The relevance of bacteriophage therapy in the era of antibiotic resistant bacteria

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Against a backdrop of rising antibiotic resistance and a dwindling pipeline of new antibacterial drugs, this thesis set out to examine the potential of bacteriophage (phage) therapy as an alternative or complementary means of treating bacterial infection. Phage therapy is used as a frontline antibacterial therapy in the former Soviet bloc countries but remains an unexplored technology in Western science. To investigate the reasons behind this and other aspects of phage therapy, this thesis undertook the development of bacteriophage-based products against two important human bacterial pathogens, methicillin-resistant Staphylococcus aureus (MRSA) and multi-drug resistant Pseudomonas aeruginosa (MRPA). To develop phage products in today’s scientific and regulatory framework it was necessary to return to basic principles. The first stage in this process involved the assembly of reference collections of the target bacteria. Once these were available, bacteriophages were isolated from a range of environmental sources, and their spectrum of activity and physical characteristics evaluated. Bacteriophages with the appropriate reactivity profile were then tested for stability, morphology, and further analysed using molecular biological techniques. Phages with therapeutic potential were then combined into mixtures or “cocktails” and their activity evaluated against clinical isolates from different geographical regions. Lastly, a commercial phage product was used in one compassionate case study involving a hospital patient to treat a refractory P. aeruginosa urinary tract infection. Fifty-two MRPA and fifty-eight MRSA phages were isolated over a period of 18 months. Selected phage therapeutic candidates were shown to be physically stable and genetically different from each other. They also showed a broad spectrum of activity against the targeted pathogens and this resulted in the production of three prototypes cocktails for each target pathogen. The MRPA cocktails achieved a reactivity of 62%-90% against clinical isolates from four geographical areas while the MRSA cocktails achieved a reactivity of 61%-96% in two geographical areas. In the clinic, a compassionate phage therapy treatment was well tolerated, produced no adverse side-effects, and in combination with antibiotics, resulted in the complete eradication of a refractory P. aeruginosa urinary tract infection. This thesis has demonstrated, for the first time in Australia, that it is possible to develop stable, fully characterised, broad-spectrum bacteriophage-based products with the potential to treat human infections caused by MRSA and MRPA. It also showed the value of phage therapy in the clinic by eradicating a chronic P. aeruginosa infection. Furthermore, though not presented in the main body of this thesis, two of the bacteriophage prototypes developed here (one MRSA and one MRPA) were recently shown to be effective in treating bacterial infections in two separate animal models. Phage therapy has the potential to play a major role in addressing the serious problems caused by the ever-widening antibiotic resistance crisis. No doubt, there will be production and regulatory hurdles to overcome and an urgent requirement to train a new generation of microbiologists and clinicians skilled at developing and administering these powerful antibacterials. However, it is now obvious that the old paradigm of depending on a constant stream of novel antibiotics is no longer valid and alternative technologies such as this must be fully explored.
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