The Enemy of our Enemy is our Friend
The Phage: the bacteria eater


To provide an introduction to the ‘phage’ we present some recent articles and reports from bacteriophage experts. A useful introduction to antimicrobial resistance (AMR) sets the background as to why there is a resurgence of interest in bacteriophages - viruses that are the natural enemy of bacteria.

Microbiology Australia - Antimicrobial Resistance

In this issue, we present a series of short overviews on important topics with a common theme. In their paper, Djordjevic and Morgan point out the impact of antimicrobial resistance on food security and remind us of the importance of understanding the relationships between animals (including humans) and the environment when considering antibiotic resistance, particularly those elements of it that are part of normal genomic plasticity and readily transferable. This sentiment is echoed in a sobering description of the classic post-antibiotic opportunist, Clostridium difficile, in Australia and overseas, by Hong et al.

Current state of compassionate phage therapy

There is a current unmet medical need for the treatment of antibiotic-resistant infections, and in the absence of approved alternatives, some clinicians are turning to empirical ones, such as phage therapy, for compassionate treatment. Phage therapy is ideal for compassionate use due to its long-standing historical use and publications, apparent lack of adverse effects, and solid support by fundamental research. Increased media coverage and peer-reviewed articles have given rise to a more widespread familiarity with its therapeutic potential. However, compassionate phage therapy (cPT) remains limited to a small number of experimental treatment centers or associated with individual physicians and researchers. It is possible, with the creation of guidelines and a greater central coordination, that cPT could reach more of those in need, starting by increasing the availability of phages. Subsequent steps, particularly production and purification, are difficult to scale, and treatment paradigms stand highly variable between cases, or are frequently not reported. This article serves both to synopsize cPT publications to date and to discuss currently available phage sources for cPT. As the antibiotic resistance crisis continues to grow and the future of phage therapy clinical trials remains undetermined, cPT represents a possibility for bridging the gap between current treatment failures and future approved alternatives. Streamlining the process of cPT will help to ensure high quality, therapeutically-beneficial, and safe treatment.
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Bacteriophage therapy: coping with the growing antibiotic resistance problem

The global problem of multidrug-resistant bacterial pathogens requires urgent actions, including the development of therapies supplementary or alternative to antibiotics. One of the infection control options could be phage therapy. This article gives a brief overview of phage therapy potentials as well as the challenges it faces in order to become a widely accepted form of infection treatment.

Microbiology Australia - Bacteriophages

In order to avoid a return to the pre-antibiotic era, alternative treatments to combat microbial diseases are urgently needed. In this context, bacteriophages, which have been used effectively in distant parts of the world during the cold war era, are now gaining significant interest in the West. This special issue of the Microbiology Australia thus focuses on bacteriophages with contributions from Australia and from the members of the Expert round table on acceptance and re-implementation of bacteriophage therapy.

Phage Therapy: A Renewed Approach to Combat Antibiotic-Resistant Bacteria

Phage therapy, long overshadowed by chemical antibiotics, is garnering renewed interest in Western medicine. This stems from the rise in frequency of multi-drug-resistant bacterial infections in humans. There also have been recent case reports of phage therapy demonstrating clinical utility in resolving these otherwise intractable infections. Nevertheless, bacteria can readily evolve phage resistance too, making it crucial for modern phage therapy to develop strategies to capitalize on this inevitability. Here, we review the history of phage therapy research. We compare and contrast phage therapy and chemical antibiotics, highlighting their potential synergies when used in combination. We also examine the use of animal models, case studies, and results from clinical trials. Throughout, we explore how the modern scientific community works to improve the reliability and success of phage therapy in the clinic and discuss how to properly evaluate the potential for phage therapy to combat antibiotic-resistant bacteria.

Phage Therapy in the Postantibiotic Era

Antibiotic resistance is arguably the biggest current threat to global health. An increasing number of infections are becoming harder or almost impossible to treat, carrying high morbidity, mortality, and financial cost. The therapeutic use of bacteriophages, viruses that infect and kill bacteria, is well suited to be part of the multidimensional strategies to combat antibiotic resistance. Although phage therapy was first implemented almost a century ago, it was brought to a standstill after the successful introduction of antibiotics. Now, with the rise of antibiotic resistance, phage therapy is experiencing a well-deserved rebirth. 

Among the admittedly vast literature recently published on this topic, this review aims to provide a forward-looking perspective on phage therapy and its role in modern society. We cover the key points of the antibiotic resistance crisis and then explain the biological and evolutionary principles that support the use of phages, their interaction with the immune system, and a comparison with antibiotic therapy. By going through up-to-date reports and, whenever possible, human clinical trials, we examine the versatility of phage therapy. We discuss conventional approaches as well as novel strategies, including the use of phage-antibiotic combinations, phage-derived enzymes, exploitation of phage resistance mechanisms, and phage bioengineering. Finally, we discuss the benefits of phage therapy beyond the clinical perspective, including opportunities for scientific outreach and effective education, interdisciplinary collaboration, cultural and economic growth, and even innovative use of social media, making the case that phage therapy is more than just an alternative to antibiotics.     Copyright © 2019 American Society for Microbiology.

Phage Therapy in the Twenty-First Century: Facing the Decline of The Antibiotic Era; Is it Finally Time for The Age of the Phage?

Burgeoning problems of antimicrobial resistance dictate that new solutions be developed to combat old foes. Use of lytic bacteriophages (phages) for the treatment of drug-resistant bacterial infections is one approach that has gained significant traction in recent years. Fueled by reports of experimental phage therapy cases with very positive patient outcomes, several early-stage clinical trials of therapeutic phage products have been launched in the United States. Eventual licensure enabling widespread access to phages is the goal; however, new paths to regulatory approval and mass-market distribution, distinct from those of small-molecule antibiotics, must be forged first. This review highlights unique aspects related to the clinical use of phages, including advantages to be reaped as well as challenges to be overcome.

Phage therapy: Current status and perspectives

The spread of antimicrobial resistant bacterial pathogens combined with the lack of new drug classes in the antibiotic pipeline causes a resurgence of the use of bacterial viruses (phages) to treat bacterial infections (phage therapy [PT]). There has been a substantial increase in patients subjected to this experimental therapy and emergence of new PT centers in Europe and the United States paralleled by one clinical trial completed in accord with good medical practice (GMP) requirements and a few others underway. What is more, evidence has been accumulating to suggest that phages can also exert anti‐inflammatory and immunomodulatory action which opens new pathways for the development of novel targets for PT. Here we present the status quo of the PT, recent regulatory, and clinical developments as well as new perspectives for its wider application in clinical medicine.

Bacteriophage therapy as an alternative treatment for human infections. A comprehensive review

Bacteriophages, or phages, are viruses that infect bacteria. They were discovered around a century ago and have been used ever since for therapeutic purposes, particularly in former Soviet Union countries. Their use in Western countries was abandoned after the discovery and broad use of penicillin. The rising problem of antimicrobial resistance has revived interest in bacteriophage therapy. The aim of this article is to provide a comprehensive review of all aspects of natural phage therapy.

Clinical indications and compassionate use of phage therapy: personal experience and literature review with a focus on osteoarticular infections

The history of phage therapy started with its first clinical application in 1919 and continues its development to this day. Phages continue to lack any market approval in Western medicine as a recognized drug, but are increasingly used as an experimental therapy for the compassionate treatment of patients experiencing antibiotic failure. The few formal experimental phage clinical trials that have been completed to date have produced inconclusive results on the efficacy of phage therapy, which contradicts the many successful treatment outcomes observed in historical accounts and recent individual case reports. It would therefore be wise to identify why such a discordance exists between trials and compassionate use in order to better develop future phage treatment and clinical applications. 

The multitude of observations reported over the years in the literature constitutes an invaluable experience, and we add to this by presenting a number of cases of patients treated compassionately with phages throughout the past decade with a focus on osteoarticular infections. Additionally, an abundance of scientific literature into phage-related areas is transforming our knowledge base, creating a greater understanding that should be applied for future clinical applications. Due to the increasing number of treatment failures anticipated from the perspective of a possible post-antibiotic era, we believe that the introduction of bacteriophages into the therapeutic arsenal seems a scientifically sound and eminently practicable consideration today as a substitute or adjuvant to antibiotic therapy. View Full-Text

The history and promising future of phage therapy in the military service

The continuous evolvement of bacterial resistance to most, if not all, available antibiotics is a worldwide problem. These strains, frequently isolated from military-associated environments, have created an urgent need to develop supplementary anti-infective modalities. One of the leading directions is phage therapy, which includes the administration of bacteriophages, viruses that specifically target bacteria, as biotherapies. Although neglected in the West until recent years, bacteriophages have been widely studied and clinically administered in the former Soviet Union and Eastern Europe for over a century, where they were found to be incredibly efficient at battling numerous infectious diseases.

In this review, we discuss the high potential of phage therapy as a solution for resistant bacterial infectious diseases relating to military medicine. By describing the historical development and knowledge acquired on phage therapy, we define the advantages of bacteriophages for combating resistant bacteria in multiple settings, such as trauma injuries and foodborne illnesses, as a preventive tool and therapy against biological warfare agents, and more. We also present the most recent successful clinical applications of bacteriophages in military settings worldwide.   We believe that augmenting military medicine by integrating phage therapy is an important and required step in preparedness for the rapidly approaching post–antibiotic era.

Phage Therapy: Past, Present and Future

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Thirty-eight articles.  188 Authors.

Phage therapy: Awakening a sleeping giant

For a century, bacterial viruses called bacteriophages have been exploited as natural antibacterial agents. However, their medicinal potential has not yet been exploited due to readily available and effective antibiotics. After years of extensive use, both properly and improperly, antibiotic-resistant bacteria are becoming more prominent and represent a worldwide public health threat. Most importantly, new antibiotics are not progressing at the same rate as the emergence of resistance. The therapeutic modality of bacteriophages, called phage therapy, offers a clinical option to combat bacteria associated with diseases. Here, we discuss traditional phage therapy approaches, as well as how synthetic biology has allowed for the creation of designer phages for new clinical applications. To implement these technologies, several key aspects and challenges still need to be addressed, such as narrow spectrum, safety, and bacterial resistance. We will summarize our current understanding of how phage treatment elicits mammalian host immune responses, as well bacterial phage resistance development, and the potential impact each will have on phage therapy effectiveness. We conclude by discussing the need for a paradigm shift on how phage therapy strategies are developed.

Phage Therapy: Combating Infections with Potential for Evolving from Merely a Treatment for Complications to Targeting Diseases

Antimicrobial resistance is considered to be one of the greatest challenges of medicine and our civilization. Lack of progress in developing new antibacterial agents has greatly revived interest in using phage therapy to combat antibiotic-resistant infections. Although a number of clinical trials are underway and more are planned, the realistic perspective of registration of phage preparations and their entering the health market and significantly contributing to the current antimicrobial crisis is rather remote. Therefore, in addition to planning further clinical trials, our present approach of phage treatment carried out as experimental therapy (compassionate use) should be expanded to address the growing and urgent needs of increasing cohorts of patients for whom no alternative treatment is currently available. During the past 11 years of our phage therapy center’s operation, we have obtained relevant clinical and laboratory data which not only confirm the safety of the therapy but also provide important information shedding more light on many aspects of the therapy, contributing to its optimization and allowing for construction of the most appropriate clinical trials. New data on phage biology and interactions with the immune system suggest that in the future phage therapy may evolve from dealing with complications to targeting diseases. However, further studies are necessary to confirm this promising trend.

Contrasted coevolutionary dynamics between a bacterial pathogen and its bacteriophages

Many antagonistic interactions between hosts and their parasites result in coevolution. Although coevolution can drive diversity and specificity within species, it is not known whether coevolutionary dynamics differ among functionally similar species. We present evidence of coevolution within simple communities of Pseudomonas aeruginosa PAO1 and a panel of bacteriophages. Pathogen identity affected coevolutionary dynamics. For five of six phages tested, time-shift assays revealed temporal peaks in bacterial resistance and phage infectivity, consistent with frequency-dependent selection (Red Queen dynamics). 

Two of the six phages also imposed additional directional selection, resulting in strongly increased resistance ranges over the entire length of the experiment (ca. 60 generations). Cross-resistance to these two phages was very high, independent of the coevolutionary history of the bacteria. We suggest that coevolutionary dynamics are associated with the nature of the receptor used by the phage for infection. Our results shed light on the coevolutionary process in simple communities and have practical application in the control of bacterial pathogens through the evolutionary training of phages, increasing their virulence and efficacy as therapeutics or disinfectants.

Land of the bacteria-eaters

For hospital workers an outbreak of harmful bacteria in the wards is a nightmare, but what gives bacteria nightmares?  Perhaps the prospect of being eaten alive by a kind of viral parasite called a bacteriophage (bacteria eater): unlike antibiotics, which some bacteria have evolved a resistance to, bacteriophages are alive and so can fight back against bacterial counter-measures. But as yet the evolutionary 'arms race' between bacteria and their viral foes is poorly understood.  In a new study by a team led by Oxford University scientists report a series of experiments examining this eternal war between bacteria and bacteriophages focusing on the bug Pseudomonas aeruginosa.  Pete Wilton asks Alex Betts of Oxford University's Department of Zoology, first author of the study, about how we might recruit bacteriophages to fight for us…

Natural solution to antibiotic resistance: bacteriophages ‘The Living Drugs’

Antibiotics have been a panacea in animal husbandry as well as in human therapy for decades. The huge amount of antibiotics used to induce the growth and protect the health of farm animals has lead to the evolution of bacteria that are resistant to the drug’s effects. Today, many researchers are working with bacteriophages (phages) as an alternative to antibiotics in the control of pathogens for human therapy as well as prevention, biocontrol, and therapy in animal agriculture. 

Phage therapy and biocontrol have yet to fulfill their promise or potential, largely due to several key obstacles to their performance. Several suggestions are shared in order to point a direction for overcoming common obstacles in applied phage technology. The key to successful use of phages in modern scientific, farm, food processing and clinical applications is to understand the common obstacles as well as best practices and to develop answers that work in harmony with nature.

PROs and CONs of Phage Therapy - NCBI

Many publications list advantages and disadvantages associated with phage therapy, which is the use of bacterial viruses to combat populations of nuisance or pathogenic bacteria. The goal of this commentary is to discuss many of those issues in a single location. In terms of “Pros,” for example, phages can be bactericidal, can increase in number over the course of treatment, tend to only minimally disrupt normal flora, are equally effective against antibiotic-sensitive and antibiotic-resistant bacteria, often are easily discovered, seem to be capable of disrupting bacterial biofilms, and can have low inherent toxicities. In addition to these assets, we consider aspects of phage therapy that can contribute to its safety, economics, or convenience, but in ways that are perhaps less essential to the phage potential to combat bacteria. For example, autonomous phage transfer between animals during veterinary application could provide convenience or economic advantages by decreasing the need for repeated phage application, but is not necessarily crucial to therapeutic success. We also consider possible disadvantages to phage use as antibacterial agents. 
These “Cons,” however, tend to be relatively minor.

Felix d’Herelle 1938 Preparation of Therapeutic Bacteriophages - Appendix 1

Translated into English by Sarah J. Kuhl and Hubert Mazure

Bacteriophage Therapy : An Alternative to Conventional Antibiotics

Bacteriophage therapy is an important alternative to antibiotics in the current era of multidrug resistant pathogens. We reviewed the studies that dealt with the therapeutic use of phages from 1966-1996 and few latest ongoing phage therapy projects via internet. Phages were used topically, orally or systemically in Polish and Soviet studies. The success rate found in these studies was 80-95% with few gastrointestinal or allergic side effects. British studies also demonstrated significant efficacy of phages against Escherichia coli, Acinetobacter spp., Pseudomonas spp and Staphylococcus aureus. US studies dealt with improving the bioavailability of phage. Problems faced in these studies have also been discussed.  In conclusion, phage therapy may prove as an important alternative to antibiotics for treating multidrug resistant pathogens.