Phage therapy, a “new” approach in the combat against bacterial infections Dr. Daniel De Vos, Laboratory for Molecular and Cellular Technology Queen Astrid Military Hospital (QAMH), Brussels, Belgium ([email protected]) WIV/ISP, Brussels, 27 November 2014
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Phage therapy, a “new” approach in the combat against
bacterial infections
Dr. Daniel De Vos, Laboratory for Molecular and Cellular Technology
Queen Astrid Military Hospital (QAMH), Brussels, Belgium
A bad understanding of AB’s and a lack of fundamental knowledge and integration of ‘evolutionary biology’ in medicine
(mechanistic medicine >< evolutionary medicine)
Overuse and misuse of AB’s (static molecules >< living system)
Resistance!
(Bacterio)phages • Bacteriospecific virus (also active
against «superbugs»!!!)
• Natural controllers/predators of bacteria
• Co-evolve with their bacterial host cell
• A self amplifying and evolving antibacterial (darwinian medicine)
• Sustainable treatment approach
Phage therapy: The mechanism
• Estimated phage number on our planet:
1031 (= at least 10x the number of bacteria)
• Present in seas, rivers (up to billion phages/ml surface water), soil, food (cheese, yogurt, salami…), plants, animals (incl. human beings!), wherever there are bacteria
• However, no infection by phages has been reported and no DNA sequence of phage origin could be detected in the human genome (<-> 10% retrovirus!)
We live in an ocean of phages
Natural bacterial controllers (Ex.: Self-limiting nature of seasonal cholera epidemics)
Faruque et al. PNAS 2005
Lytic phages constitute a symbiotic immune system against invasive bacteria
(Ex.: our gut mucus layer)
Barr et al., PNAS 2013
Phage therapy : potentially sustainable
The phage/bacterium interaction is dynamic (co-evolution): a typical ‘arms race’ consists in the repetitive emergence and fixation of new virulent parasite and countering bacterial defence characteristics.
Phages vs. Antibiotics (ABs)
PHAGES
• Very specific (species or even strain specific and does not disturb the commensal flora)
• Infecting bacteria need to be known (cocktails could solve this; use of rapid diagnostics)
• Development of new phage preparations: quick and cheap
• No side effects known so far
ANTIBIOTICS
• Not specific (disturbs the commensal flora/collateral dammage)
• Infecting bacteria don’t need to be known (large spectrum ABs)
• Development of new AB: time consuming and costly
Thousands of patients 54 died, hundreds with sequellae
In three days: several lytic phages identified
Antibiotics were of no use!
Authorities didn’t consider phage therapy
as a potential treatment
« In fact, Nestlé Research Center offered a lytic phage to the German public health
sector during the epidemic »
H. Brüssow, Virology 2012
Hurdles! • False perception of viruses as ‘enemies of life’ (L. P. Villarreal, 2005)
• Not compatible with current pharmaco-economic model • Need for an adapted regulatory framework (phages are no
conventional drugs) • Patent issues (phages are biological natural entities)
Pirnay et al., Future Virology 2012
Phage therapy in the QAMH
•Development of phage cocktails against o Pseudomonas aeruginosa and Staphylococcus aureus o Acinetobacter baumannii (incl. “IraqiBacter”) o Enterobacteriaceae (Ex.: EHEC et Klebsiella pneumoniae)
•Development of an adapted regulatory framework for phage therapy (EP, EC, DG SANCO, EMA, DG JRC,..)
•Some patients treated under the umbrella of the « Declaration of Helsinki »
•EU funded Project FP7 “PhagoBurn”
A phage cocktail (BFC-1) with QA/QC
• Lack of well defined and quality controled products
• Bacterial-Phage interaction often not optimized(empiric)
Endotoxin presence (purity)
• A “GMP-like” production product
BFC 1
• A modest and humble protocol did not allow to show clear evidence • BFC-1 application did not provoke any nefast side-effect • Medical and nursing staff got used to the phage therapeutic concept and are
convinced of its intrinsic safety and potential usefullness, especially against MultiDrugResistant (MDR) bacteria
• We are convinced that this small pilot study was a great step into the re-introduction of phage therapy in modern Western medicine
Verbeken et al., Future Medicine, 2, 485-491, 2007.
Merabishvili et al., PLoS ONE. 2009; 4(3): e4944.
Kutter et al, Current Pharmaceutical Biotechnology,11, 69-86, 2010.
Therapeutic application in burns
A first safety study at the MHQA
A phage application at the Queen Astrid Military Hospital under the umbrella of the Helsinki declaration and patients informed
consent
Phage application on shotwound at the Mil. Hosp. in Gori, Georgia