Bacteriophage Therapy: Recent Developments and Applications of a Renaissance Weapon

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

Deadline for manuscript submissions: closed (31 December 2023) | Viewed by 22287

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Guest Editor
Department of Biotechnology and Food Microbiology, Faculty of Biotechnology and Food Science, Wrocław University of Environmental and Life Sciences, Chełmońskiego 37, 51-630 Wrocław, Poland
Interests: application of bacteriophages in human and veterinary medicine, development of the methods of working with phages; interactions of bacteriophages with bacterial and non-bacterial cells
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Guest Editor
Department of Veterinary Prevention and Avian Diseases, Faculty of Veterinary Medicine, University of Life Sciences in Lublin, Głęboka 30, 20-612 Lublin, Poland
Interests: avian diseases; veterinary microbiology; bacteriophages in human and veterinary medicine; diagnostic tools for bacterial infections; antibiotic resistance; food-borne pathogens

Special Issue Information

Dear Colleagues,

During the last century, antibiotic therapy became the most powerful weapon against bacterial infections. However, the time for the universal application of these drugs seems to be running out. The number of new antibiotics being introduced to the market has been consistently decreasing and pharmaceutical companies have been reluctant to search for new products due to the high risk of failure. The diminishing potential of pharmacological treatment of bacterial infections is accompanied by an increasing number of antibiotic-resistant or, more broadly, drug-resistant strains. The inevitable need to search for and introduce new methods to combat bacterial infections is becoming unquestionable.

Bacteriophages have been used to treat bacterial infections nearly since the moment of their discovery at the beginning of the 20th century. However, overshadowed by antibiotics, phage therapy has been marginalized for decades. Nowadays, with the rapidly growing number of drug-resistant bacterial strains, phage therapy becomes one of the most promising alternatives to classical methods of treatment. Moreover, studies on bacterial viruses are not limited to human or veterinary medicine but increasingly reach new fields of biotechnology.

Dr. Aneta Skaradzińska
Dr. Anna Nowaczek
Guest Editors

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Keywords

  • bacteriophages
  • phage therapy
  • application of phages
  • antibiotic-resistance
  • antibacterial therapies

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Published Papers (11 papers)

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Research

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12 pages, 725 KiB  
Article
Adaptive Phage Therapy for the Prevention of Recurrent Nosocomial Pneumonia: Novel Protocol Description and Case Series
by Fedor Zurabov, Marina Petrova, Alexander Zurabov, Marina Gurkova, Petr Polyakov, Dmitriy Cheboksarov, Ekaterina Chernevskaya, Mikhail Yuryev, Valentina Popova, Artem Kuzovlev, Alexey Yakovlev and Andrey Grechko
Antibiotics 2023, 12(12), 1734; https://doi.org/10.3390/antibiotics12121734 - 14 Dec 2023
Viewed by 1417
Abstract
Nowadays there is a growing interest worldwide in using bacteriophages for therapeutic purposes to combat antibiotic-resistant bacterial strains, driven by the increasing ineffectiveness of drugs against bacterial infections. Despite this fact, no novel commercially available therapeutic phage products have been developed in the [...] Read more.
Nowadays there is a growing interest worldwide in using bacteriophages for therapeutic purposes to combat antibiotic-resistant bacterial strains, driven by the increasing ineffectiveness of drugs against bacterial infections. Despite this fact, no novel commercially available therapeutic phage products have been developed in the last two decades, as it is extremely difficult to register them under the current legal regulations. This paper presents a description of the interaction between a bacteriophage manufacturer and a clinical institution, the specificity of which is the selection of bacteriophages not for an individual patient, but for the entire spectrum of bacteria circulating in the intensive care unit with continuous clinical and microbiological monitoring of efficacy. The study presents the description of three clinical cases of patients who received bacteriophage complex via inhalation for 28 days according to the protocol without antibiotic use throughout the period. No adverse effects were observed and the elimination of multidrug-resistant microorganisms from the bronchoalveolar lavage contents was detected in all patients. A decrease in such inflammatory markers as C-reactive protein (CRP) and procalcitonin was also noted. The obtained results demonstrate the potential of an adaptive phage therapy protocol in intensive care units for reducing the amount of antibiotics used and preserving their efficacy. Full article
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20 pages, 4597 KiB  
Article
Vibrio Phage VMJ710 Can Prevent and Treat Disease Caused by Pathogenic MDR V. cholerae O1 in an Infant Mouse Model
by Naveen Chaudhary, Balvinder Mohan, Harpreet Kaur, Vinay Modgil, Vishal Kant, Alka Bhatia and Neelam Taneja
Antibiotics 2023, 12(6), 1046; https://doi.org/10.3390/antibiotics12061046 - 14 Jun 2023
Cited by 1 | Viewed by 1824
Abstract
Cholera, a disease of antiquity, is still festering in developing countries that lack safe drinking water and sewage disposal. Vibrio cholerae, the causative agent of cholera, has developed multi-drug resistance to many antimicrobial agents. In aquatic habitats, phages are known to influence [...] Read more.
Cholera, a disease of antiquity, is still festering in developing countries that lack safe drinking water and sewage disposal. Vibrio cholerae, the causative agent of cholera, has developed multi-drug resistance to many antimicrobial agents. In aquatic habitats, phages are known to influence the occurrence and dispersion of pathogenic V. cholerae. We isolated Vibrio phage VMJ710 from a community sewage water sample of Manimajra, Chandigarh, in 2015 during an outbreak of cholera. It lysed 46% of multidrug-resistant V. cholerae O1 strains. It had significantly reduced the bacterial density within the first 4–6 h of treatment at the three multiplicity of infection (MOI 0.01, 0.1, and 1.0) values used. No bacterial resistance was observed against phage VMJ710 for 20 h in the time–kill assay. It is nearest to an ICP1 phage, i.e., Vibrio phage ICP1_2012 (MH310936.1), belonging to the class Caudoviricetes. ICP1 phages have been the dominant bacteriophages found in cholera patients’ stools since 2001. Comparative genome analysis of phage VMJ710 and related phages indicated a high level of genetic conservation. The phage was stable over a wide range of temperatures and pH, which will be an advantage for applications in different environmental settings. The phage VMJ710 showed a reduction in biofilm mass growth, bacterial dispersal, and a clear disruption of bacterial biofilm structure. We further tested the phage VMJ710 for its potential therapeutic and prophylactic properties using infant BALB/c mice. Bacterial counts were reduced significantly when phages were administered before and after the challenge of orogastric inoculation with V. cholerae serotype O1. A comprehensive whole genome study revealed no indication of lysogenic genes, genes associated with possible virulence factors, or antibiotic resistance. Based on all these properties, phage VMJ710 can be a suitable candidate for oral phage administration and could be a viable method of combatting cholera infection caused by MDR V. cholerae pathogenic strains. Full article
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33 pages, 29840 KiB  
Article
An Edible Biopolymeric Microcapsular Wrapping Integrating Lytic Bacteriophage Particles for Salmonella enterica: Potential for Integration into Poultry Feed
by Arthur O. Pereira, Nicole M. A. Barros, Bruna R. Guerrero, Stephen C. Emencheta, Denicezar Â. Baldo, José M. Oliveira Jr., Marta M. D. C. Vila and Victor M. Balcão
Antibiotics 2023, 12(6), 988; https://doi.org/10.3390/antibiotics12060988 - 31 May 2023
Cited by 2 | Viewed by 1295
Abstract
This research work aimed at developing an edible biopolymeric microcapsular wrapping (EBMW) integrating lytic bacteriophage particles for Salmonella enterica, with potential application in poultry feed for biocontrol of that pathogen. This pathogen is known as one of the main microorganisms responsible for [...] Read more.
This research work aimed at developing an edible biopolymeric microcapsular wrapping (EBMW) integrating lytic bacteriophage particles for Salmonella enterica, with potential application in poultry feed for biocontrol of that pathogen. This pathogen is known as one of the main microorganisms responsible for contamination in the food industry and in foodstuff. The current techniques for decontamination and pathogen control in the food industry can be very expensive, not very selective, and even outdated, such as the use of broad-spectrum antibiotics that end up selecting resistant bacteria. Hence, there is a need for new technologies for pathogen biocontrol. In this context, bacteriophage-based biocontrol appears as a potential alternative. As a cocktail, both phages were able to significantly reduce the bacterial load after 12 h of treatment, at either multiplicity of infection (MOI) 1 and 10, by 84.3% and 87.6%, respectively. Entrapment of the phage virions within the EBMW matrix did not exert any deleterious effect upon their lytic activity. The results obtained showed high promise for integration in poultry feed aiming at controlling Salmonella enterica, since the edible biopolymeric microcapsular wrapping integrating lytic bacteriophage particles developed was successful in maintaining lytic phage viability while fully stabilizing the phage particles. Full article
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12 pages, 3288 KiB  
Article
Activity of Phage–Lactoferrin Mixture against Multi Drug Resistant Staphylococcus aureus Biofilms
by Katarzyna Kosznik-Kwaśnicka, Natalia Kaźmierczak and Lidia Piechowicz
Antibiotics 2022, 11(9), 1256; https://doi.org/10.3390/antibiotics11091256 - 16 Sep 2022
Cited by 3 | Viewed by 1760
Abstract
Biofilms are complex bacterial structures composed of bacterial cells embedded in extracellular polymeric substances (EPS) consisting of polysaccharides, proteins and lipids. As a result, biofilms are difficult to eradicate using both mechanical methods, i.e., scraping, and chemical methods such as disinfectants or antibiotics. [...] Read more.
Biofilms are complex bacterial structures composed of bacterial cells embedded in extracellular polymeric substances (EPS) consisting of polysaccharides, proteins and lipids. As a result, biofilms are difficult to eradicate using both mechanical methods, i.e., scraping, and chemical methods such as disinfectants or antibiotics. Bacteriophages are shown to be able to act as anti-biofilm agents, with the ability to penetrate through the matrix and reach the bacterial cells. However, they also seem to have their limitations. After several hours of treatment with phages, the biofilm tends to grow back and phage-resistant bacteria emerge. Therefore, it is now recommended to use a mixture of phages and other antibacterial agents in order to increase treatment efficiency. In our work we have paired staphylococcal phages with lactoferrin, a protein with proven anti-biofilm proprieties. By analyzing the biofilm biomass and metabolic activity, we have observed that the addition of lactoferrin to phage lysate accelerated the anti-biofilm effect of phages and also prevented biofilm re-growth. Therefore, this combination might have a potential use in biofilm eradication procedures in medical settings. Full article
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15 pages, 3167 KiB  
Article
Microbial Profiling of Potato-Associated Rhizosphere Bacteria under Bacteriophage Therapy
by Samar Mousa, Mahmoud Magdy, Dongyan Xiong, Raphael Nyaruabaa, Samah Mohamed Rizk, Junping Yu and Hongping Wei
Antibiotics 2022, 11(8), 1117; https://doi.org/10.3390/antibiotics11081117 - 18 Aug 2022
Cited by 5 | Viewed by 2407
Abstract
Potato soft rot and wilt are economically problematic diseases due to the lack of effective bactericides. Bacteriophages have been studied as a novel and environment-friendly alternative to control plant diseases. However, few experiments have been conducted to study the changes in plants and [...] Read more.
Potato soft rot and wilt are economically problematic diseases due to the lack of effective bactericides. Bacteriophages have been studied as a novel and environment-friendly alternative to control plant diseases. However, few experiments have been conducted to study the changes in plants and soil microbiomes after bacteriophage therapy. In this study, rhizosphere microbiomes were examined after potatoes were separately infected with three bacteria (Ralstonia solanacearum, Pectobacterium carotovorum, Pectobacterium atrosepticum) and subsequently treated with a single phage or a phage cocktail consisting of three phages each. Results showed that using the phage cocktails had better efficacy in reducing the disease incidence and disease symptoms’ levels when compared to the application of a single phage under greenhouse conditions. At the same time, the rhizosphere microbiota in the soil was affected by the changes in micro-organisms’ richness and counts. In conclusion, the explicit phage mixers have the potential to control plant pathogenic bacteria and cause changes in the rhizosphere bacteria, but not affect the beneficial rhizosphere microbes. Full article
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Review

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24 pages, 1358 KiB  
Review
Automating Predictive Phage Therapy Pharmacology
by Stephen T. Abedon
Antibiotics 2023, 12(9), 1423; https://doi.org/10.3390/antibiotics12091423 - 08 Sep 2023
Viewed by 1295
Abstract
Viruses that infect as well as often kill bacteria are called bacteriophages, or phages. Because of their ability to act bactericidally, phages increasingly are being employed clinically as antibacterial agents, an infection-fighting strategy that has been in practice now for over one hundred [...] Read more.
Viruses that infect as well as often kill bacteria are called bacteriophages, or phages. Because of their ability to act bactericidally, phages increasingly are being employed clinically as antibacterial agents, an infection-fighting strategy that has been in practice now for over one hundred years. As with antibacterial agents generally, the development as well as practice of this phage therapy can be aided via the application of various quantitative frameworks. Therefore, reviewed here are considerations of phage multiplicity of infection, bacterial likelihood of becoming adsorbed as a function of phage titers, bacterial susceptibility to phages also as a function of phage titers, and the use of Poisson distributions to predict phage impacts on bacteria. Considered in addition is the use of simulations that can take into account both phage and bacterial replication. These various approaches can be automated, i.e., by employing a number of online-available apps provided by the author, the use of which this review emphasizes. In short, the practice of phage therapy can be aided by various mathematical approaches whose implementation can be eased via online automation. Full article
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13 pages, 313 KiB  
Review
Bacteriophage–Antibiotic Combination Therapy against Pseudomonas aeruginosa
by Guillermo Santamaría-Corral, Abrar Senhaji-Kacha, Antonio Broncano-Lavado, Jaime Esteban and Meritxell García-Quintanilla
Antibiotics 2023, 12(7), 1089; https://doi.org/10.3390/antibiotics12071089 - 22 Jun 2023
Cited by 2 | Viewed by 1816
Abstract
Phage therapy is an alternative therapy that is being used as the last resource against infections caused by multidrug-resistant bacteria after the failure of standard treatments. Pseudomonas aeruginosa can cause pneumonia, septicemia, urinary tract, and surgery site infections mainly in immunocompromised people, although [...] Read more.
Phage therapy is an alternative therapy that is being used as the last resource against infections caused by multidrug-resistant bacteria after the failure of standard treatments. Pseudomonas aeruginosa can cause pneumonia, septicemia, urinary tract, and surgery site infections mainly in immunocompromised people, although it can cause infections in many different patient profiles. Cystic fibrosis patients are particularly vulnerable. In vitro and in vivo studies of phage therapy against P. aeruginosa include both bacteriophages alone and combined with antibiotics. However, the former is the most promising strategy utilized in clinical infections. This review summarizes the recent studies of phage-antibiotic combinations, highlighting the synergistic effects of in vitro and in vivo experiments and successful treatments in patients. Full article
18 pages, 641 KiB  
Review
Enterococcal Phages: Food and Health Applications
by Carlos Rodríguez-Lucas and Victor Ladero
Antibiotics 2023, 12(5), 842; https://doi.org/10.3390/antibiotics12050842 - 02 May 2023
Cited by 2 | Viewed by 2290
Abstract
Enterococcus is a diverse genus of Gram-positive bacteria belonging to the lactic acid bacteria (LAB) group. It is found in many environments, including the human gut and fermented foods. This microbial genus is at a crossroad between its beneficial effects and the concerns [...] Read more.
Enterococcus is a diverse genus of Gram-positive bacteria belonging to the lactic acid bacteria (LAB) group. It is found in many environments, including the human gut and fermented foods. This microbial genus is at a crossroad between its beneficial effects and the concerns regarding its safety. It plays an important role in the production of fermented foods, and some strains have even been proposed as probiotics. However, they have been identified as responsible for the accumulation of toxic compounds—biogenic amines—in foods, and over the last 20 years, they have emerged as important hospital-acquired pathogens through the acquisition of antimicrobial resistance (AMR). In food, there is a need for targeted measures to prevent their growth without disturbing other LAB members that participate in the fermentation process. Furthermore, the increase in AMR has resulted in the need for the development of new therapeutic options to treat AMR enterococcal infections. Bacteriophages have re-emerged in recent years as a precision tool for the control of bacterial populations, including the treatment of AMR microorganism infections, being a promising weapon as new antimicrobials. In this review, we focus on the problems caused by Enterococcus faecium and Enterococcus faecalis in food and health and on the recent advances in the discovery and applications of enterococcus-infecting bacteriophages against these bacteria, with special attention paid to applications against AMR enterococci. Full article
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23 pages, 661 KiB  
Review
Recent Advances in the Application of Bacteriophages against Common Foodborne Pathogens
by Kinga Hyla, Izabela Dusza and Aneta Skaradzińska
Antibiotics 2022, 11(11), 1536; https://doi.org/10.3390/antibiotics11111536 - 02 Nov 2022
Cited by 7 | Viewed by 3138
Abstract
Bacteriophage potential in combating bacterial pathogens has been recognized nearly since the moment of discovery of these viruses at the beginning of the 20th century. Interest in phage application, which initially focused on medical treatments, rapidly spread throughout different biotechnological and industrial fields. [...] Read more.
Bacteriophage potential in combating bacterial pathogens has been recognized nearly since the moment of discovery of these viruses at the beginning of the 20th century. Interest in phage application, which initially focused on medical treatments, rapidly spread throughout different biotechnological and industrial fields. This includes the food safety sector in which the presence of pathogens poses an explicit threat to consumers. This is also the field in which commercialization of phage-based products shows the greatest progress. Application of bacteriophages has gained special attention particularly in recent years, presumably due to the potential of conventional antibacterial strategies being exhausted. In this review, we present recent findings regarding phage application in fighting major foodborne pathogens, including Salmonella spp., Escherichia coli, Yersinia spp., Campylobacter jejuni and Listeria monocytogenes. We also discuss advantages of bacteriophage use and challenges facing phage-based antibacterial strategies, particularly in the context of their widespread application in food safety. Full article
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Other

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6 pages, 1914 KiB  
Case Report
Local Treatment of Driveline Infection with Bacteriophages
by Anja Püschel, Romy Skusa, Antonia Bollensdorf and Justus Gross
Antibiotics 2022, 11(10), 1310; https://doi.org/10.3390/antibiotics11101310 - 27 Sep 2022
Cited by 7 | Viewed by 1551
Abstract
Drive line infections (DLI) are common infectious complications after left ventricular assist devices (LVAD) implantation. In case of severe or persistent infections, when conservative management fails, the exchange of the total LVAD may become necessary. We present a case of successful treatment of [...] Read more.
Drive line infections (DLI) are common infectious complications after left ventricular assist devices (LVAD) implantation. In case of severe or persistent infections, when conservative management fails, the exchange of the total LVAD may become necessary. We present a case of successful treatment of DL infection with a combination of antibiotics, debridement and local bacteriophage treatment. Full article
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7 pages, 1179 KiB  
Case Report
Salphage: Salvage Bacteriophage Therapy for Recalcitrant MRSA Prosthetic Joint Infection
by James B. Doub, Vincent Y. Ng, Myounghee Lee, Andrew Chi, Alina Lee, Silvia Würstle and Benjamin Chan
Antibiotics 2022, 11(5), 616; https://doi.org/10.3390/antibiotics11050616 - 04 May 2022
Cited by 11 | Viewed by 1925
Abstract
Prosthetic joint infections are a devastating complication of joint replacement surgery. Consequently, novel therapeutics are needed to thwart the significant morbidity and enormous financial ramifications that are associated with conventional treatments. One such promising adjuvant therapeutic is bacteriophage therapy given its antibiofilm activity [...] Read more.
Prosthetic joint infections are a devastating complication of joint replacement surgery. Consequently, novel therapeutics are needed to thwart the significant morbidity and enormous financial ramifications that are associated with conventional treatments. One such promising adjuvant therapeutic is bacteriophage therapy given its antibiofilm activity and its ability to self-replicate. Herein we discuss the case of a 70-year-old female who had a recalcitrant MRSA prosthetic knee and femoral lateral plate infection who was successfully treated with adjuvant bacteriophage therapy. Moreover, this case discusses the importance of propagating bacteriophage therapeutics on bacteria that are devoid of toxins and the need to ensure bacteriophage activity to all bacterial morphologies. Overall, this case reinforces the potential benefit of using personalized bacteriophage therapy for recalcitrant prosthetic joint infections, but more translational research is needed to thereby devise effective, reproducible clinical trials. Full article
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