Experimental Phage Therapy on Multiple Drug Resistant Pseudomonas aeruginosa Infection in Mice
2013 paper -
Experimental Phage Therapy on Multiple Drug Resistant Pseudomonas aeruginosa Infection in Mice
With the rising prevalence of multiple-antibiotic resistant-bacteria (MDRs) and the lack of development of new antibiotics by the pharmaceutical industries, there is an urgent need to develop novel approaches to combat MDRs, especially Pseudomonas aeruginosa, Escherichia coli and Staphylococcus aureus. Bacteriophage therapy has been applied for decades as a means of treating bacterial infections in some parts of the world and numerous encouraging results have been documented. Here, we present evidence in murine models that animals infected with MDRs P. aeruginosa can be successfully treated with specific bacteriophages that target these MDRs microbes. We utilized three different forms of bacterial infections on Stage II and III wound on deep lower back of animals; deep wound infection and chronic infection treated the each of the infections by respective dermal application of phages. Furthermore, we successfully tested phage therapy for both acute and chronic infections. We evaluate the potential use of lytic phage on wound contraction; we observed drastic changes on the wounds after 24-hours of phage application. Pros and cons of phage therapy to treat human MDRs are discussed.
From later in the paper -
We believe that some of the reasons that phage therapy has not been globally recognized and applied may be due to three major concerns described in the literature [9]. First, the rapid lyses of a large numbers of microbes, especially Gram negative that may release endotoxin (i.e. LPS). In our study, we did not observe any so called
the Jarisch-Herxheimer reaction, in any of our experimental animals. Such results are also reported by others when mass bacteriolyses occurred after antibiotic treatment [30]. Therefore, in all experiments, the animals recovered due to rapid bacterial lysis do not appear to be a serious situation. Phage-treated mice, in fact, remained healthy weeks
after treatment. The above results become more convincing in light of numerous reports documenting phage efficacy in vivo against several [33] methicillin- resistant Staphylococcus aureus (also known as meateating bacteria) and vancomycin-resistant Enterococcus faecium [33].
The second important concern is the by-standard effect, where phages may destroy other non-target microbes and disturb the normal flora. This is not real concern since phages are highly receptor-specific and no such data has been reported elsewhere. And the retrospective history of using phage administration by different routes in several countries has reported no such outcome. There have been almost no report of serious complication related to their use [34], as phages are common entities in the environment and regularly consumed in foods, the development of neutralizing antibodies should not be a significant obstacle during the initial treatment of acute infection, because the kinetics of phage action or lytic enzymes is much faster than immune recognition and antigen processing system by the adoptive immunity. However, even if antibodies are generated by a host against a particular hosts immune system, it is unlikely that the same host will be receiving the exact same phage therapy twice [35-39].
Thirdly, there is a possibility that phage preparations may contain residual bacterial antigens or endotoxins [32]. To address this, bacteriophage production for clinical trials have to follow specific Good Manufacturing Practice (GMP) guidelines with appropriate quality controls [40], and to meet specific standards for purity and sterility.
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A 2014 review paper from the same group-
Bacteriophage therapy: a potential solution for the antibiotic resistance crisis
The emergence of multiple drug-resistant bacteria has prompted interest in alternatives to conventional antimicrobials. One of the possible replacement options for antibiotics is the use of bacteriophages as antimicrobial agents. Phage therapy is an important alternative to antibiotics in the current era of drug-resistant pathogens. Bacteriophages have played an important role in the expansion of molecular biology and have been used as antibacterial agents since 1966. In this review, we describe a brief history of bacteriophages and clinical studies on their use in bacterial disease prophylaxis and therapy. We discuss the advantages and disadvantages of bacteriophages as therapeutic agents in this regard.
The first question every presenter on phage therapy is asked is: If I were to have an infection that antibiotics cannot treat effectively, is there any place where I can receive phage therapy right now? There are two countries where treatment with phages is routinely available in Europe: Georgia [62] and Poland (Russia probably also uses phage therapy, but much less information is available). More recently, the Wound Care Center in Lubbock, Texas used phage therapy [63].
