*2.4.6 Advantages and challenges of phage therapy*

Among the principal attractive aspects of phage therapy, the main ones are: i) high specificity of the virus for the bacteria providing freedom from side effects on cells that are not targeted by the therapy; ii) activity against different bacteria, including multidrug resistant bacteria; iii) reduced treatment costs compared to antibiotic therapy; iv) prevention to the growth of secondary pathogens; v) ability to degrade bacterial biofilm by lysing bacteria; vi) high body distribution and vii) high efficacy compared to antimicrobials [32]. On the other hand, there are some limitations to the use of phages in therapy, among them: i) the possibility of antibody production by the immune system; ii) the difficulty of measuring the application dose; iii) the possibility of gene transfer among pathogens through phages, which may be responsible for passing pathogenic determinants and virulence factors, resulting in a possible resistance of bacteria; iv) the ability of bacteria to develop resistance against bacteriophages; v) elucidation of the correct route of administration and treatment time and vi) accurate and rapid diagnosis of the microorganism that is provoking the illness [32].

Fortunately, for all the limitations previously indicated, there are already studies that aim to circumvent these problems. For example, viral genome sequencing avoids the use of phages that are lysogenic or contain toxic and resistant genes. Along with this is the progressive search for new phages to be used if antibodies are produced by the immune system, or to replace phages for which the bacteria have become resistant. In addition, it is already known that viruses can mutate and adapt to resistance

mechanisms created by bacteria. In other words, after the creation of barriers that make it impossible for the phage to replicate in the bacteria, changes occur in the viruses that allow their replication cycle to continue, even with the presence of the bacterial adaptations [32]. Further in this context, the use of new diagnostic resources allows the rapid differentiation of the disease-causing bacteria, in addition to the use of cocktails with different phages for the same bacterium, enhancing even more the specificity and avoiding the manifestation of resistance [32, 66].
