Skip to main content

Clinical Trials of Bacteriophage Therapeutics

Abstract

The 100-year anniversary of the discovery of bacteriophages has come and gone. After being overshadowed by the limelight success of penicillin in the 1940s, phage therapy (PT) is once again making headlines in the wake of the antibiotic resistance crisis for its potential to cure bacterial infections. However, the decade-old adage of “the revival of phage therapy” will soon regress to the status of cliché: few clinical trials have been reported in the recent history; and zero Phase III trials exist to date. At such a rate, antibiotic resistance will outpace the exploration and development of PT and its adoption into modern medicine. The medical and scientific communities are now trying to address the enduring uncertainty about PT and recommence clinical evaluation. These phage trials conducted in more recent history, and their germane contributions, as well as valuable lessons, to the establishment of phage therapy as a Western practice, are outlined in this chapter in detail. This chapter aims to explain what phage therapy must confront and accomplish in order to insert itself into contemporary legislative frameworks and contend with the performance of standard pharmaceuticals in clinical trials so that it may be regarded as a viable treatment option beyond niche, noncommercial applications.

This is a preview of subscription content, access via your institution.

References

  • Azzopardi EA, Azzopardi E, Camilleri L, Villapalos J, Boyce DE, Dziewulski P, ⋯ Whitaker IS et al (2014) Gram negative wound infection in hospitalised adult burn patients – systematic review and metanalysis. PLoS One 9(4):e95042. doi:10.1371/journal.pone.0095042

  • Barletta F, Ochoa TJ, Mercado E, Ruiz J, Ecker L, Lopez G, ⋯ Cleary TG et al (2011) Quantitative real-time polymerase chain reaction for enteropathogenic Escherichia Coli: a tool for investigation of asymptomatic versus symptomatic infections. Clin Infect Dis 53(12):1223–1229. doi:10.1093/cid/cir730

  • Bruttin A, Brussow H (2005) Human volunteers receiving Escherichia Coli phage T4 orally: a safety test of phage therapy. Antimicrob Agents Chemother 49(7):2874–2878. doi:10.1128/AAC.49.7.2874-2878.2005

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Chan BK, Abedon ST, Loc-Carrillo C (2013) Phage cocktails and the future of phage therapy. Future Microbiol 8(6):769–783. doi:10.2217/fmb.13.47

    CAS  CrossRef  PubMed  Google Scholar 

  • Chan BK, Brown K, Kortright KE, Mao S, Turner PE (2016a) Extending the lifetime of antibiotics: how can phage therapy help? Future Microbiol 11:1105–1107. doi:10.2217/fmb-2016-0133

    CAS  CrossRef  PubMed  Google Scholar 

  • Chan BK, Sistrom M, Wertz JE, Kortright KE, Narayan D, Turner PE (2016b) Phage selection restores antibiotic sensitivity in MDR Pseudomonas Aeruginosa. Sci Rep 6:26717. doi:10.1038/srep26717

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Chibani-Chennoufi S, Sidoti J, Bruttin A, Dillmann ML, Kutter E, Qadri F, ⋯ Brussow, H. et al (2004a) Isolation of Escherichia Coli bacteriophages from the stool of pediatric diarrhea patients in Bangladesh. J Bacteriol 186(24):8287–8294. doi:10.1128/JB.186.24.8287-8294.2004

  • Chibani-Chennoufi S, Sidoti J, Bruttin A, Kutter E, Sarker S, Brussow H (2004b) In vitro and in vivo bacteriolytic activities of Escherichia Coli phages: implications for phage therapy. Antimicrob Agents Chemother 48(7):2558–2569. doi:10.1128/AAC.48.7.2558-2569.2004

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Copeland-Halperin LR, Kaminsky AJ, Bluefeld N, Miraliakbari R (2016) Sample procurement for cultures of infected wounds: a systematic review. J Wound Care 25(4): S4–S6, S8–S10. doi:10.12968/jowc.2016.25.Sup4.S4

  • Coulter LB, McLean RJ, Rohde RE, Aron GM (2014) Effect of bacteriophage infection in combination with tobramycin on the emergence of resistance in Escherichia Coli and Pseudomonas Aeruginosa biofilms. Virus 6(10):3778–3786. doi:10.3390/v6103778

    CAS  CrossRef  Google Scholar 

  • EMA (2016) Tripartite meeting held between the EMA, FDA, and PMDA at the EMA, London, on 1–2 September 2016 to discuss regulatory approaches for the evaluation of antibacterial agents

    Google Scholar 

  • Expert round table on, a., & re-implementation of bacteriophage, t (2016) Silk route to the acceptance and re-implementation of bacteriophage therapy. Biotechnol J 11(5):595–600. doi:10.1002/biot.201600023

    CrossRef  Google Scholar 

  • Faruque SM, Naser IB, Islam MJ, Faruque AS, Ghosh AN, Nair GB, ⋯ Mekalanos JJ et al (2005) Seasonal epidemics of cholera inversely correlate with the prevalence of environmental cholera phages. Proc Natl Acad Sci USA 102(5):1702–1707. doi:10.1073/pnas.0408992102

  • Fish R, Kutter E, Wheat G, Blasdel B, Kutateladze M, Kuhl S (2016) Bacteriophage treatment of intransigent diabetic toe ulcers: a case series. J Wound Care 25(Suppl 7):S27–S33. doi:10.12968/jowc.2016.25.7.S27

    CrossRef  PubMed  Google Scholar 

  • Fogelman I, Davey V, Ochs HD, Elashoff M, Feinberg MB, Mican J, ⋯ Lane HC et al (2000) Evaluation of CD4+ T cell function in vivo in HIV infected patients as measured by bacteriophage phiX174 immunization. J Infect Dis 182(2):435–441. doi:10.1086/315739

  • Group, E. E. J. W. (2009). ECDC/EMEA joint technical report: the bacterial challenge: time to react. Stockholm: Retrieved from http://www.ecdc.europa.eu/en/publications/Publications/Forms/ECDC_DispForm.aspx?ID=444

  • Guggenheim M, Zbinden R, Handschin AE, Gohritz A, Altintas MA, Giovanoli P (2009) Changes in bacterial isolates from burn wounds and their antibiograms: a 20-year study (1986–2005). Burns 35(4):553–560. doi:10.1016/j.burns.2008.09.004

    CrossRef  PubMed  Google Scholar 

  • Hawkins C, Harper D, Burch D, Anggard E, Soothill J (2010) Topical treatment of Pseudomonas Aeruginosa otitis of dogs with a bacteriophage mixture: a before/after clinical trial. Vet Microbiol 146(3–4):309–313. doi:10.1016/j.vetmic.2010.05.014

    CrossRef  PubMed  Google Scholar 

  • Hay M, Thomas DW, Craighead JL, Economides C, Rosenthal J (2014) Clinical development success rates for investigational drugs. Nat Biotechnol 32(1):40–51. doi:10.1038/nbt.2786

    CAS  CrossRef  PubMed  Google Scholar 

  • Henein A (Cartographer) (2013) What are the limitations on the wider therapeutic use of phages?

    Google Scholar 

  • Jikia D, Chkhaidze N, Imedashvili E, Mgaloblishvili I, Tsitlanadze G, Katsarava R, ⋯ Sulakvelidze A, et al (2005) 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 30(1):23–26. doi:10.1111/j.1365-2230.2004.01600.x

  • Kamal F, Dennis JJ (2015) Burkholderia cepacia complex phage-antibiotic synergy (PAS): antibiotics stimulate lytic phage activity. Appl Environ Microbiol 81(3):1132–1138. doi:10.1128/AEM.02850-14

    CrossRef  PubMed  PubMed Central  Google Scholar 

  • Kirby AE (2012) Synergistic action of gentamicin and bacteriophage in a continuous culture population of Staphylococcus Aureus. PLoS One 7(11):e51017. doi:10.1371/journal.pone.0051017

    CAS  CrossRef  PubMed  PubMed Central  Google Scholar 

  • Kutateladze M, Adamia R (2010) Bacteriophages as potential new therapeutics to replace or supplement antibiotics. Trends Biotechnol 28(12):591–595. doi:10.1016/j.tibtech.2010.08.001

    CAS  CrossRef  PubMed  Google Scholar 

  • Kvachadze L, Balarjishvili N, Meskhi T, Tevdoradze E, Skhirtladze N, Pataridze T, ⋯ Kutateladze M et al (2011) Evaluation of lytic activity of staphylococcal bacteriophage Sb-1 against freshly isolated clinical pathogens. Microb Biotechnol 4(5):643–650. doi:10.1111/j.1751-7915.2011.00259.x

  • Levin BR, Bull JJ (2004) Population and evolutionary dynamics of phage therapy. Nat Rev Microbiol 2(2):166–173. doi:10.1038/nrmicro822

    CAS  CrossRef  PubMed  Google Scholar 

  • Markoishvili K, Tsitlanadze G, Katsarava R, Morris JG Jr, 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(7):453–458

    CAS  CrossRef  PubMed  Google Scholar 

  • Marza JA, Soothill JS, Boydell P, Collyns TA (2006) Multiplication of therapeutically administered bacteriophages in Pseudomonas Aeruginosa infected patients. Burns 32(5):644–646. doi:10.1016/j.burns.2006.02.012

    CrossRef  PubMed  Google Scholar 

  • McCallin S, Alam Sarker S, Barretto C, Sultana S, Berger B, Huq S, ⋯ Brussow H et al (2013) Safety analysis of a Russian phage cocktail: from metagenomic analysis to oral application in healthy human subjects. Virology 443(2):187–196. doi:10.1016/j.virol.2013.05.022

  • Merabishvili M, Pirnay JP, Verbeken G, Chanishvili N, Tediashvili M, Lashkhi N, ⋯ Vaneechoutte M et al (2009) Quality-controlled small-scale production of a well-defined bacteriophage cocktail for use in human clinical trials. PLoS One 4(3):e4944. doi:10.1371/journal.pone.0004944

  • Miedzybrodzki R, Borysowski J, Weber-Dabrowska B, Fortuna W, Letkiewicz S, Szufnarowski K, ⋯ Gorski A et al (2012) Clinical aspects of phage therapy. Adv Virus Res 83:73–121. doi:10.1016/B978-0-12-394438-2.00003-7

  • Mullard A (2017a) Cures act shakes up the FDA and NIH. Nat Rev Drug Discov 16(9). doi:10.1038/nrd.2016.285

  • Mullard A (2017b) R&D returns continue to fall. Nat Rev Drug Discov 16(9). doi:10.1038/nrd.2016.284

  • O’Neill J (2014) Tackling drug-resistant infections globally: final report and recommendations. Review on Antimicrobial Resistance, London

    Google Scholar 

  • Ochs HD, Buckley RH, Kobayashi RH, Kobayashi AL, Sorensen RU, Douglas SD, ⋯ Hershfield MS et al (1992) Antibody responses to bacteriophage phi X174 in patients with adenosine deaminase deficiency. Blood 80(5):1163–1171

    Google Scholar 

  • Oechslin F, Piccardi P, Mancini S, Gabard J, Moreillon P, Entenza JM, ⋯ Que YA et al (2016) Synergistic interaction between phage therapy and antibiotics clears Pseudomonas Aeruginosa infection in endocarditis and reduces virulence. J Infect Dis. doi:10.1093/infdis/jiw632

  • Oliveira H, Sillankorva S, Merabishvili M, Kluskens LD, Azeredo J (2015) Unexploited opportunities for phage therapy. Front Pharmacol 6:180. doi:10.3389/fphar.2015.00180

    CrossRef  PubMed  PubMed Central  Google Scholar 

  • Perry EB, Barrick JE, Bohannan BJ (2015) The molecular and genetic basis of repeatable coevolution between Escherichia Coli and bacteriophage T3 in a laboratory microcosm. PLoS One 10(6):e0130639. doi:10.1371/journal.pone.0130639

    CrossRef  PubMed  PubMed Central  Google Scholar 

  • Pirnay JP, Blasdel BG, Bretaudeau L, Buckling A, Chanishvili N, Clark JR, ⋯ Van den Eede G et al (2015) Quality and safety requirements for sustainable phage therapy products. Pharm Res 32(7):2173–2179. doi:10.1007/s11095-014-1617-7

  • Pirnay JP, Verbeken G, Rose T, Jennes S, Zizi M, Huys I, ⋯ De Vos D et al (2012) Introducing yesterday’s phage therapy in today’s medicine. Futur Virol 7(4):379–390. doi:10.2217/fvl.12.24

  • Resch G (2015) Phage based therapies. Oral presentation at the ICAAC-ICC, San Diego

    Google Scholar 

  • Rhoads DD, Wolcott RD, Kuskowski MA, Wolcott BM, Ward LS, Sulakvelidze A (2009) Bacteriophage therapy of venous leg ulcers in humans: results of a phase I safety trial. J Wound Care 18(6):237–238, 240–233. doi:10.12968/jowc.2009.18.6.42801

  • Rose T, Verbeken G, Vos DD, Merabishvili M, Vaneechoutte M, Lavigne R, ⋯ Pirnay JP et al (2014) Experimental phage therapy of burn wound infection: difficult first steps. Int J Burns Trauma 4(2):66–73

    Google Scholar 

  • Rubinstein A, Mizrachi Y, Bernstein L, Shliozberg J, Golodner M, Liu GQ, Ochs HD (2000) Progressive specific immune attrition after primary, secondary and tertiary immunizations with bacteriophage phi X174 in asymptomatic HIV-1 infected patients. AIDS 14(4):F55–F62

    CAS  CrossRef  PubMed  Google Scholar 

  • Sarker SA, McCallin S, Barretto C, Berger B, Pittet AC, Sultana S, ⋯ Brussow H et al (2012) Oral T4-like phage cocktail application to healthy adult volunteers from Bangladesh. Virology 434(2):222–232. doi:10.1016/j.virol.2012.09.002

  • Sarker SA, Sultana S, Reuteler G, Moine D, Descombes P, Charton F, ⋯ Brussow H 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:10.1016/j.ebiom.2015.12.023

  • Tevdoradze E, Kvachadze L, Kutateladze M, Stewart CR (2014) Bactericidal genes of staphylococcal bacteriophage Sb-1. Curr Microbiol 68(2):204–210. doi:10.1007/s00284-013-0456-9

    CAS  CrossRef  PubMed  Google Scholar 

  • Torres-Barcelo C, Arias-Sanchez FI, Vasse M, Ramsayer J, Kaltz O, Hochberg ME (2014) A window of opportunity to control the bacterial pathogen Pseudomonas Aeruginosa combining antibiotics and phages. PLoS One 9(9):e106628. doi:10.1371/journal.pone.0106628

    CrossRef  PubMed  PubMed Central  Google Scholar 

  • Torres-Barcelo C, Hochberg ME (2016) Evolutionary rationale for phages as complements of antibiotics. Trends Microbiol 24(4):249–256. doi:10.1016/j.tim.2015.12.011

    CAS  CrossRef  PubMed  Google Scholar 

  • Verbeken G, De Vos D, Vaneechoutte M, Merabishvili M, Zizi M, Pirnay JP (2007) European regulatory conundrum of phage therapy. Future Microbiol 2(5):485–491. doi:10.2217/17460913.2.5.485

    CAS  CrossRef  PubMed  Google Scholar 

  • Verbeken G, Huys I, De Vos D, De Coninck A, Roseeuw D, Kets E et al (2016) Access to bacteriophage therapy: discouraging experiences from the human cell and tissue legal framework. FEMS Microbiol Lett 363(4). doi:10.1093/femsle/fnv241

  • Verbeken G, Pirnay JP, De Vos D, Jennes S, Zizi M, Lavigne R, ⋯ Huys I et al (2012) Optimizing the European regulatory framework for sustainable bacteriophage therapy in human medicine. Arch Immunol Ther Exp 60(3):161–172. doi:10.1007/s00005-012-0175-0

  • Verma V, Harjai K, Chhibber S (2010) Structural changes induced by a lytic bacteriophage make ciprofloxacin effective against older biofilm of Klebsiella Pneumoniae. Biofouling 26(6):729–737. doi:10.1080/08927014.2010.511196

    CAS  CrossRef  PubMed  Google Scholar 

  • Weber-Dabrowska B, Mulczyk M, Gorski A (2000) Bacteriophage therapy of bacterial infections: an update of our institute’s experience. Arch Immunol Ther Exp 48(6):547–551

    CAS  Google Scholar 

  • Weber-Dabrowska B, Mulczyk M, Gorski A (2001) Bacteriophage therapy for infections in cancer patients. Clin Appl Immunol Rev 1:4. doi:10.1016/S1529-1049(01)00015-0

    CrossRef  Google Scholar 

  • Weber-Dabrowska B, Mulczyk M, Gorski A (2003) Bacteriophages as an efficient therapy for antibiotic-resistant septicemia in man. Transplant Proc 35(4):1385–1386

    CAS  CrossRef  PubMed  Google Scholar 

  • WHO (2015) Global action plan on antimicrobiobial resistance. WHO Document Production Services, Geneva

    Google Scholar 

  • Wiggins BA, Alexander M (1985) Minimum bacterial density for bacteriophage replication: implications for significance of bacteriophages in natural ecosystems. Appl Environ Microbiol 49(1):19–23

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wright A, Hawkins CH, Anggard EE, Harper DR (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(4):349–357. doi:10.1111/j.1749-4486.2009.01973.x

    CAS  CrossRef  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shawna McCallin .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and Permissions

Copyright information

© 2017 Springer International Publishing AG

About this entry

Cite this entry

McCallin, S., Brüssow, H. (2017). Clinical Trials of Bacteriophage Therapeutics. In: Harper, D., Abedon, S., Burrowes, B., McConville, M. (eds) Bacteriophages. Springer, Cham. https://doi.org/10.1007/978-3-319-40598-8_38-1

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-40598-8_38-1

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-40598-8

  • Online ISBN: 978-3-319-40598-8

  • eBook Packages: Springer Reference Biomedicine & Life SciencesReference Module Biomedical and Life Sciences