Special Issue "Phage Therapy: A Biological Approach to Treatment of Bacterial Infections"

A special issue of Antibiotics (ISSN 2079-6382). This special issue belongs to the section "Bacteriophages".

Deadline for manuscript submissions: closed (31 March 2020).

Special Issue Editor

Dr. Saija Johanna Kiljunen
E-Mail Website
Guest Editor
Department of Bacteriology and Immunology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
Interests: antibiotic resistance; bacteriophage; phage therapy; phage genomics

Special Issue Information

Dear Colleagues,

The emergence of antibiotic-resistant bacteria due to prolonged use, underuse, or misuse of antibiotics presents a global challenge in terms of increased morbidity, mortality, and healthcare costs. One promising alternative to treat infections caused by antibiotic-resistant bacteria is phage therapy, where the natural predators of bacteria (bacteriophages, phages) are used to kill the pathogens. Phage therapy has a 100-year history, but it was forgotten in the Western countries after the invention of antibiotics. Now renewed interest in phage therapy is emerging and new practices for this biological treatment of bacterial infections are being developed.

This Special Issue "Phage Therapy: A biological Approach to Treatment of Bacterial Infections" covers different aspects of phage therapy. The issue welcomes various submission types, including original research papers, short communications, reviews, case reports, and perspectives. Potential topics for this special issue include, but are not limited to the following:

  • Treatment of human infections
  • Treatment of animal infections
  • Good practices in phage therapy
  • Safety of phage therapy
  • Phage pharmacokinetics
  • Phages in biofilm control and prevention
  • Phage resistance

Dr. Saija Johanna Kiljunen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Antibiotics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Bacteriophages
  • Phage therapy
  • Human infections
  • Animal infections
  • Pharmacokinetics
  • Biofilm control
  • Phage resistance

Published Papers (10 papers)

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Editorial

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Editorial
Editorial for the Special Issue: “Phage Therapy: A Biological Approach to Treatment of Bacterial Infections”
Antibiotics 2020, 9(10), 721; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9100721 - 21 Oct 2020
Viewed by 567
Abstract
The emergence of antibiotic-resistant bacteria presents a major challenge in terms of increased morbidity, mortality, and healthcare costs [...] Full article

Research

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Article
Adapting a Phage to Combat Phage Resistance
Antibiotics 2020, 9(6), 291; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9060291 - 29 May 2020
Cited by 6 | Viewed by 1668
Abstract
Phage therapy is becoming a widely recognized alternative for fighting pathogenic bacteria due to increasing antibiotic resistance problems. However, one of the common concerns related to the use of phages is the evolution of bacterial resistance against the phages, putatively disabling the treatment. [...] Read more.
Phage therapy is becoming a widely recognized alternative for fighting pathogenic bacteria due to increasing antibiotic resistance problems. However, one of the common concerns related to the use of phages is the evolution of bacterial resistance against the phages, putatively disabling the treatment. Experimental adaptation of the phage (phage training) to infect a resistant host has been used to combat this problem. Yet, there is very little information on the trade-offs of phage infectivity and host range. Here we co-cultured a myophage FCV-1 with its host, the fish pathogen Flavobacterium columnare, in lake water and monitored the interaction for a one-month period. Phage resistance was detected within one day of co-culture in the majority of the bacterial isolates (16 out of the 18 co-evolved clones). The primary phage resistance mechanism suggests defense via surface modifications, as the phage numbers rose in the first two days of the experiment and remained stable thereafter. However, one bacterial isolate had acquired a spacer in its CRISPR (Clustered Regularly Interspaced Short Palindromic Repeat)-Cas locus, indicating that also CRISPR-Cas defense was employed in the phage-host interactions. After a week of co-culture, a phage isolate was obtained that was able to infect 18 out of the 32 otherwise resistant clones isolated during the experiment. Phage genome sequencing revealed several mutations in two open reading frames (ORFs) likely to be involved in the regained infectivity of the evolved phage. Their location in the genome suggests that they encode tail genes. Characterization of this evolved phage, however, showed a direct cost for the ability to infect several otherwise resistant clones—adsorption was significantly lower than in the ancestral phage. This work describes a method for adapting the phage to overcome phage resistance in a fish pathogenic system. Full article
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Article
The Israeli Phage Bank (IPB)
Antibiotics 2020, 9(5), 269; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9050269 - 21 May 2020
Cited by 7 | Viewed by 2283
Abstract
A key element in phage therapy is the establishment of large phage collections, termed herein “banks”, where many well-characterized phages, ready to be used in the clinic, are stored. These phage banks serve for both research and clinical purposes. Phage banks are also [...] Read more.
A key element in phage therapy is the establishment of large phage collections, termed herein “banks”, where many well-characterized phages, ready to be used in the clinic, are stored. These phage banks serve for both research and clinical purposes. Phage banks are also a key element in clinical phage microbiology, the prior treatment matching of phages and antibiotics to specific bacterial targets. A worldwide network of phage banks can promote a phage-based solution for any isolated bacteria. Herein, we describe the Israeli Phage Bank (IPB) established in the Hebrew University, Jerusalem, which currently has over 300 phages matching 16 bacteria, mainly pathogens. The phage bank is constantly isolating new phages and developing methods for phage isolation and characterization. The information on the phages and bacteria stored in the bank is available online. Full article
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Article
Investigating Bacteriophages Targeting the Opportunistic Pathogen Acinetobacter baumannii
Antibiotics 2020, 9(4), 200; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9040200 - 22 Apr 2020
Cited by 7 | Viewed by 1676
Abstract
The multi-drug resistance of the opportunistic pathogen Acinetobacter baumannii is of growing concern, with many clinical isolates proving to be resistant to last resort as well as front line antibiotic treatments. The use of bacteriophages is an attractive alternative to controlling and treating [...] Read more.
The multi-drug resistance of the opportunistic pathogen Acinetobacter baumannii is of growing concern, with many clinical isolates proving to be resistant to last resort as well as front line antibiotic treatments. The use of bacteriophages is an attractive alternative to controlling and treating this emerging nosocomial pathogen. In this study, we have investigated bacteriophages collected from hospital wastewater in Thailand and we have explored their activity against clinical isolates of A. baumannii. Bacteriophage vB_AbaM_PhT2 showed 28% host range against 150 multidrug resistant (MDR) isolates and whole genome sequencing did not detect any known virulence factors or antibiotic resistance genes. Purified vB_AbaM_PhT2 samples had endotoxin levels below those recommended for preclinical trials and were not shown to be directly cytotoxic to human cell lines in vitro. The treatment of human brain and bladder cell lines grown in the presence of A. baumannii with this bacteriophage released significantly less lactate dehydrogenase compared to samples with no bacteriophage treatment, indicating that vB_AbaM_PhT2 can protect from A. baumannii induced cellular damage. Our results have also indicated that there is synergy between this bacteriophage and the end line antibiotic colistin. We therefore propose bacteriophage vB_AbaM_PhT2 as a good candidate for future research and for its potential development into a surface antimicrobial for use in hospitals. Full article
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Article
The Fate of Bacteriophages in Recirculating Aquaculture Systems (RAS)—Towards Developing Phage Therapy for RAS
Antibiotics 2019, 8(4), 192; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8040192 - 24 Oct 2019
Cited by 10 | Viewed by 2375
Abstract
Aquaculture production has increased tremendously during the last decades, and new techniques have been developed, e.g., recirculating aquaculture systems (RAS). In RAS, the majority of water volume is circulated via mechanical and biological filters and reused in the tanks. However, the prevention and [...] Read more.
Aquaculture production has increased tremendously during the last decades, and new techniques have been developed, e.g., recirculating aquaculture systems (RAS). In RAS, the majority of water volume is circulated via mechanical and biological filters and reused in the tanks. However, the prevention and treatment of diseases in these systems are challenging, as the pathogens spread throughout the system, and the addition of chemicals and antibiotics disrupts the microbiome of the biofilters. The increasing antibiotic resistance has made phage therapy a relevant alternative for antibiotics in food production. Indeed, as host-specific and self-replicating agent they might be optimal for targeted pathogen eradication in RAS. We tested the survival and spread of Flavobacterium columnare -infecting phage FCL-2 in recirculating aquaculture fish farm with rainbow trout (Oncorhynchus mykiss) in a fully controlled study. After a single addition, phage persisted in water samples collected from tank, fixed bed, moving bed, and aeration unit up to 14 days, and in the water of rearing tanks, rainbow trout mucus, and bioreactor carrier media from the fixed and moving bed biofilters for 21 days. Furthermore, phage adsorbed preferentially to moving bed carrier media, which contained biofilm attached and from which higher phage numbers were recovered. This study shows phages as a potent strategy for maintaining biosecurity in RAS systems. Full article
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Review

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Review
Phages as a Cohesive Prophylactic and Therapeutic Approach in Aquaculture Systems
Antibiotics 2020, 9(9), 564; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9090564 - 01 Sep 2020
Cited by 4 | Viewed by 1106
Abstract
Facing antibiotic resistance has provoked a continuously growing focus on phage therapy. Although the greatest emphasis has always been placed on phage treatment in humans, behind phage application lies a complex approach that can be usefully adopted by the food industry, from hatcheries [...] Read more.
Facing antibiotic resistance has provoked a continuously growing focus on phage therapy. Although the greatest emphasis has always been placed on phage treatment in humans, behind phage application lies a complex approach that can be usefully adopted by the food industry, from hatcheries and croplands to ready-to-eat products. Such diverse businesses require an efficient method for combating highly pathogenic bacteria since antibiotic resistance concerns every aspect of human life. Despite the vast abundance of phages on Earth, the aquatic environment has been considered their most natural habitat. Water favors multidirectional Brownian motion and increases the possibility of contact between phage particles and their bacterial hosts. As the global production of aquatic organisms has rapidly grown over the past decades, phage treatment of bacterial infections seems to be an obvious and promising solution in this market sector. Pathogenic bacteria, such as Aeromonas and Vibrio, have already proved to be responsible for mass mortalities in aquatic systems, resulting in economic losses. The main objective of this work is to summarize, from a scientific and industry perspective, the recent data regarding phage application in the form of targeted probiotics and therapeutic agents in aquaculture niches. Full article
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Review
A Review of Topical Phage Therapy for Chronically Infected Wounds and Preparations for a Randomized Adaptive Clinical Trial Evaluating Topical Phage Therapy in Chronically Infected Diabetic Foot Ulcers
Antibiotics 2020, 9(7), 377; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9070377 - 04 Jul 2020
Cited by 5 | Viewed by 1606
Abstract
The advent and increasing prevalence of antimicrobial resistance commensurate with the absence of novel antibiotics on the horizon raises the specter of untreatable infections. Phages have been safely administered to thousands of patients exhibiting signals of efficacy in many experiencing infections refractory to [...] Read more.
The advent and increasing prevalence of antimicrobial resistance commensurate with the absence of novel antibiotics on the horizon raises the specter of untreatable infections. Phages have been safely administered to thousands of patients exhibiting signals of efficacy in many experiencing infections refractory to antecedent antibiotics. Topical phage therapy may represent a convenient and efficacious treatment modality for chronic refractory infected cutaneous wounds spanning all classifications including venous stasis, burn-mediated, and diabetic ulcers. We will initially provide results from a systematic literature review of topical phage therapy used clinically in refractorily infected chronic wounds. We will then segue into a synopsis of the preparations for a forthcoming phase II a randomized placebo-controlled clinical trial assessing the therapeutic efficacy exploiting adjunctive personalized phage administration, delivered topically, intravenously (IV) and via a combination of both modalities (IV + topical) in the treatment of infected diabetic foot ulcers (perhaps the canonical paradigm representing complicated recalcitrant infected cutaneous wounds). Full article
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Review
Phage Therapy as a Novel Strategy in the Treatment of Urinary Tract Infections Caused by E. Coli
Antibiotics 2020, 9(6), 304; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9060304 - 05 Jun 2020
Cited by 9 | Viewed by 1612
Abstract
Urinary tract infections (UTIs) are regarded as one of the most common bacterial infections affecting millions of people, in all age groups, annually in the world. The major causative agent of complicated and uncomplicated UTIs are uropathogenic E. coli strains (UPECs). Huge problems [...] Read more.
Urinary tract infections (UTIs) are regarded as one of the most common bacterial infections affecting millions of people, in all age groups, annually in the world. The major causative agent of complicated and uncomplicated UTIs are uropathogenic E. coli strains (UPECs). Huge problems with infections of this type are their chronicity and periodic recurrences. Other disadvantages that are associated with UTIs are accompanying complications and high costs of health care, systematically increasing resistance of uropathogens to routinely used antibiotics, as well as biofilm formation by them. This creates the need to develop new approaches for the prevention and treatment of UTIs, among which phage therapy has a dominant potential to eliminate uropathogens within urinary tract. Due to the growing interest in such therapy in the last decade, the bacteriophages (natural, genetically modified, engineered, or combined with antibiotics or disinfectants) represent an innovative antimicrobial alternative and a strategy for managing the resistance of uropathogenic microorganisms and controlling UTIs. Full article
Review
Phage-Antibiotic Combination Treatments: Antagonistic Impacts of Antibiotics on the Pharmacodynamics of Phage Therapy?
Antibiotics 2019, 8(4), 182; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics8040182 - 11 Oct 2019
Cited by 29 | Viewed by 3881
Abstract
Bacteria can evolve resistance to antibiotics. Even without changing genetically, bacteria also can display tolerance to antibiotic treatments. Many antibiotics are also broadly acting, as can result in excessive modifications of body microbiomes. Particularly for antibiotics of last resort or in treating extremely [...] Read more.
Bacteria can evolve resistance to antibiotics. Even without changing genetically, bacteria also can display tolerance to antibiotic treatments. Many antibiotics are also broadly acting, as can result in excessive modifications of body microbiomes. Particularly for antibiotics of last resort or in treating extremely ill patients, antibiotics furthermore can display excessive toxicities. Antibiotics nevertheless remain the standard of care for bacterial infections, and rightly so given their long track records of both antibacterial efficacy and infrequency of severe side effects. Antibiotics do not successfully cure all treated bacterial infections, however, thereby providing a utility to alternative antibacterial approaches. One such approach is the use of bacteriophages, the viruses of bacteria. This nearly 100-year-old bactericidal, anti-infection technology can be effective against antibiotic-resistant or -tolerant bacteria, including bacterial biofilms and persister cells. Ideally phages could be used in combination with standard antibiotics while retaining their anti-bacterial pharmacodynamic activity, this despite antibiotics interfering with aspects of bacterial metabolism that are also required for full phage infection activity. Here I examine the literature of pre-clinical phage-antibiotic combination treatments, with emphasis on antibiotic-susceptible bacterial targets. I review evidence of antibiotic interference with phage infection activity along with its converse: phage antibacterial functioning despite antibiotic presence. Full article
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Other

Case Report
Bacteriophage Therapy for Critical Infections Related to Cardiothoracic Surgery
Antibiotics 2020, 9(5), 232; https://0-doi-org.brum.beds.ac.uk/10.3390/antibiotics9050232 - 05 May 2020
Cited by 8 | Viewed by 1853
Abstract
(1) Objective: Bacterial resistance to conventional antibiotic therapy is an increasingly significant worldwide challenge to human health. The objective is to evaluate whether bacteriophage therapy could complement or be a viable alternative to conventional antibiotic therapy in critical cases of bacterial infection related [...] Read more.
(1) Objective: Bacterial resistance to conventional antibiotic therapy is an increasingly significant worldwide challenge to human health. The objective is to evaluate whether bacteriophage therapy could complement or be a viable alternative to conventional antibiotic therapy in critical cases of bacterial infection related to cardiothoracic surgery. (2) Methods: Since September 2015, eight patients with multi-drug resistant or especially recalcitrant Staphylococcus aureus, Enterococcus faecium, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli infections were treated with bacteriophage preparations as a therapy of last resort according to Article 37 of the Declaration of Helsinki. Patients had infections associated with immunosuppression after organ transplantation or had infections of vascular grafts, implanted medical devices, and surgical wounds. Individualized phage preparations were administered locally, orally, or via inhalation for different durations depending on the case. All patients remained on conventional antibiotics during bacteriophage treatment. (3) Results: Patients ranged in age from 13 to 66 years old (average 48.5 ± 16.7) with seven males and one female. Eradication of target bacteria was reached in seven of eight patients. No severe adverse side effects were observed. (4) Conclusions: Phage therapy can effectively treat bacterial infections related to cardiothoracic surgery when conventional antibiotic therapy fails. Full article
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