Bacteriophage Therapy for Clinical Biofilm Infections: Parameters That Influence Treatment Protocols and Current Treatment Approaches

Abstract

Biofilm infections are extremely difficult to treat, which is secondary to the inability of conventional antibiotics to eradicate biofilms. Consequently, current definitive treatment of biofilm infections requires complete removal of the infected hardware. This causes significant morbidity and mortality to patients and therefore novel therapeutics are needed to cure these infections without removal of the infected hardware. Bacteriophages have intrinsic properties that could be advantageous in the treatment of clinical biofilm infections, but limited knowledge is known about the proper use of bacteriophage therapy in vivo. Currently titers and duration of bacteriophage therapy are the main parameters that are evaluated when devising bacteriophage protocols. Herein, several other important parameters are discussed which if standardized could allow for more effective and reproducible treatment protocols to be formulated. In addition, these parameters are correlated with the current clinical approaches being evaluated in the treatment of clinical biofilm infections.

Successful Treatment of a Recalcitrant Staphylococcus epidermidis Prosthetic Knee Infection with Intraoperative Bacteriophage Therapy

“…This initiates a bacteriophage infection in the biofilm and, given bacteriophage’s ability to self-replicate and increase its concentration, allows for theoretical stepwise degradation of biofilm [ 15 ]. It must be noted that unlike conventional antibiotics, bacteriophages behave differently, and many other parameters (duration of growth inhibition, theoretical multiplicity of infections, rates of resistance development) should be considered to contribute to effective treatment protocols [ 16 ].…”

“…This had implications on our use of this bacteriophage therapy given the unknown distribution of IV phage therapy to the synovium and the dose-dependency seen with in vitro testing displayed in Figure 2 [ 17 ]. We therefore elected to use intraarticular administration to achieve maximum local doses in line with previous reports of successful use of bacteriophage therapy in PJI [ 7 , 16 ]. As well, the use of DAIR removed most of the planktonic bacteria and removed a portion of the chronic biofilm by manual debridement thereby reducing the total number of pathogenic bacteria [ 18 ].…”

Bacteriophage-Derived Depolymerases against Bacterial Biofilm

“…They present high specificity against bacterial species and even strains. Furthermore, the development of bacteriophage resistance is another concern that arises in the case of phage therapy [ 88 ].…”

“…As indicated above, it was proposed to use bacteriophages to treat biofilm infections. Several preclinical animal studies supporting the application of phages in these kinds of infections were described and analyzed by Doub in a recent review paper [ 88 ]. Importantly, the synergistic activity of phages with antibiotics is also observed.…”

“…Importantly, the synergistic activity of phages with antibiotics is also observed. Recently, the quality of phage preparations, their titer and dosage, their routes of administration (local or intravenous), and their safety and interactions with eukaryotic cells have been evaluated and widely discussed in the literature [ 88 , 97 ]. In contrast to the treatment based on the use of whole viral particles, the application of phage-derived depolymerases may overcome these difficulties.…”