Hurdles in bacteriophage therapy: Deconstructing the parameters

Abstract

Bacterial infections in animals impact our food production, leading to economic losses due to food rejection and the need for preventive and curative measures. Since the onset of the antibiotic era, the rise of antibiotic-resistant pathogens is causing scares in health care and food producing facilities worldwide. In the search of new therapeutics, re-evaluation of bacteriophage (phage) therapy, using naturally occurring bacterial viruses to tackle infections, is gaining interest. Many studies report about phage therapy success, showing the value and power of these natural viruses. Although phages carry some interesting traits and their basic biology is now well understood, this review argues that phage therapy has not revealed all of its secrets and many parameters remain understudied, making the outcome of phage therapy highly variable depending on the disease incidence. These difficulties include poorly understood mechanisms of phage penetration and distribution throughout the body, the variable expression and accessibility of phage receptors on the bacterial host in in vivo conditions and the unusual (non-linear) phage pharmacokinetics. These parameters are not easily measured in realistic in vivo settings, but are nevertheless important hurdles to overcome the high variability of phage therapy trials. This critical approach is in accordance with Goethe's statement; "Difficulties increase the nearer we get to the goal". However, since the importance of the goal itself also rises, both difficulties and goal justify the need for additional in depth research in this domain.

Efficacy of Phage Therapy in Controlling Rabbit Colibacillosis and Changes in Cecal Microbiota

“…We assumed that the inferior phage therapy efficacy could be the results of using an insufficient phage dose. The influence of bacteriophage-to-bacterium ratio was reviewed (Hraiech et al, 2015); and a previous study concluded that a larger phage dose was superior in passive treatments (Tsonos et al, 2014). The sensitivity of ZR1 to ciprofloxacin lactate may play a key role as well.…”

Phage therapy for severe bacterial infections: a narrative review

“…Usually applied to ecological rather than pharmacological systems, the phage replication cycle is generally held to follow classic Lotka–Volterra dynamics of predator (phage) and prey (bacteria), based on population sizes and interactions between them . Classic pharmacokinetic principles, predator–prey, infectious disease model dynamics, and host immune responses must all be considered, but phage pharmacokinetics (phage distribution and clearance), pharmacodynamics (predator–prey dynamics), and ratio of phages to bacteria (multiplicity of infection [MOI], perhaps better described in terms of initial MOI input ) are subject to many, often poorly defined, variables that may influence outcomes …”

“…When administering phages orally, concern has been raised regarding recombination between modular phage genomes in the gut, although there has been little evidence from trials to date to resolve this one way or the other . Phages generally have poor oral bioavailability, but intravenous delivery is efficient to virtually all organs and tissues and first‐dose kinetics can be modelled to some extent by standard techniques, especially after initial parenteral dosing. Original observations, recently repeated overseas and in Australian studies of severe sepsis, show that intravenous phage is cleared typically in the first 60 minutes.…”

Bacterial resistance to antimicrobial agents and its impact on veterinary and human medicine

“…Alternatives to antimicrobial agents : Novel nonantibiotic approaches for prevention of and protection against infectious diseases should be explored . These include the development of vaccines (especially for animal diseases), phage therapy and phage lysin therapy, adjuvants, antivirulence therapies (including synthetic polypeptides that neutralize bacterial pathogenicity factors), pre‐ and probiotics, immunostimulants, antimicrobial peptides (such as cathelicidins, defensins and dermicins), anti‐biofilm therapies and reprogrammed nucleases that target antimicrobial resistance genes …”