Use Of Phage Therapy Research Articles

Pseudomonas aeruginosa in the Frontline of the Greatest Challenge of Biofilm Infection—Its Tolerance to Antibiotics

P. aeruginosa biofilms are aggregates of bacteria surrounded by a self-produced matrix which binds to some antibiotics such as aminoglycosides. P. aeruginosa biofilms are tolerant to antibiotics. The treatment of biofilm infections leads to a recurrence of symptoms after finishing antibiotic treatment, although the initial clinical response to the treatment is frequently favorable. There is a concentration gradient of oxygen and nutrients from the surface to the center of biofilms. Surface-located bacteria are multiplying and metabolizing, whereas deeper located bacteria are dormant and tolerant to most antibiotics. Colistin kills dormant bacteria, and combination therapy with colistin and antibiotics which kills multiplying bacteria is efficient in vitro. Some antibiotics such as imipenem induce additional production of the biofilm matrix and of chromosomal beta-lactamase in biofilms. Biofilms present a third Pharmacokinetic/Pharmacodynamic (PK/PD) micro-compartment (first: blood, second: tissue, third: biofilm) which must be taken into consideration when calculations try to predict the antibiotic concentrations in biofilms and thereby the probability of target attainment (PTA) for killing the biofilm. Treating biofilms with hyperbaric oxygen to wake up the dormant cells, destruction of the biofilm matrix, and the use of bacteriophage therapy in combination with antibiotics are promising possibilities which have shown proof of concept in in vitro experiments and in animal experiments.

The Evolution of Phage Therapy: A Comprehensive Review of Current Applications and Future Innovations.

Phage therapy, using bacteriophages to target and destroy bacteria, has evolved significantly from its early 20th-century inception to its modern resurgence as a promising alternative to antibiotics. This review explores the historical development of phage therapy, detailing its initial successes, subsequent decline with the rise of antibiotics, and recent revival in response to increasing antibiotic resistance. We examine the fundamental mechanisms of phage therapy, including the specificity of phages for bacterial targets and their ability to combat resistant strains. Current applications are discussed, highlighting the use of phage therapy in treating chronic infections, personalizing treatment strategies, and its role in veterinary and food safety contexts. Innovations in phage therapy, driven by advancements in genetic engineering and synthetic biology, are also reviewed, showcasing the development of engineered phages, phage libraries, and novel delivery systems. Despite its potential, phage therapy faces challenges such as regulatory hurdles, safety concerns, and issues related to bacterial resistance to phages. The review underscores the need for ongoing research and clinical trials to address these challenges and to integrate phage therapy into modern treatment paradigms. By offering a detailed overview of the evolution, current status, and future directions of phage therapy, this review aims to highlight its potential as a crucial component in the fight against antibiotic-resistant infections and to inform future research efforts.

Harnessing Bacteriophages to Combat Antibiotic-Resistant Infections in Africa: A Comprehensive Review.

The conventional treatment of bacterial infections with antibiotics is becoming increasingly ineffective due to the emergence of multidrug-resistant (MDR) pathogens. This literature review explores the potential of bacteriophages as an alternative or adjunctive therapy to antibiotics in combating MDR infections in Africa. This analysis focuses on current research regarding the integration of phage therapy into African healthcare, highlighting its challenges and opportunities. This review begins with the AMR crisis and the need for new treatments, then covers the history, mechanisms, benefits, and limitations of phage therapy. Key African studies are summarized, identifying major obstacles such as regulatory issues, infrastructure, and research standardization. Research efforts in West Africa that have made notable progress in bacteriophage research are highlighted. This review concludes with recommendations for policymakers, researchers, and healthcare professionals to enhance the development and use of phage therapy in Africa, aiming to reduce antibiotic resistance and improve patient outcomes. By addressing the identified challenges and leveraging the unique advantages of phages, there is potential to significantly mitigate the impact of antibiotic resistance and improve patient outcomes in Africa.

Antimicrobial resistance: use of phage therapy in the management of resistant infections.

The emergence and increase in antimicrobial resistance (AMR) is now widely recognized as a major public health challenge. Traditional antimicrobial drugs are becoming increasingly ineffective, while the development of new antibiotics is waning. As a result, alternative treatments for infections are garnering increased interest. Among these alternatives, bacteriophages, also known as phages, are gaining renewed attention and are reported to offer a promising solution to alleviate the burden of bacterial infections. This review discusses the current successes of phage therapy (PT) against multidrug-resistant organisms (MDROs), such as Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Enterobacter spp. The review also compares the efficacy of PT with that of chemical antibiotics, reporting on its benefits and limitations, while highlighting its impact on the human gut microbiome and immune system. Despite its potential, phage therapy is reported to face challenges such as the narrow antibacterial range, the complexity of developing phage cocktails, and the need for precise dosing and duration protocols. Nevertheless, continued research, improved regulatory frameworks, and increased public awareness are essential to realize its full potential and integration into standard medical practice, paving the way for innovative treatments that can effectively manage infections in an era of rising antimicrobial resistance.

Bacteriophage therapy in the management of diabetic foot ulcer infections

AbstractThe global morbidity, mortality and health economic effects of treating patients with diabetic foot ulcer infections are rapidly growing and have been exacerbated by the problem of antimicrobial resistance. With the world on the cusp of entering the postantibiotic era, alternative antimicrobial strategies are urgently needed. Bacteriophage therapy has demonstrated safety, efficacy and cost‐effectiveness in treating patients with diabetic foot ulcer infections. This review seriously considers the use of bacteriophage therapy in the care of patients with diabetic foot ulcer infections.

Bacteriophage therapy- a refurbished age-old potential strategy to treat antibiotic and multidrug resistant bacterial infections in future.

The worldwide prevalence of antimicrobial resistance coupled with the unavailability of newer antibiotics, has brought the sharp focus back among the scientific community, towards the discovery of novel alternative therapeutics to tackle the menace. Consequently, in the current post-antibiotic era, 'Bacteriophage Therapy' has emerged as one of the most promising option to address this problem. Bacteriophages, actually discovered long back, has shown greater potential to kill various bacterial pathogens, including the resistant clinical ones. Some of the other advantages for the use of bacteriophage therapy to treat infectious diseases include, wider availability of these microorganisms in nature, host-specific action, absence of any significant side-effects in humans and most often also exhibiting a broader anti-bacterial potential. In the recent times, the potential of phage therapy has been demonstrated in various treatments, clinical trials and infection models across the globe, where even antibiotics have completely failed. To address the global threat of AMR, WHO and UN have jointly illustrated "One Health" approach, recently extending the context to bacteriophage therapy. Many pharmaceutical companies have also recently started employing bacteriophages for developing different kinds of formulations for catering to medical and other industries. It has even shown great effect as combinatorial therapy along with antibiotics, to treat or manage various critical antibiotic resistant clinical infections. This continuously expanding potential of the bacteriophages holds great promise in the future, in the fight against the rising threat of AMR globally.

Application of bacteriophage therapy in the treatment of children with acute tonsillitis

Context In pediatrics, there is an increasing interest in the therapeutic efficacy of inhaled bacteriophages for treating infectious diseases of the upper respiratory tract in children. Aim To analyze the effectiveness of inhaled bacteriophage therapy in children with acute tonsillitis (AT). Settings and Design Clinical observation of patients was based on a randomized, controlled research method. Methods and Material A total of 212 sick children aged 4–15 years who had AT were examined. Bacteriophage therapy was carried out by nebulizer inhalation using the liquid polyvalent piobacteriophage. Patients were divided into two groups based on the treatment method. One group of patients received a course of bacteriophage therapy against the background of standard treatment. Results When patients sought medical help, during the general clinical examination, the following were noted: cervical lymphadenopathy (98.6%), hyperemia of the tonsils and hyperplasia (98.1%), against the background of hyperthermia. Bacteriological analysis of the pharynx mucus showed that the main causative agents of AT in children were the bacteria Streptococcus pyogenes, Staphylococcus aureus, Streptococcus pneumoniae, and Haemophilus influenzae. Patients who underwent inhaled bacteriophage therapy in the early stages of treatment experienced a 1.4-fold greater disappearance of objective signs of pathological processes in the tonsils against the backdrop of rapid improvement in the well-being of sick children. Moreover, the use of a combination of antibiotic therapy and bacteriophage therapy led to a decrease in the detection of pathogenic bacteria, and the effectiveness of drug treatment increased four times. Conclusion The use of bacteriophage therapy in the complex treatment of AT in children contributes to a more rapid relief of the acute period against the background of an improvement in the subjective assessment of well-being by up to 25%, and a decrease in the detection of pathogenic bacteria.

Current Knowledge and Perspectives of Phage Therapy for Combating Refractory Wound Infections

Wound infection is one of the most important factors affecting wound healing, so its effective control is critical to promote the process of wound healing. However, with the increasing prevalence of multi-drug-resistant (MDR) bacterial strains, the prevention and treatment of wound infections are now more challenging, imposing heavy medical and financial burdens on patients. Furthermore, the diminishing effectiveness of conventional antimicrobials and the declining research on new antibiotics necessitate the urgent exploration of alternative treatments for wound infections. Recently, phage therapy has been revitalized as a promising strategy to address the challenges posed by bacterial infections in the era of antibiotic resistance. The use of phage therapy in treating infectious diseases has demonstrated positive results. This review provides an overview of the mechanisms, characteristics, and delivery methods of phage therapy for combating pathogenic bacteria. Then, we focus on the clinical application of various phage therapies in managing refractory wound infections, such as diabetic foot infections, as well as traumatic, surgical, and burn wound infections. Additionally, an analysis of the potential obstacles and challenges of phage therapy in clinical practice is presented, along with corresponding strategies for addressing these issues. This review serves to enhance our understanding of phage therapy and provides innovative avenues for addressing refractory infections in wound healing.

Harnessing the Diversity of Burkholderia spp. Prophages for Therapeutic Potential.

Burkholderia spp. are often resistant to antibiotics, and infections with these organisms are difficult to treat. A potential alternative treatment for Burkholderia spp. infections is bacteriophage (phage) therapy; however, it can be difficult to locate phages that target these bacteria. Prophages incorporated into the bacterial genome have been identified within Burkholderia spp. and may represent a source of useful phages for therapy. Here, we investigate whether prophages within Burkholderia spp. clinical isolates can kill conspecific and heterospecific isolates. Thirty-two Burkholderia spp. isolates were induced for prophage release, and harvested phages were tested for lytic activity against the same 32 isolates. Temperate phages were passaged and their host ranges were determined, resulting in four unique phages of prophage origin that showed different ranges of lytic activity. We also analyzed the prophage content of 35 Burkholderia spp. clinical isolate genomes and identified several prophages present in the genomes of multiple isolates of the same species. Finally, we observed that Burkholdera cenocepacia isolates were more phage-susceptible than Burkholderia multivorans isolates. Overall, our findings suggest that prophages present within Burkholderia spp. genomes are a potentially useful starting point for the isolation and development of novel phages for use in phage therapy.

Phage therapy for burn wound infections in the era of antibiotic resistance

Infection of burn wounds caused by antibiotic-resistant pathogens is the leading cause of systemic infectious complications in burned patients and a key link in the pathogenesis of burn disease, causing its course and outcome. The use of phage therapy to overcome antibiotic resistance of infection agents is a promising direction, the development of which can improve the results of treatment of burned. The article discusses: 1) features of the infectious process in burned; 2) the effect of antibacterial chemotherapy of burn wound infection on the microbiome and the processes of reparative regeneration; 3) principles of phage therapy; 4) ways of delivering bacteriophages; 5) development of resistance to bacteriophages 6) personalization of phage therapy.

Antimicrobial Resistance in Sexually Transmitted Infections: Current Trends

The review article discusses current trends in antibiotic resistance in bacterial and protozoal sexually transmitted infections (STIs). Antimicrobial resistance in STIs has increased significantly in recent decades due to the overuse and misuse of antibiotics, fueled by population migration and the high incidence of STIs worldwide. While emerging cephalosporin-resistant strains of Neisseria gonorrhoeae are one of the most pressing problems in the world, other pathogenic STIs that are resistant to antibiotics, such as Mycoplasma genitalium and Chlamydia trachomatis, are increasingly being reported. The emergence of multidrugresistant strains of bacterial STIs is of particular concern for researchers. The emerging global crisis in STI treatment is the result of neglect and inattention to repeated warnings from researchers about the emergence of STI strains resistant to the existing antibiotics, as well as shifting priorities in the pharmaceutical industry, which limited the development of new antibiotics. The current antimicrobial portfolio does not provide cause for optimism, as it contains few new antibiotics, and most developments are in the early stages of clinical trials. Experts have suggested that the failure of existing STI treatment regimens is largely inevitable and have called for the creation of entirely new classes of antimicrobial drugs that would take decades to develop. Currently, there are several promising alternative strategies for the treatment of antibiotic-resistant STIs. The use of phage therapy, antimicrobial peptides, and hydrolytic enzymes are particularly promising directions.

Managing Helicobacter pylori infection: transitioning from conventional to alternative treatment approaches

Helicobacter pylori, an essential constituent of the gastric microbiome in those infected, is commonly associated with medical conditions such as chronic gastritis, peptic ulcer disease, and gastric cancer. In recent years, the growing resistance to antibiotics worldwide has emerged as a substantial hurdle in the effective treatment of H. pylori infection. Consequently, it has necessitated the exploration of innovative treatment strategies aimed at bolstering the potency of existing antibiotic-based eradication therapies. Such avant-garde strategies include the incorporation of probiotics and prebiotics as complementary measures to H. pylori treatment, the use of antimicrobial peptides as potential replacements for traditional antibiotics, and the application of photodynamic therapy via ingestible devices. Other advanced methodologies entail deploying drug delivery systems that utilize microparticles and nanoparticles, the invention of vaccines, the exploration of natural products, and the potential use of phage therapy. This review offers a contemporary synopsis of these burgeoning strategies designed to suppress H. pylori, delving into their strengths, hurdles, and aspects to consider during their development. A significant achievement would be the creation of an efficient human vaccine; however, previous attempts at developing such vaccines have met with obstacles or even cessation. Numerous natural products have displayed anti-H. pylori properties, predominantly in laboratory environments. Nonetheless, a requirement remains for more extensive clinical studies to fully comprehend their role in exterminating H. pylori. Finally, phage therapy, while demonstrating potential as a suitable alternative, grapples with considerable challenges, chiefly the isolation of highly virulent bacteriophages that specifically target H. pylori.

Putative pseudolysogeny-dependent phage gene implicated in the superinfection resistance of Cutibacterium acnes.

Objectives: Cutibacterium acnes, formerly Propionibacterium acnes, is a bacterial species characterized by tenacious acne-contributing pathogenic strains. Therefore, bacteriophage therapy has become an attractive treatment route to circumvent issues such as evolved bacterial antibiotic resistance. However, medical and commercial use of phage therapy for C. acnes has been elusive, necessitating ongoing exploration of phage characteristics that confer bactericidal capacity. Methods: A novel phage (Aquarius) was isolated and analyzed. Testing included genomic sequencing and annotation, electron microscopy, patch testing, reinfection assays, and qPCR to confirm pseudolysogeny and putative superinfection exclusion (SIE) protein expression. Results: Given a superinfection-resistant phenotype was observed, reinfection assays and patch tests were performed, which confirmed the re-cultured bacteria were resistant to superinfection. Subsequent qPCR indicated pseudolysogeny was a concomitantly present phenomenon. Phage genomic analysis identified the presence of a conserved gene (gp41) with a product containing Ltp family-like protein signatures which may contribute to phage-mediated bacterial superinfection resistance (SIR) in a pseudolysogeny-dependent manner. qPCR was performed to analyze and roughly quantify gp41 activity, and mRNA expression was high during infection, implicating a role for the protein during the phage life cycle. Conclusions: This study confirms that C. acnes bacteria are capable of harboring phage pseudolysogens and suggests that this phenomenon plays a role in bacterial SIR. This mechanism may be conferred by the expression of phage proteins while the phage persists within the host in the pseudolysogenic state. This parameter must be considered in future endeavors for efficacious application of C. acnes phage-based therapeutics.

Use of Galleria mellonella as an Animal Model for Studying the Antimicrobial Activity of Bacteriophages with Potential Use in Phage Therapy.

Interest in phage therapy has increased in the last decade, and animal models have become essential in this field. The larval stage of the wax moth, Galleria mellonella, represents an easy-to-handle model. The larvae have an innate immune response and survive at 37°C, which is ideal for infection and antimicrobial studies with bacteriophages. In this chapter, we describe the procedures used to study the antimicrobial activity of bacteriophages in a G. mellonella infection model.

The Safety and Efficacy of Phage Therapy for Infections in Cardiac and Peripheral Vascular Surgery: A Systematic Review.

New approaches to managing infections in cardiac and peripheral vascular surgery are required to reduce costs to patients and healthcare providers. Bacteriophage (phage) therapy is a promising antimicrobial approach that has been recommended for consideration in antibiotic refractory cases. We systematically reviewed the clinical evidence for phage therapy in vascular surgery to support the unlicensed use of phage therapy and inform future research. Three electronic databases were searched for articles that reported primary data about human phage therapy for infections in cardiac or peripheral vascular surgery. Fourteen reports were eligible for inclusion, representing 40 patients, among which an estimated 70.3% of patients (n = 26/37) achieved clinical resolution. A further 10.8% (n = 4/37) of patients showed improvement and 18.9% (n = 7/37) showed no improvement. Six of the twelve reports that commented on the safety of phage therapy did not report adverse effects. No adverse effects documented in the remaining six reports were directly linked to phages but reflected the presence of manufacturing contaminants or release of bacterial debris following bacterial lysis. The reports identified by this review suggest that appropriately purified phages represent a safe and efficacious treatment option for infections in cardiac and peripheral vascular surgery.

Propagation, Purification, and Characterization of Bacteriophages for Phage Therapy.

Phage therapy is an alternative approach to combat bacterial infections. In this approach, bacteriophages are used as antimicrobial agents due to their properties to infect specific bacterial cells, to propagate inside their hosts, and to lyse host cell to release progeny phages. However, to introduce bacteriophages to clinical or veterinary practice, it is necessary to construct a large library of precisely characterized phages. Therefore, in this chapter, methods for propagation, purification, and microbiological characterization of bacteriophages are presented in the light of their potential use in phage therapy. Isolation of newly discovered bacteriophages from different habitats is also described as it is a preliminary assessment of their efficacy in combating bacterial biofilms and in the treatment of bacterial infections in a simple insect model-Galleria mellonella.

Bacteriophages and their derived enzymes as promising alternatives for the treatment of Acinetobacter baumannii infections.

Nosocomial infections with the opportunistic bacterium Acinetobacter baumannii pose a severe challenge to clinical treatment, which is aggravated by the increasing occurrence of multi-drug resistance, especially resistance to carbapenems. The use of phage therapy as an alternative and supplement to the current antibiotics has become an important research topic in the post-antibiotic era. This review summarizes in vivo and in vitro studies on phage therapy against multi-drug-resistant A. baumannii infection that have used different approaches, including treatment with a single phage, combination with other phages or non-phage agents, and administration of phage-derived enzymes. We also briefly discuss the current challenges of phage-based therapy as well as promising approaches for the treatment of A. baumannii infection in the future.

Do bacteriophages have activity in synovial fluid and against synovial fluid induced bacterial aggregates?

Bacteriophage therapy is a promising adjuvant therapy for the treatment of periprosthetic joint infections. However, there is a paucity of knowledge about the activity of bacteriophages in synovial fluid. Therefore, this study evaluated the activity of a clinically used bacteriophage in synovial fluid as well as the ability of that bacteriophage to prevent the formation of and eradicate bacteria in synovial fluid induced aggregates. The results of this study reinforce that synovial fluid induced aggregates form rapidly in numerous synovial fluid concentrations. More importantly, there was a statistically significant reduction in bacteriophage activity in synovial fluid compared to tryptic soy broth (p < 0.05) and the bacteriophage could not prevent the formation synovial fluid induced aggregates. Also the bacteriophage could not significantly reduce the amount of bacteria in the synovial fluid induced aggregates when compared to controls, and this was not secondary to resistance. Rather the reduced activity seems to be caused by bacteriophages being hindered in the ability to attach to bacterial receptors. We hypothesize this occurred because the viscosity of synovial fluid slowed bacteriophage interactions with planktonic bacteria and the synovial fluid polymers obstructed the bacteriophage attachment receptors thereby preventing attachment to bacteria in the aggregates. These findings have clinical ramifications, supporting the use of bacteriophage therapy as an adjunct to surgical interventions and not in isolation, at the nascent stage. While these findings show a shortcoming of bacteriophage therapy in periprosthetic joint infections, the knowledge gained should spearhead further research to ultimately devise effective and reproducible bacteriophage therapeutics.

Compounding Achromobacter Phages for Therapeutic Applications.

Achromobacter species colonization of Cystic Fibrosis respiratory airways is an increasing concern. Two adult patients with Cystic Fibrosis colonized by Achromobacter xylosoxidans CF418 or Achromobacter ruhlandii CF116 experienced fatal exacerbations. Achromobacter spp. are naturally resistant to several antibiotics. Therefore, phages could be valuable as therapeutics for the control of Achromobacter. In this study, thirteen lytic phages were isolated and characterized at the morphological and genomic levels for potential future use in phage therapy. They are presented here as the Achromobacter Kumeyaay phage collection. Six distinct Achromobacter phage genome clusters were identified based on a comprehensive phylogenetic analysis of the Kumeyaay collection as well as the publicly available Achromobacter phages. The infectivity of all phages in the Kumeyaay collection was tested in 23 Achromobacter clinical isolates; 78% of these isolates were lysed by at least one phage. A cryptic prophage was induced in Achromobacter xylosoxidans CF418 when infected with some of the lytic phages. This prophage genome was characterized and is presented as Achromobacter phage CF418-P1. Prophage induction during lytic phage preparation for therapy interventions require further exploration. Large-scale production of phages and removal of endotoxins using an octanol-based procedure resulted in a phage concentrate of 1 × 109 plaque-forming units per milliliter with an endotoxin concentration of 65 endotoxin units per milliliter, which is below the Food and Drugs Administration recommended maximum threshold for human administration. This study provides a comprehensive framework for the isolation, bioinformatic characterization, and safe production of phages to kill Achromobacter spp. in order to potentially manage Cystic Fibrosis (CF) pulmonary infections.

The host phylogeny determines viral infectivity and replication across Staphylococcus host species.

Virus host shifts, where a virus transmits to and infects a novel host species, are a major source of emerging infectious disease. Genetic similarity between eukaryotic host species has been shown to be an important determinant of the outcome of virus host shifts, but it is unclear if this is the case for prokaryotes where anti-virus defences can be transmitted by horizontal gene transfer and evolve rapidly. Here, we measure the susceptibility of 64 strains of Staphylococcaceae bacteria (48 strains of Staphylococcus aureus and 16 non-S. aureus species spanning 2 genera) to the bacteriophage ISP, which is currently under investigation for use in phage therapy. Using three methods-plaque assays, optical density (OD) assays, and quantitative (q)PCR-we find that the host phylogeny explains a large proportion of the variation in susceptibility to ISP across the host panel. These patterns were consistent in models of only S. aureus strains and models with a single representative from each Staphylococcaceae species, suggesting that these phylogenetic effects are conserved both within and among host species. We find positive correlations between susceptibility assessed using OD and qPCR and variable correlations between plaque assays and either OD or qPCR, suggesting that plaque assays alone may be inadequate to assess host range. Furthermore, we demonstrate that the phylogenetic relationships between bacterial hosts can generally be used to predict the susceptibility of bacterial strains to phage infection when the susceptibility of closely related hosts is known, although this approach produced large prediction errors in multiple strains where phylogeny was uninformative. Together, our results demonstrate the ability of bacterial host evolutionary relatedness to explain differences in susceptibility to phage infection, with implications for the development of ISP both as a phage therapy treatment and as an experimental system for the study of virus host shifts.