Search Results (14)

As antimicrobial resistance continues to undermine the efficacy of antibiotics, the global medical community is increasingly turning to alternative treatment modalities. Among these, phage therapy has re-emerged as a promising strategy for managing multidrug-resistant bacterial infections. Herein, we present and briefly discuss eight essential attributes of clinically relevant phages for therapy, which may be categorized broadly into virological and pharmacological characteristics. Virological attributes include a broad host range, a strictly lytic life cycle and the ability to manage the emergence of bacterial resistance to phages. Comprehensive genomic and proteomic characterization forms the foundation for selecting and engineering such candidates, ensuring both safety and predictability. From a pharmacological standpoint, phages should ideally show safety across relevant formulations and routes of administration, favorable pharmacokinetics, stability during storage and scalability in manufacturing. Advances in genomic analysis, artificial intelligence-driven phage selection and formulation technologies have further accelerated the translational potential of phage therapy. By systematically addressing each of these critical attributes, this work aims to inform the rational selection and development of therapeutic phages suitable for integration into the clinical practice. Full article

Background/Objectives: Antimicrobial resistance (AMR) poses a significant public health threat, leading to increased mortality. The World Health Organization has established a priority list highlighting critical multidrug-resistant (MDR) pathogens that demand urgent research on antimicrobial treatments. Considering this and the fact that new antibiotics are only sporadically approved, natural antibacterial agents have seen a resurgence in interest as potential alternatives to conventional antibiotics and chemotherapeutics. Natural antibacterials, derived from microorganisms, higher fungi, plants, animals, natural minerals, and food sources, offer diverse mechanisms of action against MDR pathogens. Here, we present a comprehensive summary of antibacterial agents from natural sources, including a brief history of their application and highlighting key strategies for using microorganisms (microbiopredators, such as bacteriophages), plant extracts and essential oils, minerals (e.g., silver and copper), as well as compounds of animal origin, such as milk or even venoms. The review also addresses the role of prebiotics, probiotics, and antimicrobial peptides, as well as novel formulations such as nanoparticles. The mechanisms of action of these compounds, such as terpenoids, alkaloids, and phenolic compounds, are explored alongside the challenges for their application, e.g., extraction, formulation, and pharmacokinetics. Conclusions: Future research should focus on developing eco-friendly, sustainable antimicrobial agents and validating their safety and efficacy through clinical trials. Clear regulatory frameworks are essential for integrating these agents into clinical practice. Despite challenges, natural sources offer transformative potential for combating AMR and promoting sustainable health solutions. Full article

Enterotoxigenic Escherichia coli (ETEC) is a major pathogen causing diarrhea in humans and animals, with increasing antimicrobial resistance posing a growing challenge in recent years. Lytic bacteriophages (phages) offer a targeted and environmentally sustainable approach to combating bacterial infections, particularly in eliminating drug-resistant strains. In this study, ETEC strains were utilized as indicators, and a stable, high-efficiency phage, designated vB_EcoM_JE01 (JE01), was isolated from pig farm manure. The genome of JE01 was a dsDNA molecule, measuring 168.9 kb, and a transmission electron microscope revealed its characteristic T4-like Myoviridae morphology. JE01 effectively lysed multi-drug-resistant ETEC isolates. Stability assays demonstrated that JE01 retained its activity across a temperature range of 20 °C to 50 °C and a pH range of 3–11, showing resilience to ultraviolet radiation and chloroform exposure. Furthermore, JE01 effectively suppressed ETEC adhesion to porcine intestinal epithelial cells (IPEC-J2), mitigating the inflammatory response triggered by ETEC. To investigate the in vivo antibacterial efficacy of phage JE01 preparations, a diarrhea model was established using germ-free mice infected with a drug-resistant ETEC strain. The findings indicated that 12 h post-ETEC inoculation, intragastric administration of phage JE01 significantly reduced mortality, alleviated gastrointestinal lesions, decreased ETEC colonization in the jejunum, and suppressed the expression of the cytokines IL-6 and IL-8. These results demonstrate a therapeutic benefit of JE01 in treating ETEC-induced diarrhea in mice. Additionally, a fluorescent phage incorporating red fluorescent protein (RFP) was engineered, and the pharmacokinetics of phage therapy were preliminarily assessed through intestinal fluorescence imaging in mice. The results showed that the phage localized to ETEC in the jejunum rapidly, within 45 min. Moreover, the pharmacokinetics of the phage were markedly slowed in the presence of its bacterial target in the gut, suggesting sustained bacteriolytic activity in the ETEC-infected intestine. In conclusion, this study establishes a foundation for the development of phage-based therapies against ETEC. Full article

Prosthetic joint infections (PJIs) are a serious complication of orthopedic surgery. Bacteriophage (phage) therapy shows promise as an adjunctive treatment but requires further study, particularly in its pharmacokinetics. Consequently, we performed a pharmacokinetic assessment of phage therapy for PJIs using a Staphylococcus epidermidis Kirschner wire-based prosthesis rat model. We used 52 male Sprague–Dawley rats in four groups: negative controls (no phage, sterile implant), PJI controls (bacteria, no phage), sterile phage (phages given, sterile implant), and PJI (bacteria, phages given). The PJI groups were inoculated with ~10⁶ CFU of S. epidermidis. The groups receiving phage were intra-articularly injected with ~10⁸ PFU of vB_SepM_Alex five days post-implantation. The rats were euthanized between 30 min and 48 h post-injection. The measured phage concentrations between the PJI rats and the sterile controls in periarticular tissues were not significantly different. In a noncompartmental pharmacokinetic analysis, the estimated phage half-lives were under 6 h (combined: 3.73 [IQR, 1.45, 10.07]). The maximum phage concentrations were reached within 2 h after administration (combined: 0.75 [0.50, 1.75]). The estimated phage mean residence time was approximately three hours (combined: 3.04 [1.44, 4.19]). Our study provides a preliminary set of pharmacokinetic parameters that can inform future phage dosing studies and animal models of phage therapy for PJIs. Full article

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. Full article

Prosthetic Joint Infection (PJI) causes significant morbidity and mortality for patients globally. Delivery of antibiotics to the site of infection has potential to improve the treatment outcomes and enhance biofilm eradication. These antibiotics can be delivered using an intra-articular catheter or combined with a carrier substance to enhance pharmacokinetic properties. Carrier options include non-resorbable polymethylmethacrylate (PMMA) bone cement and resorbable calcium sulphate, hydroxyapatite, bioactive glass, and hydrogels. PMMA allows for creation of structural spacers used in multi-stage revision procedures, however it requires subsequent removal and antibiotic compatibility and the levels delivered are variable. Calcium sulphate is the most researched resorbable carrier in PJI, but is associated with wound leakage and hypercalcaemia, and clinical evidence for its effectiveness remains at the early stage. Hydrogels provide a versatile combability with antibiotics and adjustable elution profiles, but clinical usage is currently limited. Novel anti-biofilm therapies include bacteriophages which have been used successfully in small case series. Full article

Antibiotic resistance has emerged as a significant issue to be resolved around the world. Bacteriophage (phage), in contrast to antibiotics, can only kill the target bacteria with no adverse effect on the normal bacterial flora. In this review, we described the biological characteristics of phage, and summarized the phage application in China, including in mammals, ovipara, aquatilia, and human clinical treatment. The data showed that phage had a good therapeutic effect on drug-resistant bacteria in veterinary fields, as well as in the clinical treatment of humans. However, we need to take more consideration of the narrow lysis spectrum, the immune response, the issues of storage, and the pharmacokinetics of phages. Due to the particularity of bacteriophage as a bacterial virus, there is no unified standard or regulation for the use of bacteriophage in the world at present, which hinders the application of bacteriophage as a substitute for antibiotic biological products. We aimed to highlight the rapidly advancing field of phage therapy as well as the challenges that China faces in reducing its reliance on antibiotics. Full article

With concern growing over antibiotics resistance, the use of bacteriophages to combat resistant bacteria has been suggested as an alternative strategy with which to enable the selective control of targeted pathogens. One major challenge that restrains the therapeutic application of bacteriophages as antibacterial agents is their short lifespan, which limits their antibacterial effect in vivo. Here, we developed a polylactic-co-glycolic acid (PLGA)/alginate-composite microsphere for increasing the lifespan of bacteriophages in vivo. The alginate matrix in PLGA microspheres encapsulated the bacteriophages and protected them against destabilization by an organic solvent. Encapsulated bacteriophages were detected in the tissue for 28 days post-administration, while the bacteriophages administered without advanced encapsulation survived in vivo for only 3–5 days. The bacteriophages with extended fate showed prophylaxis against the bacterial pathogens for 28 days post-administration. This enhanced prophylaxis is presumed to have originated from the diminished immune response against these encapsulated bacteriophages because of their controlled release. Collectively, composite encapsulation has prophylactic potential against bacterial pathogens that threaten food safety and public health. Full article

Bacterial infectious diseases cause serious harm to human health. At present, antibiotics are the main drugs used in the treatment of bacterial infectious diseases, but the abuse of antibiotics has led to the rapid increase in drug-resistant bacteria and to the inability to effectively control infections. Bacteriophages are a kind of virus that infects bacteria and archaea, adopting bacteria as their hosts. The use of bacteriophages as antimicrobial agents in the treatment of bacterial diseases is an alternative to antibiotics. At present, phage therapy (PT) has been used in various fields and has provided a new technology for addressing diseases caused by bacterial infections in humans, animals, and plants. PT uses bacteriophages to infect pathogenic bacteria so to stop bacterial infections and treat and prevent related diseases. However, PT has several limitations, due to a narrow host range, the lysogenic phenomenon, the lack of relevant policies, and the lack of pharmacokinetic data. The development of reasonable strategies to overcome these limitations is essential for the further development of this technology. This review article described the current applications and limitations of PT and summarizes the existing solutions for these limitations. This information will be useful for clinicians, people working in agriculture and industry, and basic researchers. Full article

Pseudomonas aeruginosa is one of the most common causes of healthcare-associated diseases and is among the top three priority pathogens listed by the World Health Organization (WHO). This Gram-negative pathogen is especially difficult to eradicate because it displays high intrinsic and acquired resistance to many antibiotics. In addition, growing concerns regarding the scarcity of antibiotics against multidrug-resistant (MDR) and extensively drug-resistant (XDR) P. aeruginosa infections necessitate alternative therapies. Bacteriophages, or phages, are viruses that target and infect bacterial cells, and they represent a promising candidate for combatting MDR infections. The aim of this review was to highlight the clinical pharmacology considerations of phage therapy, such as pharmacokinetics, formulation, and dosing, while addressing several challenges associated with phage therapeutics for MDR P. aeruginosa infections. Further studies assessing phage pharmacokinetics and pharmacodynamics will help to guide interested clinicians and phage researchers towards greater success with phage therapy for MDR P. aeruginosa infections. Full article

Antimicrobial resistance necessitates action to reduce and eliminate infectious disease, ensure animal and human health, and combat emerging diseases. Species such as Acinetobacter baumanniii, vancomycin resistant Enterococcus, methicillin resistance Staphylococcus aureus, and Pseudomonas aeruginosa, as well as other WHO priority pathogens, are becoming extremely difficult to treat. In 2017, the EU adopted the “One Health” approach to combat antibiotic resistance in animal and human medicine and to prevent the transmission of zoonotic disease. As the current therapeutic agents become increasingly inadequate, there is a dire need to establish novel methods of treatment under this One Health Framework. Bacteriophages (phages), viruses infecting bacterial species, demonstrate clear antimicrobial activity against an array of resistant species, with high levels of specificity and potency. Bacteriophages play key roles in bacterial evolution and are essential components of all ecosystems, including the human microbiome. Factors such are their specificity, potency, biocompatibility, and bactericidal activity make them desirable options as therapeutics. Issues remain, however, relating to their large-scale production, formulation, stability, and bacterial resistance, limiting their implementation globally. Phages used in therapy must be virulent, purified, and well characterized before administration. Clinical studies are warranted to assess the in vivo pharmacokinetics and pharmacodynamic characteristics of phages to fully establish their therapeutic potential. Full article

Pharmacology can be differentiated into two key aspects, pharmacodynamics and pharmacokinetics. Pharmacodynamics describes a drug's impact on the body while pharmacokinetics describes the body's impact on a drug. Another way of understanding these terms is that pharmacodynamics is a description of both the positive and negative consequences of drugs attaining certain concentrations in the body while pharmacokinetics is concerned with our ability to reach and then sustain those concentrations. Unlike the drugs for which these concepts were developed, including antibiotics, the bacteriophages (or 'phages') that we consider here are not chemotherapeutics but instead are the viruses of bacteria. Here we review the pharmacology of these viruses, particularly as they can be employed to combat bacterial infections (phage therapy). Overall, an improved pharmacological understanding of phage therapy should allow for more informed development of phages as antibacterial 'drugs', allow for more rational post hoc debugging of phage therapy experiments, and encourage improved design of phage therapy protocols. Contrasting with antibiotics, however, phages as viruses impact individual bacterial cells as single virions rather than as swarms of molecules, and while they are killing bacteria, bacteriophages also can amplify phage numbers, in situ. Explorations of phage therapy pharmacology consequently can often be informed as well by basic principles of the ecological interactions between phages and bacteria as by study of the pharmacology of drugs. Bacteriophages in phage therapy thus can display somewhat unique as well as more traditional pharmacological aspects. Full article

Multidrug-resistant (MDR) Klebsiella pneumoniae represents an increasing threat to human health, causing difficult-to-treat infections with a high mortality rate. Since colistin is one of the few treatment options for carbapenem-resistant K. pneumoniae infections, colistin resistance represents a challenge due to the limited range of potentially available effective antimicrobials, including tigecycline, gentamicin, fosfomycin and ceftazidime/avibactam. Moreover, the choice of these antimicrobials depends on their pharmacokinetics/pharmacodynamics properties, the site of infection and the susceptibility profile of the isolated strain, and is sometimes hampered by side effects. This review describes the features of colistin resistance in K. pneumoniae and the characteristics of the currently available antimicrobials for colistin-resistant MDR K. pneumoniae, as well as the characteristics of novel antimicrobial options, such as the soon-to-be commercially available plazomicin and cefiderocol. Finally, we consider the future use of innovative therapeutic strategies in development, including bacteriophages therapy and monoclonal antibodies. Full article

The emergence of multidrug-resistant bacteria constitutes a great challenge for modern medicine, recognized by leading medical experts and politicians worldwide. Rediscovery and implementation of bacteriophage therapy by Western medicine might be one solution to the problem of increasing antibiotic failure. In some Eastern European countries phage therapy is used for treating infectious diseases. However, while the European Medicines Agency (EMA) advised that the development of bacteriophage-based therapies should be expedited due to its significant potential, EMA emphasized that phages cannot be recommended for approval before efficacy and safety have been proven by appropriately designed preclinical and clinical trials. More evidence-based data is required, particularly in the areas of pharmacokinetics, repeat applications, immunological reactions to the application of phages as well as the interactions and effects on bacterial biofilms and organ-specific environments. In this brief review we summarize advantages and disadvantages of phage therapy and discuss challenges to the establishment of phage therapy as approved treatment for multidrug-resistant bacteria. Full article