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Viruses
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State-of-the-Art Phage Therapy Development in Europe
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State-of-the-Art Phage Therapy Development in Europe

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Bacterial Viruses".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 80280

Special Issue Editors

Dr. Ryszard Międzybrodzki

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Guest Editor
Bacteriophage Laboratory, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences (HIIET PAS), 53-114 Wrocław, Poland
Interests: bacteriophage; phage therapy
Prof. Dr. Nina Chanishvili

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Guest Editor
Eliava Institute of Bacteriophage, Microbiology and Virology, Tbilisi 0160, Georgia
Interests: bacteriophage research; phage therapy
Special Issues, Collections and Topics in MDPI journals
Dr. Nina V. Tikunova

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Guest Editor
Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, 630090 Novosibirsk, Russia
Interests: bacteriophage research; phage therapy
Special Issues, Collections and Topics in MDPI journals
Dr. Jean-Paul Pirnay

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Guest Editor
Laboratory for Molecular and Cellular Technology, Queen Astrid Military Hospital, 1120 Brussels, Belgium
Interests: bacteriophage; phage therapy
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Petar Knezevic

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Guest Editor
Department of Biology and Ecology, Faculty of Sciences, Trg Dositeja Obradovica 3, University of Novi Sad, 21000 Novi Sad, Serbia
Interests: bacteriophages; antimicrobial agents; bacterial biofilm; multidrug-resistant bacteria; Pseudomonas aeruginosa; phage therapy
Special Issues, Collections and Topics in MDPI journals
Dr. Shawna McCallin

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Guest Editor
Phage Therapy and Research Group, Department of Neuro-Urology, Balgrist University Hospital, University of Zürich, 340 Forchstrasse 8008 Zürich, Switzerland
Interests: bacteriophage; phage therapy

Special Issue Information

Dear Colleagues,

Phage therapy, the use of bacteriophages—the viruses of bacteria—to treat bacterial infections, has been studied since 1919, with substantial use of bacteriophages in Europe and North America. However, since the 1950s, the interest in phage therapy has slowly declined in favor of antibiotics. Today, Western countries are trying to rehabilitate phage therapy as an additional tool in the fight against antibiotic-resistant infections. Meanwhile, medicinal product development, manufacturing and marketing requirements have become significantly more stringent. However, even though bacteriophages have been classified as medicinal products in Europe, they have a number of peculiarities (e.g., target specificity and antagonistic coevolution) making them quite different from conventional medicines. This Special Issue of the journal Viruses is focused on the solutions being explored by European phage therapy stakeholders to accelerate the availability of bacteriophages for the treatment of an increasing number of desperate patients.

In this Special Issue we aim to address the topics related to:  

  • experimental and applied phage therapy;
  • host–pathogen interactions and co-evolution;
  • phage therapy in animal models;
  • principle for selection and construction of bacteriophages for therapy;
  • immune response to phage therapy;
  • case studies;
  • clinical trials.

We welcome the submission of resesearch articles, short communications and reviews.

Dr. Ryszard Międzybrodzki
Dr. Nina Chanishvili
Dr. Nina V. Tikunova
Dr. Jean-Paul Pirnay
Dr. Petar Knezevic
Dr. Shawna McCallin
Guest Editors

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 submissions that pass pre-check are 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. Viruses 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 2600 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.

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Published Papers (19 papers)

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33 pages, 7671 KiB  
Article
Phenotypic and Genetic Characterization of Aeromonas hydrophila Phage AhMtk13a and Evaluation of Its Therapeutic Potential on Simulated Aeromonas Infection in Danio rerio
by Nino Janelidze, Ekaterine Jaiani, Elene Didebulidze, Ia Kusradze, Adam Kotorashvili, Kristine Chalidze, Ketevan Porchkhidze, Tinatin Khukhunashvili, George Tsertsvadze, Dodo Jgenti, Tamaz Bajashvili and Marina Tediashvili
Viruses 2022, 14(2), 412; https://0-doi-org.brum.beds.ac.uk/10.3390/v14020412 - 17 Feb 2022
Cited by 4 | Viewed by 2737
Abstract
Phage therapy can be an effective alternative to standard antimicrobial chemotherapy for control of Aeromonas hydrophila infections in aquaculture. Aeromonas hydrophila-specific phages AhMtk13a and AhMtk13b were studied for basic biological properties and genome characteristics. Phage AhMtk13a (Myovirus, 163,879 bp genome, 41.21% CG [...] Read more.
Phage therapy can be an effective alternative to standard antimicrobial chemotherapy for control of Aeromonas hydrophila infections in aquaculture. Aeromonas hydrophila-specific phages AhMtk13a and AhMtk13b were studied for basic biological properties and genome characteristics. Phage AhMtk13a (Myovirus, 163,879 bp genome, 41.21% CG content) was selected based on broad lytic spectrum and physiologic parameters indicating its lytic nature. The therapeutic potential of phage AhMtk13a was evaluated in experimental studies in zebrafish challenged with A. hydrophila GW3-10 via intraperitoneal injection and passive immersion in aquaria water. In experimental series 1 with single introduction of AhMtk13a phage to aquaria water at phage–bacteria ratio 10:1, cumulative mortality 44% and 62% was registered in fish exposed to phage immediately and in 4 h after bacterial challenge, correspondingly, compared to 78% mortality in the group with no added phage. In experimental series 2 with triple application of AhMtk13a phage at ratio 100:1, the mortality comprised 15% in phage-treated group compared to the 55% in the control group. Aeromonas hydrophila GW3-10 was not detectable in aquaria water from day 9 but still present in fish at low concentration. AhMtk13a phage was maintained in fish and water throughout the experiment at the higher concentration in infected fish. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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18 pages, 7828 KiB  
Article
Preclinical Assessment of Bacteriophage Therapy against Experimental Acinetobacter baumannii Lung Infection
by Sandra-Maria Wienhold, Markus C. Brack, Geraldine Nouailles, Gopinath Krishnamoorthy, Imke H. E. Korf, Claudius Seitz, Sarah Wienecke, Kristina Dietert, Corinne Gurtner, Olivia Kershaw, Achim D. Gruber, Anton Ross, Holger Ziehr, Manfred Rohde, Jens Neudecker, Jasmin Lienau, Norbert Suttorp, Stefan Hippenstiel, Andreas C. Hocke, Christine Rohde and Martin Witzenrathadd Show full author list remove Hide full author list
Viruses 2022, 14(1), 33; https://0-doi-org.brum.beds.ac.uk/10.3390/v14010033 - 24 Dec 2021
Cited by 5 | Viewed by 3979
Abstract
Respiratory infections caused by multidrug-resistant Acinetobacter baumannii are difficult to treat and associated with high mortality among critically ill hospitalized patients. Bacteriophages (phages) eliminate pathogens with high host specificity and efficacy. However, the lack of appropriate preclinical experimental models hampers the progress of [...] Read more.
Respiratory infections caused by multidrug-resistant Acinetobacter baumannii are difficult to treat and associated with high mortality among critically ill hospitalized patients. Bacteriophages (phages) eliminate pathogens with high host specificity and efficacy. However, the lack of appropriate preclinical experimental models hampers the progress of clinical development of phages as therapeutic agents. Therefore, we tested the efficacy of a purified lytic phage, vB_AbaM_Acibel004, against multidrug-resistant A. baumannii clinical isolate RUH 2037 infection in immunocompetent mice and a human lung tissue model. Sham- and A. baumannii-infected mice received a single-dose of phage or buffer via intratracheal aerosolization. Group-specific differences in bacterial burden, immune and clinical responses were compared. Phage-treated mice not only recovered faster from infection-associated hypothermia but also had lower pulmonary bacterial burden, lower lung permeability, and cytokine release. Histopathological examination revealed less inflammation with unaffected inflammatory cellular recruitment. No phage-specific adverse events were noted. Additionally, the bactericidal effect of the purified phage on A. baumannii was confirmed after single-dose treatment in an ex vivo human lung infection model. Taken together, our data suggest that the investigated phage has significant potential to treat multidrug-resistant A. baumannii infections and further support the development of appropriate methods for preclinical evaluation of antibacterial efficacy of phages. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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14 pages, 3112 KiB  
Article
Phage Therapy Related Microbial Succession Associated with Successful Clinical Outcome for a Recurrent Urinary Tract Infection
by Austen Terwilliger, Justin Clark, Maile Karris, Haroldo Hernandez-Santos, Sabrina Green, Saima Aslam and Anthony Maresso
Viruses 2021, 13(10), 2049; https://0-doi-org.brum.beds.ac.uk/10.3390/v13102049 - 12 Oct 2021
Cited by 30 | Viewed by 7587
Abstract
We rationally designed a bacteriophage cocktail to treat a 56-year-old male liver transplant patient with complex, recurrent prostate and urinary tract infections caused by an extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) (UCS1). We screened our library for phages that killed [...] Read more.
We rationally designed a bacteriophage cocktail to treat a 56-year-old male liver transplant patient with complex, recurrent prostate and urinary tract infections caused by an extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli (E. coli) (UCS1). We screened our library for phages that killed UCS1, with four promising candidates chosen for their virulence, mucolytic properties, and ability to reduce bacterial resistance. The patient received 2 weeks of intravenous phage cocktail with concomitant ertapenem for 6 weeks. Weekly serum and urine samples were collected to track the patient’s response. The patient tolerated the phage therapy without any adverse events with symptom resolution. The neutralization of the phage activity occurred with sera collected 1 to 4 weeks after the first phage treatment. This was consistent with immunoassays that detected the upregulation of immune stimulatory analytes. The patient developed asymptomatic recurrent bacteriuria 6 and 11 weeks following the end of phage therapy—a condition that did not require antibiotic treatment. The bacteriuria was caused by a sister strain of E. coli (UCS1.1) that remained susceptible to the original phage cocktail and possessed putative mutations in the proteins involved in adhesion and invasion compared to UCS1. This study highlights the utility of rationally designed phage cocktails with antibiotics at controlling E. coli infection and suggests that microbial succession, without complete eradication, may produce desirable clinical outcomes. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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11 pages, 1182 KiB  
Article
In Vitro Evaluation of the Therapeutic Potential of Phage VA7 against Enterotoxigenic Bacteroides fragilis Infection
by Nata Bakuradze, Maya Merabishvili, Khatuna Makalatia, Elene Kakabadze, Nino Grdzelishvili, Jeroen Wagemans, Cedric Lood, Irakli Chachua, Mario Vaneechoutte, Rob Lavigne, Jean-Paul Pirnay, Ivane Abiatari and Nina Chanishvili
Viruses 2021, 13(10), 2044; https://0-doi-org.brum.beds.ac.uk/10.3390/v13102044 - 11 Oct 2021
Cited by 4 | Viewed by 2163
Abstract
Since the beginning of the 20th century, bacteriophages (phages), i.e., viruses that infect bacteria, have been used as antimicrobial agents for treating various infections. Phage preparations targeting a number of bacterial pathogens are still in use in the post-Soviet states and are experiencing [...] Read more.
Since the beginning of the 20th century, bacteriophages (phages), i.e., viruses that infect bacteria, have been used as antimicrobial agents for treating various infections. Phage preparations targeting a number of bacterial pathogens are still in use in the post-Soviet states and are experiencing a revival in the Western world. However, phages have never been used to treat diseases caused by Bacteroides fragilis, the leading agent cultured in anaerobic abscesses and postoperative peritonitis. Enterotoxin-producing strains of B. fragilis have been associated with the development of inflammatory diarrhea and colorectal carcinoma. In this study, we evaluated the molecular biosafety and antimicrobial properties of novel phage species vB_BfrS_VA7 (VA7) lysate, as well as its impact on cytokine IL-8 production in an enterotoxigenic B. fragilis (ETBF)-infected colonic epithelial cell (CEC) culture model. Compared to untreated infected cells, the addition of phage VA7 to ETBF-infected CECs led to significantly reduced bacterial counts and IL-8 levels. This in vitro study confirms the potential of phage VA7 as an antibacterial agent for use in prophylaxis or in the treatment of B. fragilis infections and associated colorectal carcinoma. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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14 pages, 5796 KiB  
Article
Phages from Genus Bruynoghevirus and Phage Therapy: Pseudomonas Phage Delta Case
by Petar Knezevic, Aleksandra Petrovic Fabijan, Damir Gavric, Jovana Pejic, Zsolt Doffkay and Gábor Rakhely
Viruses 2021, 13(10), 1965; https://0-doi-org.brum.beds.ac.uk/10.3390/v13101965 - 30 Sep 2021
Cited by 4 | Viewed by 2810
Abstract
The applicability and safety of bacteriophage Delta as a potential anti-Pseudomonas aeruginosa agent belonging to genus Bruynoghevirus (family Podoviridae) was characterised. Phage Delta belongs to the species Pseudomonas virus PaP3, which has been described as a temperate, with cos sites [...] Read more.
The applicability and safety of bacteriophage Delta as a potential anti-Pseudomonas aeruginosa agent belonging to genus Bruynoghevirus (family Podoviridae) was characterised. Phage Delta belongs to the species Pseudomonas virus PaP3, which has been described as a temperate, with cos sites at the end of the genome. The phage Delta possesses a genome of 45,970 bp that encodes tRNA for proline (Pro), aspartic acid (Asp) and asparagine (Asn) and does not encode any known protein involved in lysogeny formation or persistence. Analysis showed that phage Delta has 182 bp direct terminal repeats at the end of genome and lysogeny was confirmed, neither upon infection at low nor at high multiplicity of infection (MOI). The turbid plaques that appear on certain host lawns can result from bacteriophage insensitive mutants that occur with higher frequency (10−4). In silico analysis showed that the genome of Delta phage does not encode any known bacterial toxin or virulence factor, determinants of antibiotic resistance and known human allergens. Based on the broad host range and high lytic activity against planktonic and biofilm cells, phage Delta represents a promising candidate for phage therapy. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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20 pages, 2926 KiB  
Article
A Design of Experiment Approach to Optimize Spray-Dried Powders Containing Pseudomonas aeruginosaPodoviridae and Myoviridae Bacteriophages
by Emilie Tabare, Tea Glonti, Christel Cochez, Cyrille Ngassam, Jean-Paul Pirnay, Karim Amighi and Jonathan Goole
Viruses 2021, 13(10), 1926; https://0-doi-org.brum.beds.ac.uk/10.3390/v13101926 - 24 Sep 2021
Cited by 6 | Viewed by 3011
Abstract
In the present study, we evaluated the effect of spray-drying formulations and operating parameters of a laboratory-scale spray-dryer on the characteristics of spray-dried powders containing two Pseudomonas aeruginosa bacteriophages exhibiting different morphotypes: a podovirus (LUZ19) and a myovirus (14-1). We optimized the production [...] Read more.
In the present study, we evaluated the effect of spray-drying formulations and operating parameters of a laboratory-scale spray-dryer on the characteristics of spray-dried powders containing two Pseudomonas aeruginosa bacteriophages exhibiting different morphotypes: a podovirus (LUZ19) and a myovirus (14-1). We optimized the production process for bacteriophage-loaded powders, with an emphasis on long-term storage under ICH (international conference on harmonization) conditions. D-trehalose-/L-isoleucine-containing bacteriophage mixtures were spray-dried from aqueous solutions using a Büchi Mini Spray-dryer B-290 (Flawil, Switzerland). A response surface methodology was used for the optimization of the spray-drying process, with the following as-evaluated parameters: Inlet temperature, spray gas flow rate, and the D-trehalose/L-isoleucine ratio. The dried powders were characterized in terms of yield, residual moisture content, and bacteriophage lytic activity. L-isoleucine has demonstrated a positive impact on the activity of LUZ19, but a negative impact on 14-1. We observed a negligible impact of the inlet temperature and a positive correlation of the spray gas flow rate with bacteriophage activity. After optimization, we were able to obtain dry powder preparations of both bacteriophages, which were stable for a minimum of one year under different ICH storage conditions (up to and including 40 °C and 75% relative humidity). Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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15 pages, 7637 KiB  
Article
Phage Treatment Trial to Eradicate LA-MRSA from Healthy Carrier Pigs
by Henni Tuomala, Marie Verkola, Anna Meller, Jasper Van der Auwera, Sheetal Patpatia, Asko Järvinen, Mikael Skurnik, Annamari Heikinheimo and Saija Kiljunen
Viruses 2021, 13(10), 1888; https://0-doi-org.brum.beds.ac.uk/10.3390/v13101888 - 22 Sep 2021
Cited by 5 | Viewed by 3724
Abstract
The increase of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) causes a threat to human health. LA-MRSA can be transmitted from animals to animal caretakers, which may further spread MRSA to communities and health care facilities. The objective of this work was to study the [...] Read more.
The increase of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) causes a threat to human health. LA-MRSA can be transmitted from animals to animal caretakers, which may further spread MRSA to communities and health care facilities. The objective of this work was to study the efficacy of phage treatment in the eradication of LA-MRSA from healthy carrier pigs. A total of 19 MRSA -positive weanling pigs were assigned to a test (n = 10) and a control group (n = 9). A phage cocktail containing three Staphylococcus phages, or a control buffer was administered to the nares and skin of the pigs three times every two days, after which the phage and MRSA levels in nasal and skin swab samples were monitored for a three-week period. The sensitivity of the strains isolated during the follow-up period to the phage cocktail and each phage individually was analyzed and the pig sera were tested for antibodies against the phages used in the cocktail. The phage treatment did not cause any side effects to the pigs. Phages were found in the skin and nasal samples on the days following the phage applications, but there was no reduction in the MRSA levels in the sampled animals. Phage-resistant strains or phage-specific antibodies were not detected during the experiment. The MRSA load in these healthy carrier animals was only 10–100 CFU/swab or nasal sample, which was likely below the replication threshold of phages. The effectiveness of phage treatment to eradicate MRSA from the pigs could thus not be (reliably) determined. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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10 pages, 1076 KiB  
Article
Bacteriophage Rescue Therapy of a Vancomycin-Resistant Enterococcus faecium Infection in a One-Year-Old Child following a Third Liver Transplantation
by Kevin Paul, Maya Merabishvili, Ronen Hazan, Martin Christner, Uta Herden, Daniel Gelman, Leron Khalifa, Ortal Yerushalmy, Shunit Coppenhagen-Glazer, Theresa Harbauer, Sebastian Schulz-Jürgensen, Holger Rohde, Lutz Fischer, Saima Aslam, Christine Rohde, Ran Nir-Paz, Jean-Paul Pirnay, Dominique Singer and Ania Carolina Muntau
Viruses 2021, 13(9), 1785; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091785 - 07 Sep 2021
Cited by 29 | Viewed by 3843
Abstract
Phage therapy is an experimental therapeutic approach used to target multidrug-resistant bacterial infections. A lack of reliable data with regard to its efficacy and regulatory hurdles hinders a broad application. Here we report, for the first time, a case of vancomycin-resistant Enterococcus faecium [...] Read more.
Phage therapy is an experimental therapeutic approach used to target multidrug-resistant bacterial infections. A lack of reliable data with regard to its efficacy and regulatory hurdles hinders a broad application. Here we report, for the first time, a case of vancomycin-resistant Enterococcus faecium abdominal infection in a one-year-old, critically ill, and three times liver transplanted girl, which was successfully treated with intravenous injections (twice per day for 20 days) of a magistral preparation containing two Enterococcus phages. This correlated with a reduction in baseline C-reactive protein (CRP), successful weaning from mechanical ventilation and without associated clinical adverse events. Prior to clinical use, phage genome was sequenced to confirm the absence of genetic determinants conferring lysogeny, virulence or antibiotic resistance, and thus their safety. Using a phage neutralization assay, no neutralizing anti-phage antibodies in the patient’s serum could be detected. Vancomycin-susceptible E. faecium isolates were identified in close relation to phage therapy and, by using whole-genome sequencing, it was demonstrated that vancomycin-susceptible E. faecium emerged from vancomycin-resistant progenitors. Covering a one year follow up, we provide further evidence for the feasibility of bacteriophage therapy that can serve as a basis for urgently needed controlled clinical trials. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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17 pages, 23571 KiB  
Article
Are Bordetella bronchiseptica Siphoviruses (Genus Vojvodinavirus) Appropriate for Phage Therapy—Bacterial Allies or Foes?
by Aleksandra Petrovic Fabijan, Verica Aleksic Sabo, Damir Gavric, Zsolt Doffkay, Gábor Rakhely and Petar Knezevic
Viruses 2021, 13(9), 1732; https://0-doi-org.brum.beds.ac.uk/10.3390/v13091732 - 31 Aug 2021
Cited by 2 | Viewed by 3051
Abstract
Bordetella bronchiseptica is a respiratory animal pathogen that shows growing resistance to commonly used antibiotics, which has necessitated the examination of new antimicrobials, including bacteriophages. In this study, we examined the previously isolated and partially characterized B. bronchiseptica siphoviruses of the genus Vojvodinavirus [...] Read more.
Bordetella bronchiseptica is a respiratory animal pathogen that shows growing resistance to commonly used antibiotics, which has necessitated the examination of new antimicrobials, including bacteriophages. In this study, we examined the previously isolated and partially characterized B. bronchiseptica siphoviruses of the genus Vojvodinavirus (LK3, CN1, CN2, FP1 and MW2) for their ability to inhibit bacterial growth and biofilm, and we examined other therapeutically important properties through genomic analysis and lysogeny experiments. The phages inhibited bacterial growth at a low multiplicity of infection (MOI = 0.001) of up to 85% and at MOI = 1 for >99%. Similarly, depending on the phages and MOIs, biofilm formation inhibition ranged from 65 to 95%. The removal of biofilm by the phages was less efficient but still considerably high (40–75%). Complete genomic sequencing of Bordetella phage LK3 (59,831 bp; G + C 64.01%; 79 ORFs) showed integrase and repressor protein presence, indicating phage potential to lysogenize bacteria. Lysogeny experiments confirmed the presence of phage DNA in bacterial DNA upon infection using PCR, which showed that the LK3 phage forms more or less stable lysogens depending on the bacterial host. Bacterial infection with the LK3 phage enhanced biofilm production, sheep blood hemolysis, flagellar motility, and beta-lactam resistance. The examined phages showed considerable anti-B. bronchiseptica activity, but they are inappropriate for therapy because of their temperate nature and lysogenic conversion of the host bacterium. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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9 pages, 1489 KiB  
Article
Characterization of Anti-Bacterial Effect of the Two New Phages against Uropathogenic Escherichia coli
by Lívia Slobodníková, Barbora Markusková, Michal Kajsík, Michal Andrezál, Marek Straka, Adriána Liptáková and Hana Drahovská
Viruses 2021, 13(7), 1348; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071348 - 12 Jul 2021
Cited by 5 | Viewed by 2358
Abstract
Urinary tract infections (UTIs) are among the events that most frequently need medical intervention. Uropathogenic Escherichia coli are frequently their causative agents and the infections are sometimes complicated by the presence of polyresistant nosocomial strains. Phage therapy is a tool that has good [...] Read more.
Urinary tract infections (UTIs) are among the events that most frequently need medical intervention. Uropathogenic Escherichia coli are frequently their causative agents and the infections are sometimes complicated by the presence of polyresistant nosocomial strains. Phage therapy is a tool that has good prospects for the treatment of these infections. In the present study, we isolated and characterized two bacteriophages with broad host specificity against a panel of local uropathogenic E. coli strains and combined them into a phage cocktail. According to genome sequencing, these phages were closely related and belonged to the Tequatrovirus genus. The newly isolated phages showed very good activity on a panel of local clinical E. coli strains from urinary tract infections. In the form of a two-phage cocktail, they were active on E. coli strains belonging to phylogroups B2 and D, with relatively lower activity in B1 and no response in phylogroup A. Our study is a preliminary step toward the establishment of a national phage bank containing local, well-characterized phages with therapeutic potential for patients in Slovakia. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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18 pages, 5481 KiB  
Article
Investigation of Salmonella Phage–Bacteria Infection Profiles: Network Structure Reveals a Gradient of Target-Range from Generalist to Specialist Phage Clones in Nested Subsets
by Khatuna Makalatia, Elene Kakabadze, Nata Bakuradze, Nino Grdzelishvili, Ben Stamp, Ezra Herman, Avraam Tapinos, Aidan Coffey, David Lee, Nikolaos G. Papadopoulos, David L. Robertson, Nina Chanishvili and Spyridon Megremis
Viruses 2021, 13(7), 1261; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071261 - 28 Jun 2021
Cited by 4 | Viewed by 3647
Abstract
Bacteriophages that lyse Salmonella enterica are potential tools to target and control Salmonella infections. Investigating the host range of Salmonella phages is a key to understand their impact on bacterial ecology, coevolution and inform their use in intervention strategies. Virus–host infection networks have [...] Read more.
Bacteriophages that lyse Salmonella enterica are potential tools to target and control Salmonella infections. Investigating the host range of Salmonella phages is a key to understand their impact on bacterial ecology, coevolution and inform their use in intervention strategies. Virus–host infection networks have been used to characterize the “predator–prey” interactions between phages and bacteria and provide insights into host range and specificity. Here, we characterize the target-range and infection profiles of 13 Salmonella phage clones against a diverse set of 141 Salmonella strains. The environmental source and taxonomy contributed to the observed infection profiles, and genetically proximal phages shared similar infection profiles. Using in vitro infection data, we analyzed the structure of the Salmonella phage–bacteria infection network. The network has a non-random nested organization and weak modularity suggesting a gradient of target-range from generalist to specialist species with nested subsets, which are also observed within and across the different phage infection profile groups. Our results have implications for our understanding of the coevolutionary mechanisms shaping the ecological interactions between Salmonella phages and their bacterial hosts and can inform strategies for targeting Salmonella enterica with specific phage preparations. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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17 pages, 2957 KiB  
Article
Influence of Caudovirales Phages on Humoral Immunity in Mice
by Anton Chechushkov, Yuliya Kozlova, Ivan Baykov, Vera Morozova, Bogdana Kravchuk, Tatyana Ushakova, Alevtina Bardasheva, Ekaterina Zelentsova, Lina Al Allaf, Artem Tikunov, Valentin Vlassov and Nina Tikunova
Viruses 2021, 13(7), 1241; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071241 - 26 Jun 2021
Cited by 4 | Viewed by 2606
Abstract
Bacteriophages are promising antibacterial agents. Although they have been recognized as bacterial viruses and are considered to be non-interacting with eukaryotic cells, there is growing evidence that phages may have a significant impact on the immune system via interactions with macrophages, neutrophils, and [...] Read more.
Bacteriophages are promising antibacterial agents. Although they have been recognized as bacterial viruses and are considered to be non-interacting with eukaryotic cells, there is growing evidence that phages may have a significant impact on the immune system via interactions with macrophages, neutrophils, and T-cell polarization. In this study, the influence of phages of podovirus, siphovirus, and myovirus morphotypes on humoral immunity of CD-1 mice was investigated. In addition, tissue distribution of the phages was tested in these mice. No common patterns were found either in the distribution of phages in mice or in changes in the levels of cytokines in the sera of mice once injected with phages. Importantly, pre-existing IgM-class antibodies directed against capsid proteins of phages with myovirus and siphovirus morphotypes were identified in mice before immunization. After triple immunization of CD1-mice with phages without any adjuvant, levels of anti-phage serum polyclonal IgG antibodies increased. Immunogenic phage proteins recognized by IgM and/or IgG antibodies were identified using Western blot analysis and mass spectrometry. In addition, mice serum collected after immunization demonstrated neutralizing properties, leading to a substantial decrease in infectivity of investigated phages with myovirus and siphovirus morphotypes. Moreover, serum samples collected before administration of these phages exhibited some ability to reduce the phage infectivity. Furthermore, Proteus phage PM16 with podovirus morphotype did not elicit IgM or IgG antibodies in immunized mice, and no neutralizing activities against PM16 were revealed in mouse serum samples before and after immunization. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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16 pages, 3968 KiB  
Article
Characterization of Salmonella Isolates from Various Geographical Regions of the Caucasus and Their Susceptibility to Bacteriophages
by Khatuna Makalatia, Elene Kakabadze, Jeroen Wagemans, Nino Grdzelishvili, Nata Bakuradze, Gulnara Natroshvili, Nino Macharashvili, Anahit Sedrakyan, Karine Arakelova, Zhanna Ktsoyan, Magdalina Zakharyan, Zaruhi Gevorgyan, Armine Mnatsakanyan, Farida Tishkova, Cédric Lood, Dieter Vandenheuvel, Rob Lavigne, Jean-Paul Pirnay, Daniel De Vos, Nina Chanishvili and Maia Merabishviliadd Show full author list remove Hide full author list
Viruses 2020, 12(12), 1418; https://0-doi-org.brum.beds.ac.uk/10.3390/v12121418 - 10 Dec 2020
Cited by 15 | Viewed by 3298
Abstract
Non-typhoidal Salmonella present a major threat to animal and human health as food-borne infectious agents. We characterized 91 bacterial isolates from Armenia and Georgia in detail, using a suite of assays including conventional microbiological methods, determining antimicrobial susceptibility profiles, matrix assisted laser desorption/ionization-time [...] Read more.
Non-typhoidal Salmonella present a major threat to animal and human health as food-borne infectious agents. We characterized 91 bacterial isolates from Armenia and Georgia in detail, using a suite of assays including conventional microbiological methods, determining antimicrobial susceptibility profiles, matrix assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry, serotyping (using the White-Kauffmann-Le Minor scheme) and genotyping (repetitive element sequence-based PCR (rep-PCR)). No less than 61.5% of the isolates were shown to be multidrug-resistant. A new antimicrobial treatment strategy is urgently needed. Phage therapy, the therapeutic use of (bacterio-) phages, the bacterial viruses, to treat bacterial infections, is increasingly put forward as an additional tool for combatting antibiotic resistant infections. Therefore, we used this representative set of well-characterized Salmonella isolates to analyze the therapeutic potential of eleven single phages and selected phage cocktails from the bacteriophage collection of the Eliava Institute (Georgia). All isolates were shown to be susceptible to at least one of the tested phage clones or their combinations. In addition, genome sequencing of these phages revealed them as members of existing phage genera (Felixounavirus, Seunavirus, Viunavirus and Tequintavirus) and did not show genome-based counter indications towards their applicability against non-typhoidal Salmonella in a phage therapy or in an agro-food setting. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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Review

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20 pages, 5014 KiB  
Review
Past and Future of Phage Therapy and Phage-Derived Proteins in Patients with Bone and Joint Infection
by Tristan Ferry, Camille Kolenda, Thomas Briot, Aubin Souche, Sébastien Lustig, Jérôme Josse, Cécile Batailler, Fabrice Pirot, Mathieu Medina, Gilles Leboucher, Frédéric Laurent, on behalf of the Lyon BJI Study Group and on behalf of the PHAGEinLYON Study Group
Viruses 2021, 13(12), 2414; https://0-doi-org.brum.beds.ac.uk/10.3390/v13122414 - 02 Dec 2021
Cited by 15 | Viewed by 5027
Abstract
Phage-derived therapies comprise phage therapy and the use of phage-derived proteins as anti-bacterial therapy. Bacteriophages are natural viruses that target specific bacteria. They were proposed to be used to treat bacterial infections in the 1920s, before the discovery and widespread over-commercialized use of [...] Read more.
Phage-derived therapies comprise phage therapy and the use of phage-derived proteins as anti-bacterial therapy. Bacteriophages are natural viruses that target specific bacteria. They were proposed to be used to treat bacterial infections in the 1920s, before the discovery and widespread over-commercialized use of antibiotics. Phage therapy was totally abandoned in Western countries, whereas it is still used in Poland, Georgia and Russia. We review here the history of phage therapy by focusing on bone and joint infection, and on the development of phage therapy in France in this indication. We discuss the rationale of its use in bacterial infection and show the feasibility of phage therapy in the 2020s, based on several patients with complex bone and joint infection who recently received phages as compassionate therapy. Although the status of phage therapy remains to be clarified by health care authorities, obtaining pharmaceutical-grade therapeutic phages (i.e., following good manufacturing practice guidelines or being “GMP-like”) targeting bacterial species of concern is essential. Moreover, multidisciplinary clinical expertise has to determine what could be the relevant indications to perform clinical trials. Finally “phage therapy 2.0” has to integrate the following steps: (i) follow the status of phage therapy, that is not settled and defined; (ii) develop in each country a close relationship with the national health care authority; (iii) develop industrial–academic partnerships; (iv) create academic reference centers; (v) identify relevant clinical indications; (vi) use GMP/GMP-like phages with guaranteed quality bioproduction; (vii) start as salvage therapy; (vii) combine with antibiotics and adequate surgery; and (viii) perform clinical trials, to finally (ix) demonstrate in which clinical settings phage therapy provides benefit. Phage-derived proteins such as peptidoglycan hydrolases, polysaccharide depolymerases or lysins are enzymes that also have anti-biofilm activity. In contrast to phages, their development has to follow the classical process of medicinal products. Phage therapy and phage-derived products also have a huge potential to treat biofilm-associated bacterial diseases, and this is of crucial importance in the worldwide spread of antimicrobial resistance. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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20 pages, 714 KiB  
Review
The Safety and Toxicity of Phage Therapy: A Review of Animal and Clinical Studies
by Dan Liu, Jonas D. Van Belleghem, Christiaan R. de Vries, Elizabeth Burgener, Qingquan Chen, Robert Manasherob, Jenny R. Aronson, Derek F. Amanatullah, Pranita D. Tamma and Gina A. Suh
Viruses 2021, 13(7), 1268; https://0-doi-org.brum.beds.ac.uk/10.3390/v13071268 - 29 Jun 2021
Cited by 107 | Viewed by 10674
Abstract
Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and [...] Read more.
Increasing rates of infection by antibiotic resistant bacteria have led to a resurgence of interest in bacteriophage (phage) therapy. Several phage therapy studies in animals and humans have been completed over the last two decades. We conducted a systematic review of safety and toxicity data associated with phage therapy in both animals and humans reported in English language publications from 2008–2021. Overall, 69 publications met our eligibility criteria including 20 animal studies, 35 clinical case reports or case series, and 14 clinical trials. After summarizing safety and toxicity data from these publications, we discuss potential approaches to optimize safety and toxicity monitoring with the therapeutic use of phage moving forward. In our systematic review of the literature, we found some adverse events associated with phage therapy, but serious events were extremely rare. Comprehensive and standardized reporting of potential toxicities associated with phage therapy has generally been lacking in the published literature. Structured safety and tolerability endpoints are necessary when phages are administered as anti-infective therapeutics. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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Other

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13 pages, 1057 KiB  
Case Report
Phage Therapy Experience at the Eliava Phage Therapy Center: Three Cases of Bacterial Persistence
by Elisabed Zaldastanishvili, Lika Leshkasheli, Mariam Dadiani, Lia Nadareishvili, Lia Askilashvili, Nino Kvatadze, Marina Goderdzishvili, Mzia Kutateladze and Nana Balarjishvili
Viruses 2021, 13(10), 1901; https://0-doi-org.brum.beds.ac.uk/10.3390/v13101901 - 23 Sep 2021
Cited by 21 | Viewed by 3904
Abstract
In this retrospective descriptive study we focus on cases of three patients who underwent phage therapy procedures at Eliava Phage Therapy Center (EPTC) in Tbilisi, Georgia. Patients with chronic infectious diseases related to Pseudomonas aeruginosa (two patients, lower respiratory tract infection (LRTI)) and [...] Read more.
In this retrospective descriptive study we focus on cases of three patients who underwent phage therapy procedures at Eliava Phage Therapy Center (EPTC) in Tbilisi, Georgia. Patients with chronic infectious diseases related to Pseudomonas aeruginosa (two patients, lower respiratory tract infection (LRTI)) and Klebsiella pneumoniae (one patient, urinary tract infection (UTI)) are among those very few EPTC patients whose pathogens persisted through phage therapy. By looking at bacterial strains and personalized phages used against them we tried to point towards possible adaptation strategies that are employed by these pathogens. Genome restriction-based Pulsed Field Gel Electrophoresis (PFGE) profiling of strains isolated before and after phage therapy hints towards two strategies of adaptation. In one patient case (Pseudomonas aeruginosa related lung infection) bacterial strains before and after phage therapy were indistinguishable according to their PFGE profiles, but differed in their phage susceptibility properties. On the other hand, in two other patient cases (Pseudomonas aeruginosa related LRTI and Klebsiella pneumoniae related UTI) bacterial adaptation strategy seemed to have resulted in diversification of infecting strains of the same species. With this work we want to attract more attention to phage resistance in general as well as to its role in phage therapy. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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12 pages, 2548 KiB  
Case Report
A Case of In Situ Phage Therapy against Staphylococcus aureus in a Bone Allograft Polymicrobial Biofilm Infection: Outcomes and Phage-Antibiotic Interactions
by Brieuc Van Nieuwenhuyse, Christine Galant, Bénédicte Brichard, Pierre-Louis Docquier, Sarah Djebara, Jean-Paul Pirnay, Dimitri Van der Linden, Maya Merabishvili and Olga Chatzis
Viruses 2021, 13(10), 1898; https://0-doi-org.brum.beds.ac.uk/10.3390/v13101898 - 22 Sep 2021
Cited by 16 | Viewed by 3176
Abstract
Phage therapy (PT) shows promising potential in managing biofilm infections, which include refractory orthopedic infections. We report the case of a 13-year-old girl who developed chronic polymicrobial biofilm infection of a pelvic bone allograft after Ewing’s sarcoma resection surgery. Chronic infection by Clostridium [...] Read more.
Phage therapy (PT) shows promising potential in managing biofilm infections, which include refractory orthopedic infections. We report the case of a 13-year-old girl who developed chronic polymicrobial biofilm infection of a pelvic bone allograft after Ewing’s sarcoma resection surgery. Chronic infection by Clostridium hathewayi, Proteus mirabilis and Finegoldia magna was worsened by methicillin-susceptible Staphylococcus aureus exhibiting an inducible Macrolides-Lincosamides-Streptogramin B resistance phenotype (iMLSB). After failure of conventional conservative treatment, combination of in situ anti-S. aureus PT with surgical debridement and intravenous antibiotic therapy led to marked clinical and microbiological improvement, yet failed to prevent a recurrence of infection on the midterm. This eventually led to surgical graft replacement. Multiple factors can explain this midterm failure, among which incomplete coverage of the polymicrobial infection by PT. Indeed, no phage therapy against C. hathewayi, P. mirabilis or F. magna could be administered. Phage-antibiotic interactions were investigated using OmniLog® technology. Our results suggest that phage-antibiotic interactions should not be considered “unconditionally synergistic”, and should be assessed on a case-by-case basis. Specific pharmacodynamics of phages and antibiotics might explain these differences. More than two years after final graft replacement, the patient remains cured of her sarcoma and no further infections occurred. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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12 pages, 1046 KiB  
Study Protocol
Bacteriophage Therapy for Difficult-to-Treat Infections: The Implementation of a Multidisciplinary Phage Task Force (The PHAGEFORCE Study Protocol)
by Jolien Onsea, Saartje Uyttebroek, Baixing Chen, Jeroen Wagemans, Cédric Lood, Laura Van Gerven, Isabel Spriet, David Devolder, Yves Debaveye, Melissa Depypere, Lieven Dupont, Paul De Munter, Willy E. Peetermans, Vera van Noort, Maia Merabishvili, Jean-Paul Pirnay, Rob Lavigne and Willem-Jan Metsemakers
Viruses 2021, 13(8), 1543; https://0-doi-org.brum.beds.ac.uk/10.3390/v13081543 - 05 Aug 2021
Cited by 20 | Viewed by 4189
Abstract
In times where only a few novel antibiotics are to be expected, antimicrobial resistance remains an expanding global health threat. In case of chronic infections caused by therapy-resistant pathogens, physicians have limited therapeutic options, which are often associated with detrimental consequences for the [...] Read more.
In times where only a few novel antibiotics are to be expected, antimicrobial resistance remains an expanding global health threat. In case of chronic infections caused by therapy-resistant pathogens, physicians have limited therapeutic options, which are often associated with detrimental consequences for the patient. This has resulted in a renewed interest in alternative strategies, such as bacteriophage (phage) therapy. However, there are still important hurdles that currently impede the more widespread implementation of phage therapy in clinical practice. First, the limited number of good-quality case series and clinical trials have failed to show the optimal application protocol in terms of route of administration, frequency of administration, treatment duration and phage titer. Second, there is limited information on the systemic effects of phage therapy. Finally, in the past, phage therapy has been applied intuitively in terms of the selection of phages and their combination as parts of phage cocktails. This has led to an enormous heterogeneity in previously published studies, resulting in a lack of reliable safety and efficacy data for phage therapy. We hereby present a study protocol that addresses these scientific hurdles using a multidisciplinary approach, bringing together the experience of clinical, pharmaceutical and molecular microbiology experts. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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10 pages, 451 KiB  
Case Report
A Case of Phage Therapy against Pandrug-Resistant Achromobacter xylosoxidans in a 12-Year-Old Lung-Transplanted Cystic Fibrosis Patient
by David Lebeaux, Maia Merabishvili, Eric Caudron, Damien Lannoy, Leen Van Simaey, Hans Duyvejonck, Romain Guillemain, Caroline Thumerelle, Isabelle Podglajen, Fabrice Compain, Najiby Kassis, Jean-Luc Mainardi, Johannes Wittmann, Christine Rohde, Jean-Paul Pirnay, Nicolas Dufour, Stefan Vermeulen, Yannick Gansemans, Filip Van Nieuwerburgh and Mario Vaneechoutte
Viruses 2021, 13(1), 60; https://0-doi-org.brum.beds.ac.uk/10.3390/v13010060 - 05 Jan 2021
Cited by 61 | Viewed by 5055
Abstract
Bacteriophages are a promising therapeutic strategy among cystic fibrosis and lung-transplanted patients, considering the high frequency of colonization/infection caused by pandrug-resistant bacteria. However, little clinical data are available regarding the use of phages for infections with Achromobacter xylosoxidans. A 12-year-old lung-transplanted cystic [...] Read more.
Bacteriophages are a promising therapeutic strategy among cystic fibrosis and lung-transplanted patients, considering the high frequency of colonization/infection caused by pandrug-resistant bacteria. However, little clinical data are available regarding the use of phages for infections with Achromobacter xylosoxidans. A 12-year-old lung-transplanted cystic fibrosis patient received two rounds of phage therapy because of persistent lung infection with pandrug-resistant A. xylosoxidans. Clinical tolerance was perfect, but initial bronchoalveolar lavage (BAL) still grew A. xylosoxidans. The patient’s respiratory condition slowly improved and oxygen therapy was stopped. Low-grade airway colonization by A. xylosoxidans persisted for months before samples turned negative. No re-colonisation occurred more than two years after phage therapy was performed and imipenem treatment was stopped. Whole genome sequencing indicated that the eight A. xylosoxidans isolates, collected during phage therapy, belonged to four delineated strains, whereby one had a stop mutation in a gene for a phage receptor. The dynamics of lung colonisation were documented by means of strain-specific qPCRs on different BALs. We report the first case of phage therapy for A. xylosoxidans lung infection in a lung-transplanted patient. The dynamics of airway colonization was more complex than deduced from bacterial culture, involving phage susceptible as well as phage resistant strains. Full article
(This article belongs to the Special Issue State-of-the-Art Phage Therapy Development in Europe)
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