Bacteriophage therapy
isopycnic gradient centrifugation). 37 Additional procedures may also be performed, such as gene sequencing and the identification of target bacterial receptors. After the preparation process, phages are usually administered in the form of phage cocktails (a concoction of different phages that target the same bacterial strain) to the site of infection for them to immediately initiate their lytic life cycle, either via IV or topical administration. Ideally, following the elimination of the target pathogen, phages, as foreign viral particles whose survival is largely dependent upon the presence of their host, will, therefore, circulate around the body and be degraded by the human body’s innate immu ne system. In the context of AMR, phages exhibit several key pharmacological advantages over traditional broad- spectrum antibiotics. Typically, antibiotics are uniform chemicals with fixed molecular formulae, whereas phages are highly specific and variable viral parasites. When administered, broad-spectrum antibiotics target a comparatively wide range of bacteria throughout the whole body, indiscriminately eliminating a considerable number of bacteria as long as it comes into contact with regardless of their pathogenicity (whether they are the actual pathogenic bacteria responsible for the infection or not). For example, the commensal flora in our intestines that are usually biologically beneficial to our health will also inevitably undergo a massacre, which will eventually lead to a significant disturbance to the pre- established harmonic and dynamic equilibrium of the microbiota ecosystem in the intestines. 38 Phages, by contrast, only target the responsible strain(s) of bacteria without leaving any significant damage to the commensal flora due to their strictly specific nature, thereby helping to maintain the dynamic equilibrium while decimating the pathogenic bacteria. Another promising attribute of phages is their ability to self-amplify at the site of infection. When administered orally or intravenously as a given dose, antibiotics will normally evenly disperse throughout the body, indicating a relatively lower concentration of effective antimicrobial drugs at the site of infection. The high specificity and viral characteristics of phages allow them to reproduce and become selectively concentrated at the site of infection, meaning that, hypothetically, a very small dose of active phages is enough to decimate a specific phage-sensitive bacterial population no matter whether the bacterial target possesses AMR or not. First reported by d’Hérelle (1931), the most distinctive advantage of phages is that they demonstrate dynamic co-evolutionary patterns and superior adaptability with their bacterial hosts. 39 As pathogens mutate, phages evolve nearly simultaneously at a rate no slower than that of bacterial mutations, indicating a type of sustainable ecological equilibrium brought about by nature. Inert antibiotic chemicals, however, will certainly and solely lead to treatment-driven pathogen evolution. In order for antibiotics to tackle this issue using the co-evolutionary model adopted by phages, antibiotics have to be frequently reviewed, regularly updated, and tested continuously in randomized controlled trials (RCTs) as part of the regulatory approval process. Precisely for this reason, the overall process of developing new classes of antibiotics is impracticably expensive, and the pharmaceutical industry is unwilling to spend their research budgets on new products that are bound to offer an unsatisfactory return on investment as it will not take long for bacteria to evolve and develop resistance accordingly against new antibiotics before breaking the even. 40 In view of the fact that new and genuinely
37 Biswas et al. 2002; Luong et al. 2020. 38 Gagliardia et al. 2018. 39 Williams 2009. 40 Pirnay et al. 2018.
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