage therapy: what factors shape phagepharmacokinetics and bioavailability? Systematic and critical review, Med. Res. Rev., 1, 1-26, doi: https://doi.org/10.1002/med.21572.

    Article  Google Scholar 

  42. Bochkareva, S. S., Aleshkin, A. V., Ershova, O. N., Novikova, L. I., Karaulov, A. V., Kiseleva, I. A., et al. (2017) Anti-phage antibody response in phage therapy against healthcare-associated infections (HAIs), Infektsionnye Bolezn., 15, 35-40, doi: https://doi.org/10.20953/1729-9225-2017-1-35-40.

    Article  Google Scholar 

  43. Weber-Dąbrowska, B., Zimecki, M., and Mulczyk, M. (2000) Effective phage therapy is associated with normalization of cytokine production by blood cell cultures, Arch. Immunol. Ther. Exp. (Warsz), 48, 31-37.

    Google Scholar 

  44. Roach, D. R., Chollet-martin, S., Noël, B., and Granger, V. (2019) Human neutrophil response to Pseudomonas 3 bacteriophages, BioRxiv, doi: https://doi.org/10.1101/786905.

  45. Roach, D. R., Leung, C. Y., Henry, M., Morello, E., Singh, D., Di Santo, J. P., Weitz, J. S., and Debarbieux, L. (2017) Synergy between the host immune system and bacteriophage is essential for successful phage therapy against an acute respiratory pathogen, Cell Host Microbe, 22, 38-47.e4, doi: https://doi.org/10.1016/j.chom.2017.06.018.

    Article  CAS  PubMed  Google Scholar 

  46. Dickey, J., and Perrot, V. (2019) Adjunct phage treatment enhances the effectiveness of low antibiotic concentration against Staphylococcus aureus biofilms in vitro, PLoS One, 14, e0209390, doi: https://doi.org/10.1371/journal.pone.0209390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Rodriguez-Gonzalez, R. A., Leung, C. Y., Chan, B. K., Turner, P. E., and Weitz, J. S. (2020) Quantitative models of phage-antibiotic combination therapy, mSystems, 5, e00756-19, doi: https://doi.org/10.1128/mSystems.00756-19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Poglazov, B. F. (1973) Morphogenesis of T-even bacteriophages, Karger Publishers.

  49. Letarov, A. V. (2019) Sovremennye kontsepsii biologii bakteriofagov, DeLi, Moscow.

  50. Tikunova, N. V., Voroshilova, N. N., Polygach, O. A., Morozova, V. V., Tikunov, A. Yu., Kuril’shchikov, A. M., and Vlasov, V. V. (2016) Genetic characteristics and antibacterial spectrume of bacteriophages in the industrial series of the product Piobakteriofag polyvalent purified, Epidemiol. Vaktsinoprof., 15, 93-100, doi: https://doi.org/10.31631/2073-3046-2016-15-2-93-100.

    Article  Google Scholar 

  51. Polygach, O. A., Voroshilova, N. N., Tikunova, N. V., Morozova, V. V., Tikunov, A. Yu., Krylov, V. N., Yunusova, A. A., and Dabizheva, A. N. (2018) Modern approaches to developing the phage base of the medicinal and preventive product of Pseudomonas aeruginosa bacteriophages, Epidemiol. Vaktsinoprof., 2, 37-45, doi: https://doi.org/10.24411/2073-3046-2018-10004.

    Article  Google Scholar 

  52. Malik, D. J., Sokolov, I. J., Vinner, G. K., Mancuso, F., Cinquerrui, S., et al. (2017) Formulation, stabilisation and encapsulation of bacteriophage for phage therapy, Adv. Colloid Interface Sci., 249, 100-133, doi: https://doi.org/10.1016/j.cis.2017.05.014.

    Article  CAS  PubMed  Google Scholar 

  53. Manohar, P., and Ramesh, N. (2019) Improved lyophilization conditions for long-term storage of bacteriophages, Sci. Rep., 9, 15242, doi: https://doi.org/10.1038/s41598-019-51742-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Chadha, P., Katare, O. P., and Chhibber, S. (2017) Liposome loaded phage cocktail: Enhanced therapeutic potential in resolving Klebsiella pneumoniae mediated burn wound infections, Burns, 43, 1532-1543, doi: https://doi.org/10.1016/j.burns.2017.03.029.

    Article  PubMed  Google Scholar 

  55. Chang, R. Y. K., Wallinb, M., Lina, Y., Leung, S. S. Y., Wang, Y., Morales, S., and Chan, H.-K. (2018) Phage therapy for respiratory infections, Adv. Drug Deliv. Rev., 133, 76-86, doi: https://doi.org/10.1016/j.addr.2018.08.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Otero, J., García-Rodríguez, A., Cano-Sarabia, M., Maspoch, D., Marcos, R., Cortés, P., and Llagostera, M. (2019) Biodistribution of liposome-encapsulated bacteriophages and their transcytosis during oral phage therapy, Front. Microbiol., 10, 689, doi: https://doi.org/10.3389/fmicb.2019.00689.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Singla, S., Harjai, K., Katare, O. P., and Chhibber, S. (2016) Encapsulation of bacteriophage in liposome accentuates its entry in to macrophage and shields it from neutralizing antibodies, PLoS One, 11, e0153777, doi: https://doi.org/10.1371/journal.pone.0153777.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Kim, K. P., Cha, J. D., Jang, E. H., Klumpp, J., Hagens, S., Hardt, W.-D., Lee, K.-J., Loessner, M. J. (2008) PEGylation of bacteriophages increases blood circulation time and reduces T-helper type 1 immune response, Microb. Biotechnol., 1, 247-257, doi: https://doi.org/10.1111/j.1751-7915.2008.00028.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Rita Costa, A., Milho, C., Azeredo, J., and Pires, D. P. (2018) Synthetic biology to engineer bacteriophage genomes, Methods Mol. Biol., 1693, 285-300, doi: https://doi.org/10.1007/978-1-4939-7395-8_21.

    Article  CAS  PubMed  Google Scholar 

  60. Pires, D. P., Cleto, S., Sillankorva, S., Azeredo, J., and Lu, T. K. (2016) Genetically engineered phages: a review of advances over the last decade, Microbiol. Mol. Biol. Rev., 80, 523-543, doi: https://doi.org/10.1128/MMBR.00069-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Ando, H., Lemire, S., Pires, D. P., and Lu, T. K. (2015) Engineering modular viral scaffolds for targeted bacterial population editing, Cell Syst., 1, 187-196, doi: https://doi.org/10.1016/j.cels.2015.08.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lu, T. K., and Koeris, M. S. (2011) The next generation of bacteriophage therapy, Curr. Opin. Microbiol., 14, 524-531, doi: https://doi.org/10.1016/j.mib.2011.07.028.

    Article  PubMed  Google Scholar 

  63. Kilcher, S., Studer, P., Muessner, C., Klumpp, J., and Loessner, M. J. (2018) Cross-genus rebooting of custom-made, synthetic bacteriophage genomes in L-form bacteria, Proc. Natl. Acad. Sci. USA, 115, 567-572, doi: https://doi.org/10.1073/pnas.1714658115.

    Article  CAS  PubMed  Google Scholar 

  64. Lu, T. K., and Collins, J. J. (2007) Dispersing biofilms with engineered enzymatic bacteriophage, Proc. Natl. Acad. Sci. USA, 104, 11197-11202, doi: https://doi.org/10.1073/pnas.0704624104.

    Article  CAS  PubMed  Google Scholar 

  65. Cobb, L. H., Park, J., Swanson, E. A., Beard, M. C., McCabe, E. M., et al. (2019) CRISPR-Cas9 modified bacteriophage for treatment of Staphylococcus aureus induced osteomyelitis and soft tissue infection, PLoS One, 14, e0220421, doi: https://doi.org/10.1371/journal.pone.0220421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Yehl, K., Lemire, S., Yang, A. C., Ando, H., Mimee, M., et al. (2019) Engineering phage host-range and suppressing bacterial resistance through phage tail fiber mutagenesis, Cell, 179, 459-469, doi: https://doi.org/10.1016/j.cell.2019.09.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Barr, J. J. (2017) A bacteriophages journey through the human body, Immunol. Rev., 279, 106-122, doi: https://doi.org/10.1111/imr.12565.

    Article  CAS  PubMed  Google Scholar 

  68. Cooper, C. J., Denyer, S. P., and Maillard, J. Y. (2014) Stability and purity of a bacteriophage cocktail preparation for nebulizer delivery, Lett. Appl. Microbiol., 58, 118-122, doi: https://doi.org/10.1111/lam.12161.

    Article  CAS  PubMed  Google Scholar 

  69. Carrigy, N. B., Chang, R.Y., Leungm, S. S. Y., Harrison, M., Petrova, Z., et al. (2017) Anti-tuberculosis bacteriophage D29 delivery with a vibrating mesh nebulizer, jet nebulizer, and soft mist inhaler, Pharm. Res., 34, 2084-2096, doi: https://doi.org/10.1007/s11095-017-2213-4.

    Article  CAS  PubMed  Google Scholar 

  70. Astudillo, A., Leung, S. S. Y., Kutter, E., Morales, S., and Chan, H. K. (2018) Nebulization effects on structural stability of bacteriophage PEV 44, Eur. J. Pharm. Biopharm., 125, 124-130, doi: https://doi.org/10.1016/j.ejpb.2018.01.010.

    Article  CAS  PubMed  Google Scholar 

  71. Samokhin, A. G., Kozlova, Yu. N., Korneev, D. V., Taranov, O. S., Fedorov, E. A., Pavlov, V. V., Morozova, V. V., and Tikunova, N. V. (2018) Experimental study of the antibacterial activity of the lytic Staphylococcus aureus bacteriophage ph20 and lytic Pseudomonas aeruginosa bacteriophage ph57 during modelling of its impregnation into poly(methylmetacrylate) orthopedic implants (bone cement), Vestn. Ross. Akad. Med. Nauk, 73, 59-68, doi: https://doi.org/10.15690/vramn905.

    Article  Google Scholar 

  72. Aleshkin, A. V., Zul’karneev, E. R., Kiseleva, I. A., Emel’yanenko, K. A., Emel’yanenko, A. M., and Boinovich, L. B. (2018) Experimental application of organic–inorganic hybrid coatings with adsorbed bacteriophages for reducing the risk of STEC infections, Byull. Experiment. Biol. Med., 165, 473-476.

    Google Scholar 

  73. Morris, J., Kelly, N., Elliott, L., Grant, A., Wilkinson, M., Hazratwala, K., and McEwen, P. (2019) Evaluation of bacteriophage anti-biofilm activity for potential control of orthopedic implant-related infections caused by Staphylococcus aureus, Surg. Infect. (Larchmt), 20, 16-24, doi: https://doi.org/10.1089/sur.2018.135.

    Article  Google Scholar 

  74. Gelman, D., Eisenkraft, A., Chanishvili, N., Nachman, D., Glazer, C. S., and Hazan, R. (2018) The history and promising future of phage therapy in the military service, J. Trauma Acute Care Surg., 85, S18-S26, doi: https://doi.org/10.1097/TA.0000000000001809.

    Article  PubMed  Google Scholar 

  75. Kortright, K. E., Chan, B. K., Koff, J. L., and Turner, P. E. (2019) Phage therapy: a renewed approach to combat antibiotic-resistant bacteria, Cell Host Microbe, 25, 219-232, doi: https://doi.org/10.1016/j.chom.2019.01.014.

    Article  CAS  PubMed  Google Scholar 

  76. Abedon, S. T. (2019) Use of phage therapy to treat long-standing, persistent, or chronic bacterial infections, Adv. Drug Deliv. Rev., 145, 18-39, doi: https://doi.org/10.1016/j.addr.2018.06.018.

    Article  CAS  PubMed  Google Scholar 

  77. Principi, N., Silvestri, E., and Esposito, S. (2019) Advantages and limitations of bacteriophages for the treatment of bacterial infections, Front. Pharmacol., 10, 513, doi: https://doi.org/10.3389/fphar.2019.00513.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Capparelli, R., Parlato, M., Borriello, G., Salvatore, P., and Iannelli, D. (2007) Experimental phage therapy against Staphylococcus aureus in mice, Antimicrob. Agents Chemother., 51, 2765-2773.

    Article  CAS  Google Scholar 

  79. Hawkins, C., Harper, D., Burch, D., Anggard, E., and Soothill, J. (2010) Topical treatment of Pseudomonas aeruginosa otitis of dogs with a bacteriophage mixture: a before/after clinical trial, Vet. Microbiol., 145, 309-313.

    Article  Google Scholar 

  80. Kishor, C., Mishra, R. R., Saraf, S. K., Kumar, M., Srivastav, A. K., and Nath, G. (2016) Phage therapy of staphylococcal chronic osteomyelitis in experimental animal model, Indian J. Med. Res., 143, 87-94.

    Article  Google Scholar 

  81. Kumari, S., Harjai, K., and Chhibber, S. (2011) Bacteriophage versus antimicrobial agents for the treatment of murine burn wound infection caused by Klebsiella pneumoniae B5055, J. Med. Microbiol., 60, 205-210.

    Article  Google Scholar 

  82. Mai, V., Ukhanova, M., Reinhard, M. K., Li, M., and Sulakvelidze, A. (2015) Bacteriophage administration significantly reduces Shigella colonization and shedding by Shigella-challenged mice without deleterious side effects and distortions in the gut microbiota, Bacteriophage, 5, e1088124.

    Article  CAS  Google Scholar 

  83. Mendes, J. J., Leandro, C., Corte-Real, S., Barbosa, R., Cavaco-Silva, P., Melo-Cristino, J., Gorski, A., and Garcia, M. (2013) Wound healing potential of topical bacteriophage therapy on diabetic cutaneous wounds, Wound Repair Regen., 21, 595-603.

    Article  Google Scholar 

  84. Pabary, R., Singh, C., Morales, S., Bush, A., Alshafi, K., Bilton, D., Alton, E. W., Smithyman, A., and Davies, J. C. (2016) Antipseudomonal bacteriophage reduces infective burden and inflammatory response in murine lung, Antimicrob. Agents Chemother., 60, 744-751.

    Article  CAS  Google Scholar 

  85. Semler, D. D., Goudie, A. D., Finlay, W. H., and Dennis, J. J. (2014) Aerosol phage therapy efficacy in Burkholderia cepacia complex respiratory infections, Antimicrob. Agents Chemother., 58, 4005-4013.

    Article  Google Scholar 

  86. Shivaswamy, V. C., Kalasuramath, S. B., Sadanand, C. K., Basavaraju, A. K., Ginnavaram, V., Bille, S., Ukken, S. S., and Pushparaj, U. N. (2015) Ability of bacteriophage in resolving wound infection caused by multidrug-resistant Acinetobacter baumannii in uncontrolled diabetic rats, Microb. Drug Resist., 21, 171-177.

    Article  CAS  Google Scholar 

  87. Waters, E. M., Neill, D. R., Kaman, B., Sahota, J. S., Clokie, M. R., Winstanley, C., and Kadioglu, A. (2017) Phage therapy is highly effective against chronic lung infections with Pseudomonas aeruginosa, Thorax, 72, 666-667.

    Article  Google Scholar 

  88. Wills, Q. F., Kerrigan, C., and Soothill, J. S. (2005) Experimental bacteriophage protection against Staphylococcus aureus abscesses in a rabbit model, Antimicrob. Agents Chemother., 49, 1220-1221.

    Article  CAS  Google Scholar 

  89. Albac, S., Medina, M., Labrousse, D., Hayez, D., Bonnot, D., et al. (2020) Efficacy of bacteriophages in a Staphylococcus aureus nondiabetic or diabetic foot infection murine model, Antimicrob. Agents Chemother., 64, e01870-19, doi: https://doi.org/10.1128/AAC.01870-19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Morozova, V. V., Vlassov, V. V., and Tikunova, N. V. (2018) Applications of bacteriophages in the treatment of localized infections in humans, Front. Microbiol., 9, 1696, doi: https://doi.org/10.3389/fmicb.2018.01696.

    Article  PubMed  PubMed Central  Google Scholar 

  91. Sulakvelidze, A., Alavidze, Z., and Morris, J. G. (2001) Bacteriophage therapy, Antimicrob. Agents Chemother., 45, 649-659, doi: https://doi.org/10.1128/AAC.45.3.649-659.2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Chanishvili, N. (2009) A Literature Review of the Practical Application of Bacteriophage Research, Nova Science Publishers, New York.

  93. Chanishvili, N. (2016) Bacteriophages as therapeutic and prophylactic means: summary of the soviet and post-soviet experiences, Curr. Drug Deliv., 13, 309-323, doi: https://doi.org/10.2174/156720181303160520193946.

    Article  CAS  PubMed  Google Scholar 

  94. Schmidt, C. (2019) Phage therapy’s latest makeover, Nat. Biotechnol., 37, 58-586, doi: https://doi.org/10.1038/s41587-019-0133-z.

    Article  CAS  Google Scholar 

  95. Altamirano, F., and Barr, J. (2019) Phage therapy in the postantibiotic era, Clin. Microbiol. Rev., 32, e00066-18, doi: https://doi.org/10.1128/CMR.00066-18.

    Article  CAS  Google Scholar 

  96. Rhoads, D. D., Wolcott, R. D., Kuskowski, M. A., Wolcott, B. M., Ward, L. S., and Sulakvelidze, A. (2009) Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial, J. Wound Care, 18, 240-243.

    Article  Google Scholar 

  97. Markoishvili, K., Tsitlanadze, G., Katsarava, R., Morris, J. G., and Sulakvelidze, A. (2002) A novel sustained-release matrix based on biodegradable poly(ester amide) s and impregnated with bacteriophages and an antibiotic shows promise in management of infected venous stasis ulcers and other poorly healing wounds, Int. J. Dermatol., 41, 453-458, doi: https://doi.org/10.1046/j.1365-4362.2002.01451.x.

    Article  CAS  PubMed  Google Scholar 

  98. Wright, A., Hawkins, C. H., Anggård, E. E., and Harper, D. R. (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, doi: https://doi.org/10.1111/j.1749-4486.2009.01973.x.

    Article  CAS  PubMed  Google Scholar 

  99. Jault, P., Leclerc, T., Jennes, S., Pirnay, J. P., Que, Y. A., et al. (2018) 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, 35-45, doi: https://doi.org/10.1016/S1473-3099(18)30482-1.

    Article  PubMed  Google Scholar 

  100. Sarker, S. A., McCallin, S., Barretto, C., Berger, B., Pittet, A. C., et al. (2012) Oral T4-like phage cocktail application to healthy adult volunteers from Bangladesh, Virology, 434, 222-232, doi: https://doi.org/10.1016/j.virol.2012.09.002.

    Article  CAS  PubMed  Google Scholar 

  101. Sarker, S. A., Sultana, S., Reuteler, G., Moine, D., Descombes, P., Charton, F., et al. (2016) Oral phage therapy of acute bacterial diarrhea with two coliphage preparations: a randomized trial in children from Bangladesh, EBioMedicine, 4, 124-137, doi: https://doi.org/10.1016/j.ebiom.2015.12.023.

    Article  PubMed  PubMed Central  Google Scholar 

  102. McCallin, S., Sarker, S. A., and Barretto, C. (2013) Safety analysis of a Russian phage cocktail: from metagenomic analysis to oral application in healthy human subjects, Virology, 443, 187-196, doi: https://doi.org/10.1016/j.virol.2013.05.022.

    Article  CAS  PubMed  Google Scholar 

  103. Fabijan, A. P., Lin, R. C. Y., Ho, J., Maddocks, S., Ben Zakour, N. L., and Iredell, J. R. (2020) Safety of bacteriophage therapy in severe Staphylococcus aureus infection, Nat. Microbiol., 5, 465-472, doi: https://doi.org/10.1038/s41564-019-0634-z.

    Article  CAS  Google Scholar 

  104. Febvre, H. P., Rao, S., Gindin, M., Goodwin, N. D. M., Finer, E., et al. (2019) PHAGE study: effects of supplemental bacteriophage intake on inflammation and gut microbiota in healthy adults, Nutrients, 11, E666, doi: https://doi.org/10.3390/nu11030666.

    Article  CAS  PubMed  Google Scholar 

  105. Gindin, M., Febvre, H. P., Rao, S., Wallace, T. C., and Weir, T. L. (2019) Bacteriophage for gastrointestinal health (PHAGE) study: evaluating the safety and tolerability of supplemental bacteriophage consumption, J. Am. Coll. Nutr., 38, 68-75, doi: https://doi.org/10.1080/07315724.2018.1483783.

    Article  CAS  PubMed  Google Scholar 

  106. Leitner, L., Sybesma, W., Chanishvili, N., Goderdzishvili, M., Chkhotua, A., 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, doi: https://doi.org/10.1186/s12894-017-0283-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Ujmajuridze, A., Chanishvili, N., Goderdzishvili, M., Leitner, L., Mehnert, U., Chkhotua, A., Kessler, T. M., and Sybesma, W. (2018) Adapted bacteriophages for treating urinary tract infections, Front. Microbiol., 9, 1832, doi: https://doi.org/10.3389/fmicb.2018.01832.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Międzybrodzki, R., Borysowski, J., Weber-Dąbrowska, B., Wojciech Fortuna, W., et al. (2012) Clinical aspects of phage therapy, Adv. Virus Res., 83, 73-121, doi: https://doi.org/10.1016/B978-0-12-394438-2.00003-7.

    Article  CAS  PubMed  Google Scholar 

  109. Goren, M., Yosef, I., and Qimron, U. (2017) Sensitizing pathogens to antibiotics using the CRISPR-Cas system, Drug Resist. Updat., 30, 1-6, doi: https://doi.org/10.1016/j.drup.2016.11.001.

    Article  PubMed  Google Scholar 

  110. Park, J. Y., Moon, B. Y., Park, J. W., Thornton, J. A., Park, Y. H., and Seo, K. S. (2017) Genetic engineering of a temperate phage-based delivery system for CRISPR/Cas9 antimicrobials against Staphylococcus aureus, Sci. Rep., 7, 44929, doi: https://doi.org/10.1038/srep44929.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Pursey, E., Sünderhauf, D., Gaze, W. H., Westra, E. R., and Van Houte, S. (2018) CRISPR-Cas antimicrobials: challenges and future prospects, PLoS Pathog., 14, e1006990, doi: https://doi.org/10.1371/journal.ppat.1006990.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Pirnay, J. P., Verbeken, G., Ceyssens, P. J., Huys, I., De Vos, D., Ameloot, C., and Fauconnier, A. (2018) The magistral phage, Viruses, 10, 64, doi: https://doi.org/10.3390/v10020064.

    Article  PubMed Central  Google Scholar 

Download references

Funding

This work was financially supported by the Russian Foundation for Basic Research (project no. 18-29-08015).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to V. V. Vlassov.

Ethics declarations

The authors declare no conflict of interest in financial or any other sphere. This article does not contain any studies with human participants or animals performed by any of the authors.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Vlassov, V.V., Tikunova, N.V. & Morozova, V.V. Bacteriophages as Therapeutic Preparations: What Restricts Their Application in Medicine. Biochemistry Moscow 85, 1350–1361 (2020). https://doi.org/10.1134/S0006297920110061

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1134/S0006297920110061

Keywords

Navigation