Practical Assessment of an Interdisciplinary Bacteriophage Delivery Pipeline for Personalized Therapy of Gram-Negative Bacterial Infections (original) (raw)
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PLOS One, 2009
We describe the small-scale, laboratory-based, production and quality control of a cocktail, consisting of exclusively lytic bacteriophages, designed for the treatment of Pseudomonas aeruginosa and Staphylococcus aureus infections in burn wound patients. Based on succesive selection rounds three bacteriophages were retained from an initial pool of 82 P. aeruginosa and 8 S. aureus bacteriophages, specific for prevalent P. aeruginosa and S. aureus strains in the Burn Centre of the Queen Astrid Military Hospital in Brussels, Belgium. This cocktail, consisting of P. aeruginosa phages 14/1 (Myoviridae) and PNM (Podoviridae) and S. aureus phage ISP (Myoviridae) was produced and purified of endotoxin. Quality control included Stability (shelf life), determination of pyrogenicity, sterility and cytotoxicity, confirmation of the absence of temperate bacteriophages and transmission electron microscopy-based confirmation of the presence of the expected virion morphologic particles as well as of their specific interaction with the target bacteria. Bacteriophage genome and proteome analysis confirmed the lytic nature of the bacteriophages, the absence of toxin-coding genes and showed that the selected phages 14/1, PNM and ISP are close relatives of respectively F8, wKMV and phage G1. The bacteriophage cocktail is currently being evaluated in a pilot clinical study cleared by a leading Medical Ethical Committee.
Phage therapy for severe bacterial infections: a narrative review
Medical Journal of Australia
Bacteriophage susceptibility testing Phage-susceptibility testing of bacterial isolates with the standard double-layer method: 33 (A) susceptible isolate-productive infection and formation of individual plaques detectable at serially diluted phage lysate-and (B) resistant isolate-single plaques absent and early bacterial lysis present only at high concertation of phages. Liquid culture-based system: (C) across a gradient of multiplicity of infections (MOIs) against eight bacteria on a single 96-well plate. There are seven MOIs tested from highest to lowest (left to right). Column eight and nine are phage-only and bacteria-only controls. (D) Bacterial growth kinetics in presence of phage at differing MOIs. ◆ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Constructing and Characterizing Bacteriophage Libraries for Phage Therapy of Human Infections
Frontiers in Microbiology, 2019
Phage therapy requires libraries of well-characterized phages. Here we describe the generation of phage libraries for three target species: Escherichia coli, Pseudomonas aeruginosa, and Enterobacter cloacae. The basic phage characteristics on the isolation host, sequence analysis, growth properties, and host range and virulence on a number of contemporary clinical isolates are presented. This information is required before phages can be added to a phage library for potential human use or sharing between laboratories for use in compassionate use protocols in humans under eIND (emergency investigational new drug). Clinical scenarios in which these phages can potentially be used are discussed. The phages presented here are currently being characterized in animal models and are available for eINDs.
Open Forum Infectious Diseases, 2020
Background Due to increasing multidrug-resistant (MDR) infections, there is an interest in assessing the use of bacteriophage therapy (BT) as an antibiotic alternative. After the first successful case of intravenous BT to treat a systemic MDR infection at our institution in 2017, the Center for Innovative Phage Applications and Therapeutics (IPATH) was created at the University of California, San Diego, in June 2018. Methods We reviewed IPATH consult requests from June 1, 2018, to April 30, 2020, and reviewed the regulatory process of initiating BT on a compassionate basis in the United States. We also reviewed outcomes of the first 10 cases at our center treated with intravenous BT (from April 1, 2017, onwards). Results Among 785 BT requests to IPATH, BT was administered to 17 of 119 patients in whom it was recommended. One-third of requests were for Pseudomonas aeruginosa, Staphylococcus aureus, and Mycobacterium abscessus. Intravenous BT was safe with a successful outcome in 7/10...
Viruses
Bacteriophages represent an effective, natural, and safe strategy against bacterial infections. Multiple studies have assessed phage therapy’s efficacy and safety as an alternative approach to combat the emergence of multi drug-resistant pathogens. This systematic review critically evaluates and summarizes published articles on phages as a treatment option for Staphylococcus aureus, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Enterococcus faecalis infection models. It also illustrates appropriate phage selection criteria, as well as recommendations for successful therapy. Published studies included in this review were identified through EMBASE, PubMed, and Web of Science databases and were published in the years between 2010 to 2020. Among 1082 identified articles, 29 studies were selected using specific inclusion and exclusion criteria and evaluated. Most studies (93.1%) showed high efficacy and safety for the tested phages, and a few studies also examined the effect of phag...
A Way Forward for Phage Therapy in the United States
Georgetown medical review, 2024
Phage therapy is a potentially life-saving treatment for antibiotic-resistant infections, but it is not commonly available in the United States as it is in other parts of the world. Phage therapy is a historical practice in the former Soviet Union and Russia to treat bacterial infections. Since phages are naturally present in the environment, only synthetic bacteriophage that has been genetically engineered can be patented by pharmaceutical companies which makes it a difficult practice to integrate into clinical care in the United States. However, the growing costs of antibiotic resistance and recent advances in biotechnology are prompting US government agencies to partner with industry to support the development synthetic phage to combat antibiotic resistance. Although very few phages therapy clinical trials have progressed past phase two, there is incredible potential for further development. This review evaluates the outlook of phage therapy in the U.S. by evaluating the risk of widespread phage resistance against its potential benefits as effective products that target bacterial resistance mechanisms and increase antibiotic susceptibility.
Defence Life Science Journal
Emerging antibiotic resistance is one of the most important microbiological issues of the 21st century. This poses a query regarding the future use of antibiotics and availability of other promising therapeutic alternatives. The awareness about antibiotic misuse has improved insufficiently and is evident by the increased incidences of multidrug resistant infections globally. Amongst different antibacterial therapeutic approaches phage therapy has created a niche of its own due to continuous use for treatment of human infections in Eastern Europe. Synergistic compounds along with phages have also been proposed as a better alternative compared to antibiotics or phage alone for treatment of chronic cases and seriously debilitating diseases. As such, why not allow custom made phage therapy for treatment of chronic infections? However, the success of phage therapy will depend upon instant availability of characterised bacteriophages from bacteriophage banks which may serve as the major c...
Journal of Clinical Microbiology, 2019
Treatment of bacterial infections is increasingly challenged by resistance to currently available antibacterial agents. Not only are such agents less likely to be active today than they were in the past, but their very use has selected for and continues to select for further resistance. Additional strategies for the management of bacterial illnesses must be identified. In this review, bacteriophage-based therapies are presented as one promising approach. In anticipation of their potential expansion into clinical medicine, clinical microbiologists may wish to acquaint themselves with bacteriophages and their antibacterial components and, specifically, with methods for testing them. Here, we reviewed the literature spanning January 2007 to March 2019 on bacteriophage and phage-encoded protein therapies of relevance to clinical microbiology. KEYWORDS bacteriophages F ollowing the early therapeutic application of bacteriophages (phages) in France in the 1930s, industrial investment in phage production took place across Europe, the former Soviet Union, and the United States (1). The popularity of human phage therapy waned in Western countries with the advent of antibiotics; as chemicals, antibiotics were easier to test in the clinical laboratory and administer than were bacteriophages. At the time, there was also an underdeveloped understanding of phage biology and a lack of standardized in vitro methods to assess bacteriophage activity, alongside a lack of clinical trial methodologies to evaluate them; what clinical data were available yielded inconsistent results (1). Today, phages continue to be used clinically in parts of Eastern Europe as well as the former Soviet Union (e.g., Poland, the Republic of Georgia) (1-4) and are also used in agronomy and food processing (5), as well as in veterinary medicine (6). With the current challenge of antibiotic resistance, the case for human phage therapy in Western medicine has been reopened. In addition, the potential use of phage components as antibacterial agents is being evaluated. While there are no U.S. Food and Drug Administration (FDA)-approved bacteriophages or phage component products available for human clinical application in the United States, some are being administered on an expanded-access basis, with others being used in clinical trials. Clinical microbiologists have historically used phages for phage typing to differentiate between bacterial strains as part of outbreak investigations, though with the advent of molecular techniques, including, most recently, whole-genome sequencing, younger clinical microbiologists may be unfamiliar with phage-based testing. In anticipation of the potential expansion of phage therapy into clinical medicine, clinical microbiologists may wish to acquaint themselves with bacteriophages and their antibacterial components and specifically with methods for testing them. Here, we review