Phage Therapy of Pseudomonas aeruginosa Infection in a Mouse Burn Wound Model

Department of Microbiology and Immunology, Texas Tech University Health Sciences Center, 3601 4th Street, Lubbock, TX 79430, USA.
Antimicrobial Agents and Chemotherapy (Impact Factor: 4.48). 07/2007; 51(6):1934-8. DOI: 10.1128/AAC.01028-06
Source: PubMed


Mice compromised by a burn wound injury and subjected to a fatal infection with Pseudomonas aeruginosa were administered a single dose of a Pseudomonas aeruginosa phage cocktail consisting of three different P. aeruginosa phages by three different routes: the intramuscular (i.m.), subcutaneous (s.c.), or intraperitoneal (i.p.) route. The results
of these studies indicated that a single dose of the P. aeruginosa phage cocktail could significantly decrease the mortality of thermally injured, P. aeruginosa-infected mice (from 6% survival without treatment to 22 to 87% survival with treatment) and that the route of administration
was particularly important to the efficacy of the treatment, with the i.p. route providing the most significant (87%) protection.
The pharmacokinetics of phage delivery to the blood, spleen, and liver suggested that the phages administered by the i.p.
route were delivered at a higher dose, were delivered earlier, and were delivered for a more sustained period of time than
the phages administered by the i.m. or s.c. route, which may explain the differences in the efficacies of these three different
routes of administration.

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Available from: Joe A Fralick, Nov 17, 2015
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    • "Moreover, only minor side effects were found with antistaphylococcal phages (Kutter & Sulakvelidze, 2004) and no safety concerns were observed when bacteriophages targeting Escherichia coli (Bruttin & Brussow, 2005) or Pseudomonas aeruginosa (Wright et al., 2009) were administered to human volunteers. While recent experiments with patients (Khawaldeh et al., 2011; Pirnay et al., 2011) and animal models (Mcvay et al., 2007; Debarbieux et al., 2010; Morello et al., 2011) show promising results, the biggest and relatively unexplored advantage of phage therapy is the ability of phages to adapt to evolving bacteria (Mizoguchi et al., 2003; Levin & Bull, 2004; Debarbieux et al., 2010; Morello et al., 2011; Betts et al., 2013, 2014). One significant limitation of phage therapy is that bacteria readily evolve resistance to phages (Levin & Bull, 2004; Betts et al., 2013, 2014). "
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    ABSTRACT: Recent years have seen renewed interest in phage therapy - the use of viruses to specifically kill disease-causing bacteria - because of the alarming rise in antibiotic resistance. However, a major limitation of phage therapy is the ease at with bacteria can evolve resistance to phages. Here we determined if in vitro experimental coevolution can increase the efficiency of phage therapy by limiting the resistance evolution of intermittent and chronic cystic fibrosis Pseudomonas aeruginosa lung isolates to four different phages. We first pre-adapted all phage strains against all bacterial strains and then compared the efficacy of pre-adapted and non-adapted phages against ancestral bacterial strains. We found that evolved phages were more efficient in reducing bacterial densities than ancestral phages. This was primarily because only 50% of bacterial strains were able to evolve resistance to evolved phages, while all bacteria were able to evolve some level of resistance to ancestral phages. While the rate of resistance evolution did not differ between intermittent and chronic isolates, it incurred a relatively higher growth cost for chronic isolates when measured in the absence of phages. This is likely to explain why evolved phages were more effective in reducing the densities of chronic isolates. Our data shows that pathogen genotypes respond differently to phage pre-adaptation, and as a result, phage therapies might need to be individually adjusted for different patients. This article is protected by copyright. All rights reserved.
    Journal of Evolutionary Biology 10/2015; DOI:10.1111/jeb.12774 · 3.23 Impact Factor
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    • "Intraperitoneal route provides 87% protection. The pharmacokinetics of bacteriophages suggests that dose delivered to blood, spleen, and liver by intraperitoneal route were delivered earlier, and were delivered for more sustained period of time than doses given by intramascular or subcutaneous route (Catherine et al., 2007). "
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    ABSTRACT: The evolution of antibiotic-resistant in bacteria has aggravated curiosity in development of alternative therapy to conventional drugs. One of the emerging drugs that can be used alternative to antibiotics is bacteriophage therapy. The use of living phages in the cure of lethal infectious life threatening diseases caused by Gram positive and Gram negative bacteria has been reported. Another development in the field of bacteriophage therapy is the use of genetically modified and non replicating phages in the treatment of bacterial infection. Genetically engineered bacteriophages can be used as adjuvant along with antibiotic therapy. Phages encoded with lysosomal enzymes are also effectual in the treatment of infectious diseases.
    Pakistan journal of pharmaceutical sciences 01/2015; 28(1):265-270. · 0.68 Impact Factor
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    • "Phages were shown to be able to rescue burned mice from infection caused by P. aeruginosa and Klebsiella pneumonia [9] [10]. In 1990, in Egypt, 30 patients with burn wounds were treated during 5-17 days with between 15 and 45 phage-saturated dressings [11]. "
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    ABSTRACT: Antibiotic resistance has become a major public health problem and the antibiotics pipeline is running dry. Bacteriophages (phages) may offer an 'innovative' means of infection treatment, which can be combined or alternated with antibiotic therapy and may enhance our abilities to treat bacterial infections successfully. Today, in the Queen Astrid Military Hospital, phage therapy is increasingly considered as part of a salvage therapy for patients in therapeutic dead end, particularly those with multidrug resistant infections. We describe the application of a well-defined and quality controlled phage cocktail, active against Pseudomonas aeruginosa and Staphylococcus aureus, on colonized burn wounds within a modest clinical trial (nine patients, 10 applications), which was approved by a leading Belgian Medical Ethical Committee. No adverse events, clinical abnormalities or changes in laboratory test results that could be related to the application of phages were observed. Unfortunately, this very prudent 'clinical trial' did not allow for an adequate evaluation of the efficacy of the phage cocktail. Nevertheless, this first 'baby step' revealed several pitfalls and lessons for future experimental phage therapy and helped overcome the psychological hurdles that existed to the use of viruses in the treatment of patients in our burn unit.
    International Journal of Burns and Trauma 10/2014; 4(2):66-73.
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