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Population and evolutionary dynamics of phage therapy

Nature Reviews Microbiology volume 2, pages 166–173 (2004)Cite this article

Abstract

Following a sixty-year hiatus in western medicine, bacteriophages (phages) are again being advocated for treating and preventing bacterial infections. Are attempts to use phages for clinical and environmental applications more likely to succeed now than in the past? Will phage therapy and prophylaxis suffer the same fates as antibiotics — treatment failure due to acquired resistance and ever-increasing frequencies of resistant pathogens? Here, the population and evolutionary dynamics of bacterial–phage interactions that are relevant to phage therapy and prophylaxis are reviewed and illustrated with computer simulations.

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References

  1. Radetsky, P. The good virus. Discover 17, 52 (1996).

    Google Scholar 

  2. Alisky, J., Iczkowski, K., Rapoport, A. & Troitsky, N. Bacteriophages show promise as antimicrobial agents. J. Infect. 36, 5–15 (1998).

    Article  CAS  Google Scholar 

  3. Kutter, E. [online], (cited 3 Dec 2003), <http://www.evergreen.edu/phage/phagetherapy/phagetherapy.html> (2000).

  4. Summers, W. C. Bacteriophage therapy. Annu. Rev. Microbiol. 55, 437–451 (2001).

    Article  CAS  Google Scholar 

  5. Sulakvelidze, A. & Morris, J. G. Jr. Bacteriophages as therapeutic agents. Ann. Med. 33, 507–509 (2001).

    Article  CAS  Google Scholar 

  6. Sulakvelidze, A., Alavidze, Z. & Morris, J. G. Jr. Bacteriophage therapy. Antimicrob. Agents Chemother. 45, 649–659 (2001).

    Article  CAS  Google Scholar 

  7. Merril, C. R., Scholl, D. & Adhya, S. L. The prospect for bacteriophage therapy in western medicine. Nature Rev. Drug Discov. 2, 489–497 (2003).

    Article  CAS  Google Scholar 

  8. Finland, M. Adventures with antibacterial drugs. Clin. Pharmacol. Ther. 13, 469–511 (1972).

    Article  CAS  Google Scholar 

  9. Keller, M. A. & Stiehm, E. R. Passive immunity in prevention and treatment of infectious diseases. Clin. Microbiol. Rev. 13, 602–614 (2000).

    Article  CAS  Google Scholar 

  10. Smith, H. W. & Hugggins, M. B. Successful treatment of experimental Escherichia coli infections in mice using phage: its general superiority over antibiotics. J. Gen. Microbiol. 128, 307–318 (1982).

    CAS  PubMed  Google Scholar 

  11. Smith, H. W. & Huggin, M. B. Effectiveness of phages in treating experimental Escherichia coli diarrhoea in calves, piglets and lambs. J. Gen. Microbiol. 129, 2659–2675 (1983).

    CAS  PubMed  Google Scholar 

  12. Smith, H. W., Huggins, M. B. & Shaw, K. M. The control of experimental Escherichia coli diarrhoea in calves by means of bacteriophage. J. Gen. Microbiol. 133, 1111–1126 (1987).

    CAS  PubMed  Google Scholar 

  13. Soothill, J. S. Treatment of experimental infections of mice with bacteriophage. J. Med. Microbiol. 37, 258–262 (1992).

    Article  CAS  Google Scholar 

  14. Soothill, J. S. Bacteriophage prevents destruction of skin grafts by Pseudomonas aeruginosa. Burns 20, 209–11 (1994).

    Article  CAS  Google Scholar 

  15. Merril, C. R. et al. Long-circulating bacteriophage as antibacterial agents. Proc. Natl Acad. Sci. USA 93, 3188–3192 (1996).

    Article  CAS  Google Scholar 

  16. Matsuzaki, S. et al. Experimental protection of mice against lethal Staphylococcus aureus infection by novel bacteriophage φ MR11. J. Infect. Dis. 187, 613–624 (2003).

    Article  CAS  Google Scholar 

  17. Biswas, B. et al. Bacteriophage therapy rescues mice bacteremic from a clinical isolate of vancomycin-resistant Enterococcus faecium. Infect. Immun. 70, 204–210 (2002).

    Article  CAS  Google Scholar 

  18. Park, S. C. & Nakai, T. Bacteriophage control of Pseudomonas plecoglossicida infection in ayu Plecoglossus altivelis. Dis Aquat Organ 53, 33–9 (2003).

    Article  Google Scholar 

  19. Weld, R. J. & A. J. Heinemann, J. Journal of Theoretical Biology (in the press).

  20. Levin, B. R. & Bull, J. J. Phage therapy revisited: the population biology of a bacterial infection and its treatment with bacteria and antibiotics. Am. Nat. 147, 881–898 (1996).

    Article  Google Scholar 

  21. Payne, R. J. & Jansen, V. A. Phage therapy: the peculiar kinetics of self-replicating pharmaceuticals. Clin. Pharmacol. Ther. 68, 225–230 (2000).

    Article  CAS  Google Scholar 

  22. Payne, R. J. & Jansen, V. A. Understanding bacteriophage therapy as a density-dependent kinetic process. J. Theor. Biol. 208, 37–48 (2001).

    Article  CAS  Google Scholar 

  23. Payne, R. J. & Jansen, V. A. Pharmacokinetic principles of bacteriophage therapy. Clin. Pharmacokinet. 42, 315–325 (2003).

    Article  CAS  Google Scholar 

  24. Kasman, L. M. et al. Overcoming the phage replication threshold: a mathematical model with implications for phage therapy. J. Virol. 76, 5557–5564 (2002).

    Article  CAS  Google Scholar 

  25. Adams, M. H. Bacteriophages (Wiley, New York, 1959).

    Google Scholar 

  26. Stent, G. S. Molecular Biology of Bacterial Viruses (Freeman, San Francisco, 1963).

    Google Scholar 

  27. Campbell, A. The future of bacteriophage biology. Nature Rev. Genet. 4, 471–477 (2003).

    Article  CAS  Google Scholar 

  28. Westwater, C. et al. Use of genetically engineered phage to deliver antimicrobial agents to bacteria: an alternative therapy for treatment of bacterial infections. Antimicrob. Agents Chemother. 47, 1301–1307 (2003).

    Article  CAS  Google Scholar 

  29. Leverentz, B. et al. Examination of bacteriophage as a biocontrol method for Salmonella on fresh-cut fruit: a model study. J. Food Prot. 64, 1116–1121 (2001).

    Article  CAS  Google Scholar 

  30. Leverentz, B. et al. Biocontrol of Listeria monocytogenes on fresh-cut produce by treatment with lytic bacteriophages and a bacteriocin. Appl. Environ. Microbiol. 69, 4519–4526 (2003).

    Article  CAS  Google Scholar 

  31. Huff, W. E., Huff, G. R., Rath, N. C., Balog, J. M. & Donoghue, A. M. Prevention of Escherichia coli infection in broiler chickens with a bacteriophage aerosol spray. Poult. Sci. 81, 1486–1491 (2002).

    Article  CAS  Google Scholar 

  32. Nakai, T. & Park, S. C. Bacteriophage therapy of infectious diseases in aquaculture. Res. Microbiol. 153, 13–8 (2002).

    Article  Google Scholar 

  33. Holtzman, D. Phage eyed as agents to control foodborne pathogens. ASM News 69, 489–490 (2003).

    Google Scholar 

  34. Bull, J. J., Levin, B. R., DeRouin, T., Walker, N. & Bloch, C. A. Dynamics of success and failure in phage and antibiotic therapy in experimental infections. BMC Microbiol. 2, 35 (2002).

    Article  CAS  Google Scholar 

  35. Tuomanen, E. Phenotypic tolerance: the search for β-lactam antibiotics that kill non-growing bacteria. Rev. Infect. Dis. 8, S279–S291 (1986).

    Article  CAS  Google Scholar 

  36. Kruger, D. H. & Bickle, T. A. Bacteriophage survival: multiple mechanisms for avoiding the deoxyribonucleic acid restriction systems of their hosts. Microbiol. Rev. 47, 345–360 (1983).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Lenski, R. E. & Levin, B. R. Constraints on the coevolution of bacteria and virulent phage: a model, some experiments, and predictions for natural communities. Am. Nat. 125, 585–602 (1985).

    Article  Google Scholar 

  38. Bohannan, B. J. M. & Lenski, R. E. Linking genetic change to community evolution: insights from studies of bacteria and bacteriophage. Ecol. Lett. 3, 362–377 (2000).

    Article  Google Scholar 

  39. Chao, L., Levin, B. R. & Stewart, F. M. A complex community in a simple habitat: an experimental study with bacteria and phage. Ecology 58, 369–378 (1977).

    Article  Google Scholar 

  40. Bohannan, B. J., Kerr, B., Jessup, C. M., Hughes, J. B. & Sandvik, G. Trade-offs and coexistence in microbial microcosms. Antonie Van Leeuwenhoek 81, 107–115 (2002).

    Article  CAS  Google Scholar 

  41. Buckling, A. & Rainey, P. B. Antagonistic coevolution between a bacterium and a bacteriophage. Proc. R. Soc. Lond. B Biol. Sci. 269, 931–936 (2002).

    Article  Google Scholar 

  42. Mizoguchi, K. et al. Coevolution of bacteriophage PP01 and Escherichia coli O157:H7 in continuous culture. Appl. Environ. Microbiol. 69, 170–176 (2003).

    Article  CAS  Google Scholar 

  43. Campbell, A. Conditions for the existence of bacteriophage. Evolution 15, 153–165 (1961).

    Article  Google Scholar 

  44. Levin, B. R., Stewart, F. M. & Chao, L. Resource-limited growth, competition, and predation: a model and experimental studies with bacteria and bacteriophage. Am. Nat. 977, 3–24 (1977).

    Article  Google Scholar 

  45. Lenski, R. E. Dynamics of interactions between bacteria and virulent bacteriophage. Adv. Microb. Ecol. 10, 1–44 (1988).

    Article  CAS  Google Scholar 

  46. Schrag, S. & Mittler, J. E. Host parasite coexistence: the role of spatial refuges in stabilizing bacteria–phage interactions. Am. Nat. 148, 438–477 (1996).

    Article  Google Scholar 

  47. Korona, R. & Levin, B. R. Phage-mediated selection and the evolution and maintenance of restriction-modification. Evolution 47, 556–575 (1993).

    Article  Google Scholar 

  48. Ahmad, S. I. Treatment of post-burns bacterial infections by bacteriophages, specifically ubiquitous Pseudomonas spp. notoriously resistant to antibiotics. Med. Hypotheses 58, 327–331 (2002).

    Article  CAS  Google Scholar 

  49. Broxmeyer, L. et al. Killing of Mycobacterium avium and Mycobacterium tuberculosis by a mycobacteriophage delivered by a nonvirulent mycobacterium: a model for phage therapy of intracellular bacterial pathogens. J. Infect. Dis. 186, 1155–1160 (2002).

    Article  Google Scholar 

  50. Schrag, S. & Perrot, V. Reducing antibiotic resistance. Nature 28, 120–121 (1996).

    Article  Google Scholar 

  51. Schrag, S., Perrot, V. & Levin, B. Adaptation to the fitness cost of antibiotic resistance in Escherichia coli. Proc. R. Soc. Lond. B Biol. Sci. 264, 1287–1291 (1997).

    Article  CAS  Google Scholar 

  52. Bjorkman, J. & Andersson, D. I. The cost of antibiotic resistance from a bacterial perspective. Drug Resist. Update 3, 237–245 (2000).

    Article  CAS  Google Scholar 

  53. Nagaev, I., Bjorkman, J., Andersson, D. I. & Hughes, D. Biological cost and compensatory evolution in fusidic acid-resistant Staphylococcus aureus. Mol. Microbiol. 40, 433–439 (2001).

    Article  CAS  Google Scholar 

  54. Spitznagel, J. K. in Mechanisms of Microbial Diseases (eds Schaechter, M., Medhoff, M. G. & Eisenstein, B. J.) 90–114 (Williams and Wilkins, Baltimore, USA, 1993).

    Google Scholar 

  55. Zeigler, H. K. in Mechanisms of Microbial Diseases (eds Schaechter, M., Medhoff, M. G. & Eisenstein, B. J.) 114–153 (Williams and Wilkins, Baltimore, USA, 1993).

    Google Scholar 

  56. Antia, R., Levin, B. R. & May, R. M. Within-host population dynamics and the evolution and maintenance of microparasite virulence. Am. Nat. 144, 457–472 (1994).

    Article  Google Scholar 

  57. Twort, F. W. An investigation on the nature of ultra-microscopic viruses. Lancet 11, 1241–1243 (1915).

    Article  Google Scholar 

  58. d'Herelle, F. In The Bacteriophage and its Behavior. 490–541 (Williams and Wilkins, Baltimore, Maryland, 1926).

    Google Scholar 

  59. Eaton, M. D. & Bayne-Jones, S. Bacteriophage therapy. JAMA 103, 1769–1776, 1847–1853 & 1934–1939 (1934).

    Article  CAS  Google Scholar 

  60. Asheshov, I. N., Wilson, J. & Topley, W. W. C. The effect of an anti-VI bacteriophage on typhoid infection in mice. Lancet 1, 319–320 (1937).

    Article  Google Scholar 

  61. Dubos, R. J., Straus, J. H. & Pierce, C. The multiplication of bacteriophage in vivo and its protective effects against expermiental infection with Shigella dysenteria. J. Exp. Med. 20, 161–169 (1943).

    Article  Google Scholar 

  62. Monod, J. The growth of bacterial cultures. Annu. Rev. Microbiol. 3, 371–394 (1949).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank S. Adhya, M. Lee, C. Merril, I. Mouleux, and the members of the EcLF for stimulating and useful discussions and commentary. We also wish to acknowledge and, now that we made the revisions, express our gratitude, for the considerable effort the anonymous reviewers put into an earlier draft of this article and for the value of their comments and suggestions. This enterprise was supported by grants from the IPRAVE/Wellcome Trust and the US National institutes of Health, J.J.B. is also supported as the J. Friedrich Miescher Professor at the University of Texas. We dedicate this article to the memory of H. Williams Smith.

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  1. Department of Biology, Emory University, Atlanta, 30307, Georgia, USA

    Bruce R. Levin

  2. Section of Integrative Biology and Institute for Cellular and Molecular Biology, University of Texas, Austin, 78712, Texas, USA

    James J. Bull

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Correspondence to Bruce R. Levin.

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Levin, B., Bull, J. Population and evolutionary dynamics of phage therapy. Nat Rev Microbiol 2, 166–173 (2004). https://doi.org/10.1038/nrmicro822

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