Export file:


  • RIS(for EndNote,Reference Manager,ProCite)
  • BibTex
  • Text


  • Citation Only
  • Citation and Abstract

Active bacteriophage biocontrol and therapy on sub-millimeter scales towards removal of unwanted bacteria from foods and microbiomes

Department of Microbiology, the Ohio State University, 1680 University Dr., Mansfield, OH 44906, USA

Topical Section: Phage and phage therapy

Bacteriophages can be used as antibacterial agents as a form of biological control, e.g., such as phage therapy. With active treatment, phages must “actively” produce new virions, in situ, to attain “inundative” densities, i.e., sufficient titers to eradicate bacteria over reasonable timeframes. Passive treatment, by contrast, can be accomplished using phages that are bactericidal but incapable of generating new phage virions in situ during their interaction with target bacteria. These ideas of active versus passive treatment come from theoretical considerations of phage therapy pharmacology, particularly as developed in terms of phage application to well-mixed cultures consisting of physically unassociated bacteria. Here I extend these concepts to bacteria which instead are physically associated. These are bacteria as found making up cellular arrangements or bacterial microcolonies—collectively, clonal bacterial “clumps”. I consider circumstances where active phage replication would be required to effect desired levels of bacterial clearance, but populations of bacteria nevertheless are insufficiently prevalent to support phage replication to bacteria-inundative densities across environments. Clumped bacteria, however, may still support active treatment at more local, i.e., sub-millimeter, within-clump spatial scales, and potential consequences of this are explored mathematically. Application is to the post-harvest biocontrol of foodborne pathogens, and potentially also to precise microbiome editing. Adequate infection performance by phages in terms of timely burst sizes, that is, other than just adsorption rates and bactericidal activity, thus could be important for treatment effectiveness even if bacterial densities overall are insufficient to support active treatment across environments. Poor phage replication during treatment of even low bacterial numbers, such as given food refrigeration during treatment, consequently could be problematic to biocontrol success. In practical terms, this means that the characterization of phages for such purposes should include their potential to generate new virions under realistic in situ conditions across a diversity of potential bacterial targets.
  Article Metrics


1. Abedon ST, Kuhl SJ, Blasdel BG, et al. (2011) Phage treatment of human infections. Bacteriophage 1: 66–85.    

2. Abedon ST (2017) Bacteriophage clinical use as antibactertial "drugs": utility, precedent. Microbiol Spectr.

3. Abedon ST (2015) Ecology of anti-biofilm agents I. antibiotics versus bacteriophages. Pharmaceuticals 8: 525–558.

4. Abedon ST (2009) Kinetics of phage-mediated biocontrol of bacteria. Foodborne Pathog Dis 6: 807–815.    

5. Meyer CJ, Deglon DA (2011) Particle collision modeling-a review. Miner Eng 24: 719–730.    

6. Bigwood T, Hudson JA, Billington C (2009) Influence of host and bacteriophage concentrations on the inactivation of food-borne pathogenic bacteria by two phages. FEMS Microbiol Lett 291: 59–64.    

7. Abedon ST (2014) Bacteriophages as drugs: the pharmacology of phage therapy, In: Borysowski J, Miedzybrodzki R, Górski A, Editors, Phage Therapy: Current Research and Applications, Norfolk, UK: Caister Academic Press, 69–100.

8. Abedon ST (2017) Phage "delay" towards enhancing bacterial escape from biofilms: a more comprehensive way of viewing resistance to bacteriophages. AIMS Microbiol 3: 186–226.    

9. Abedon ST, Thomas-Abedon C (2010) Phage therapy pharmacology. Curr Pharm Biotechnol 11: 28–47.    

10. Górski A, Weber-Dąbrowska B (2005) The potential role of endogenous bacteriophages in controlling invading pathogens. Cell Mol Life Sci 62: 511–519.    

11. Payne RJH, Phil D, Jansen VAA (2000) Phage therapy: The peculiar kinetics of self-replicating pharmaceuticals. Clin Pharmacol Ther 68: 225–230.    

12. Payne RJH, Jansen VAA (2001) Understanding bacteriophage therapy as a density-dependent kinetic process. J Theor Biol 208: 37–48.    

13. Payne RJH, Jansen VAA (2003) Pharmacokinetic principles of bacteriophage therapy. Clin Pharmacokinet 42: 315–325.    

14. Levin BR, Bull JJ (2004) Population and evolutionary dynamics of phage therapy. Nat Rev Microbiol 2: 166–173.    

15. Abedon S (2011) Phage therapy pharmacology: calculating phage dosing. Adv Appl Microbiol 77: 1–40.    

16. Worley-Morse TO, Gunsch CK (2015) Modeling phage induced bacterial disinfection rates and the resulting design implications. Water Res 68: 627–636.    

17. Abedon ST (2015) Ecology of anti-biofilm agents II. bacteriophage exploitation and biocontrol of biofilm bacteria. Pharmaceuticals 8: 559–589.

18. Hagens S, Loessner MJ (2010) Bacteriophage for biocontrol of foodborne pathogens: calculations and considerations. Curr Pharm Biotechnol 11: 58–68.    

19. 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: 237–244.    

20. 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 Otolaryng 34: 349–357.    

21. Miedzybrodzki R, Borysowski J, Weber-Dąbrowska B, et al. (2012) Clinical aspects of phage therapy. Adv Virus Res 83: 73–121.    

22. 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.    

23. Rose T, Verbeken G, Vos DD, et al. (2014) Experimental phage therapy of burn wound infection: difficult first steps. Int J Burns Trauma 4: 66–73.

24. 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–S33.

25. Sarker SA, Sultana S, Reuteler G, 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.    

26. Speck P, Smithyman A (2016) Safety and efficacy of phage therapy via the intravenous route. FEMS Microbiol Lett 363.

27. Sarhan WA, Azzazy HM (2015) Phage approved in food, why not as a therapeutic? Expert Rev Anti Infect Ther 13: 91–101.    

28. Hyman P, Abedon ST (2010) Bacteriophage host range and bacterial resistance. Adv Appl Microbiol 70: 217–248.    

29. Mirzaei MK, Nilsson AS (2015) Isolation of phages for phage therapy: a comparison of spot tests and efficiency of plating analyses for determination of host range and efficacy. PLoS One 10: e0118557.    

30. Abedon ST (2008) Phage, bacteria, and food. Appendix: Rate of adsorption is function of phage density, In: Abedon ST, Editor, Bacteriophage Ecology, Cambridge, UK: Cambridge University Press, 321–324.

31. Guenther S, Loessner MJ (2011) Bacteriophage biocontrol of Listeria monocytogenes on soft ripened white mold and red-smear cheeses. Bacteriophage 1: 94–100.    

32. Abedon ST (2015) Bacteriophage secondary infection. Virol Sin 30: 3–10.    

33. Abedon ST (2012) Spatial vulnerability: bacterial arrangements, microcolonies, and biofilms as responses to low rather than high phage densities. Viruses 4: 663–687.    

34. Stent GS (1963) Molecular Biology of Bacterial Viruses, San Francisco, CA: WH Freeman and Co.

35. Abedon ST (2016) Phage therapy dosing: The problem(s) with multiplicity of infection (MOI). Bacteriophage 6: e1220348.    

36. Dulbecco R (1949) Appendix: On the reliability of the Poisson distribution as a distribution of the number of phage particles infecting individual bacteria in a population. Genetics 34: 122–125.

37. Abedon ST (2017) Information phage therapy research should report. Pharmaceuticals (Basel) 10: 43.    

38. Bryan D, El-Shibiny A, Hobbs Z, et al. (2016) Bacteriophage T4 infection of stationary phase E. coli: life after log from a phage perspective. Front Microbiol 7: 1391.

39. Doolittle MM, Cooney JJ, Caldwell DE (1996) Tracing the interaction of bacteriophage with bacterial biofilms using fluorescent and chromogenic probes. J Indust Microbiol 16: 331–341.    

40. Sutherland IW, Hughes KA, Skillman LC, et al. (2004) The interaction of phage and biofilms. FEMS Microbiol Lett 232: 1–6.    

41. Filippini M, Buesing N, Bettarel Y, et al. (2006) Infection paradox: high abundance but low impact of freshwater benthic viruses. Appl Environ Microbiol 72: 4893–4898.    

42. Azeredo J, Sutherland IW (2008) The use of phages for the removal of infectious biofilms. Curr Pharm Biotechnol 9: 261–266.    

43. Bull JJ, Vegge CS, Schmerer M, et al. (2014) Phenotypic resistance and the dynamics of bacterial escape from phage control. PLoS One 9: e94690.    

44. Abedon ST (2011) Bacteriophages and Biofilms: Ecology, Phage Therapy, Plaques, Hauppauge, New York: Nova Science Publishers.

45. Bull JJ, Regoes RR (2006) Pharmacodynamics of non-replicating viruses, bacteriocins and lysins. Proc R Soc Lond B Biol Sci 273: 2703–2712.    

46. Goodridge LD (2010) Designing phage therapeutics. Curr Pharm Biotechnol 11: 15–27.    

47. Olszowska-Zaremba N, Borysowski J, Dabrowska J, et al. (2012) Phage translocation, safety, and immunomodulation, In: Hyman P, Abedon ST, Editors, Bacteriophages in Health and Disease, Wallingford, UK: CABI Press, 168–184.

48. Curtright AJ, Abedon ST (2011) Phage therapy: emergent property pharmacology. J Bioanalyt Biomed S3: 010.

49. Abedon ST (2014) Phage therapy: eco-physiological pharmacology. Scientifica 2014: 581639.

50. Stewart PS, Franklin MJ (2008) Physiological heterogeneity in biofilms. Nat Rev Microbiol 6: 199–210.    

51. Wang IN, Dykhuizen DE, Slobodkin LB (1996) The evolution of phage lysis timing. Evol Ecol 10: 545–558.    

52. Abedon ST, Herschler TD, Stopar D (2001) Bacteriophage latent-period evolution as a response to resource availability. Appl Environ Microbiol 67: 4233–4241.    

53. Niu YD, Stanford K, McAllister TA, et al. (2012) Role of phages in control of bacterial pathogens in food, In: Hyman P, Abedon ST, Editors, Bacteriophages in Health and Disease, Wallingford, UK: CABI Press, 240–255.

54. Bai J, Kim YT, Ryu S, et al. (2016) Biocontrol and rapid detection of food-borne pathogens using bacteriophages and endolysins. Front Microbiol 7: 474.

55. Gill JJ, Young R (2011) Therapeutic applications of phage biology: history, practice and recommendations, In: Miller AA, Miller PF, Editors, Emerging Trends in Antibacterial Discovery: Answering the Call to Arms, Norfolk,UK: Caister Academic Press, 367–410.

56. Hudson J, Billington C, Premaratne A, et al. (2016) Inactivation of Escherichia coli O157:H7 using ultraviolet light-treated bacteriophages. Food Sci Technol Int 22: 3–9.

57. Young VB (2017) The role of the microbiome in human health and disease: an introduction for clinicians. Brit Med J 356: j831.

58. Autenrieth IB (2017) The microbiome in health and disease: a new role of microbes in molecular medicine. J Mol Med 95: 1–3.

59. McCarville JL, Caminero A, Verdu EF (2016) Novel perspectives on therapeutic modulation of the gut microbiota. Therap Adv Gastroenterol 9: 580–593.    

60. Bjarnsholt T (2013) The role of bacterial biofilms in chronic infections. Apmis 121: 1–51.

61. Carlson K (2005) Working with bacteriophages: common techniques and methodological approaches, In: Kutter E, Sulakvelidze A, Editors, Bacteriophages: Biology and Application, Boca Raton, Florida: CRC Press, 437–494.

62. Abedon ST, Expected efficacy: applying killing titer estimations to phage therapy experiments, 2017. Available from: http://killingtiter.phage-therapy.org.

63. Abedon ST, Killing titer calculator, 2017. Available from: http://killingtiter.phage-therapy.org/calculator.html.

Copyright Info: © 2017, Stephen T. Abedon, licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution Licese (http://creativecommons.org/licenses/by/4.0)

Download full text in PDF

Export Citation

Article outline

Show full outline
Copyright © AIMS Press All Rights Reserved