A Localized Phage-Based Antimicrobial System: Effect of Alginate on Phage Desorption from β-TCP Ceramic Bone Substitutes

Tricalcium phosphate (TCP) is a prosthetic material commonly used as a bone substitute to repair osteoarticular diseases and injuries. In this type of bone reconstruction surgery, antibiotics remain the common preventive and therapeutic treatment for bacterial infection. Nevertheless, the emergence of multi-resistant strains requires complimentary or alternative treatments. Today, one of the promising alternative approaches is phage therapy. Phages are bacterial viruses that have several advantages over chemotherapy, such as the specificity of bacterial strain, the absence of side effects, and a rapid response. In this work, we studied the impact of alginate hydrogels for overlaying λvir-phage-loaded β-TCP ceramic bone substitutes, delaying the phage desorption. The results show that the use of a 1% alginate–CaCl2 hydrogel overlapping the β-TCP ceramic pellets leads to higher initial phage concentration on the material and extends the released time of phages to two weeks when compared with control pellets. These alginate-coated biomaterials also generate faster bacterial lysis kinetics and could therefore be a good practical prosthetic device for bone and joint surgeries by allowing local treatment of bacterial infections with phage therapy for a longer period of time.

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The Safety and Efficacy of Phage Therapy for Superficial Bacterial Infections: A Systematic Review

Antibiotics ◽

10.3390/antibiotics9110754 ◽

2020 ◽

Vol 9 (11) ◽

pp. 754

Author(s):

Angharad Steele ◽

Helen J. Stacey ◽

Steven de Soir ◽

Joshua D. Jones

Keyword(s):

Systematic Review ◽

Adverse Effects ◽

Bacterial Infections ◽

Chronic Wound ◽

Phage Therapy ◽

Data Extraction ◽

Primary Data ◽

Burn Wound ◽

Promising Alternative ◽

Safety And Efficacy

Superficial bacterial infections, such as dermatological, burn wound and chronic wound/ulcer infections, place great human and financial burdens on health systems globally and are often complicated by antibiotic resistance. Bacteriophage (phage) therapy is a promising alternative antimicrobial strategy with a 100-year history of successful application. Here, we report a systematic review of the safety and efficacy of phage therapy for the treatment of superficial bacterial infections. Three electronic databases were systematically searched for articles that reported primary data about human phage therapy for dermatological, burn wound or chronic wound/ulcer infections secondary to commonly causative bacteria. Two authors independently assessed study eligibility and performed data extraction. Of the 27 eligible reports, eight contained data on burn wound infection (n = 156), 12 on chronic wound/ulcer infection (n = 327) and 10 on dermatological infections (n = 1096). Cautionary pooled efficacy estimates from the studies that clearly reported efficacy data showed clinical resolution or improvement in 77.5% (n = 111) of burn wound infections, 86.1% (n = 310) of chronic wound/ulcer infections and 94.14% (n = 734) of dermatological infections. Over half of the reports that commented on safety (n = 8/15), all published in or after 2002, did not express safety concerns. Seven early reports (1929–1987), described adverse effects consistent with the administration of raw phage lysate and co-administered bacterial debris or broth. This review strongly suggests that the use of purified phage to treat superficial bacterial infections can be highly effective and, by various routes of administration, is safe and without adverse effects.

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Functional diversity increases the efficacy of phage combinations

10.1101/2021.07.09.451746 ◽

2021 ◽

Author(s):

Rosanna C. T. Wright ◽

Ville Friman ◽

Margaret C. M. Smith ◽

Michael Brockhurst

Keyword(s):

Functional Diversity ◽

Functional Traits ◽

Bacterial Infections ◽

Phage Therapy ◽

Promising Alternative ◽

Functionally Diverse

Phage therapy is a promising alternative to traditional antibiotics for treating bacterial infections. Such phage-based therapeutics typically contain multiple phages, but how the efficacy of phage combinations scales with phage richness, identity and functional traits is unclear. Here, we experimentally tested the efficacy of 827 unique phage combinations ranging in phage richness from 1 to 12 phages. The efficacy of phage combinations increased with phage richness. However, complementarity between functionally diverse phages allowed efficacy to be maximised at lower levels of phage richness in functionally diverse combinations. These findings suggest that phage functional diversity is the key property of effective phage combinations, enabling the design of simple but effective phage therapies that overcome the practical and regulatory hurdles that limit development of more diverse phage therapy cocktails.

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Resistance Evolution against Phage Combinations Depends on the Timing and Order of Exposure

mBio ◽

10.1128/mbio.01652-19 ◽

2019 ◽

Vol 10 (5) ◽

Cited By ~ 13

Author(s):

Rosanna C. T. Wright ◽

Ville-Petri Friman ◽

Margaret C. M. Smith ◽

Michael A. Brockhurst

Keyword(s):

Pseudomonas Aeruginosa ◽

Bacterial Infections ◽

Phage Therapy ◽

Multidrug Resistant ◽

Fitness Costs ◽

Evolutionary Trajectory ◽

Promising Alternative ◽

Content Type ◽

Resistance Evolution

ABSTRACTPhage therapy is a promising alternative to chemotherapeutic antibiotics for the treatment of bacterial infections. However, despite recent clinical uses of combinations of phages to treat multidrug-resistant infections, a mechanistic understanding of how bacteria evolve resistance against multiple phages is lacking, limiting our ability to deploy phage combinations optimally. Here, we show, usingPseudomonas aeruginosaand pairs of phages targeting shared or distinct surface receptors, that the timing and order of phage exposure determine the strength, cost, and mutational basis of resistance. Whereas sequential exposure allowed bacteria to acquire multiple resistance mutations effective against both phages, this evolutionary trajectory was prevented by simultaneous exposure, resulting in quantitatively weaker resistance. The order of phage exposure determined the fitness costs of sequential resistance, such that certain sequential orders imposed much higher fitness costs than the same phage pair in the reverse order. Together, these data suggest that phage combinations can be optimized to limit the strength of evolved resistances while maximizing their associated fitness costs to promote the long-term efficacy of phage therapy.IMPORTANCEGlobally rising rates of antibiotic resistance have renewed interest in phage therapy where combinations of phages have been successfully used to treat multidrug-resistant infections. To optimize phage therapy, we first need to understand how bacteria evolve resistance against combinations of multiple phages. Here, we use simple laboratory experiments and genome sequencing to show that the timing and order of phage exposure determine the strength, cost, and mutational basis of resistance evolution in the opportunistic pathogenPseudomonas aeruginosa. These findings suggest that phage combinations can be optimized to limit the emergence and persistence of resistance, thereby promoting the long-term usefulness of phage therapy.

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Functional diversity increases the efficacy of phage combinations

Microbiology ◽

10.1099/mic.0.001110 ◽

2021 ◽

Vol 167 (12) ◽

Author(s):

Rosanna C. T. Wright ◽

Ville-Petri Friman ◽

Margaret C. M. Smith ◽

Michael A. Brockhurst

Keyword(s):

Functional Diversity ◽

Functional Traits ◽

Bacterial Infections ◽

Phage Therapy ◽

Promising Alternative ◽

Functionally Diverse

Phage therapy is a promising alternative to traditional antibiotics for treating bacterial infections. Such phage-based therapeutics typically contain multiple phages, but how the efficacy of phage combinations scales with phage richness, identity and functional traits is unclear. Here, we experimentally tested the efficacy of 827 unique phage combinations ranging in phage richness from one to 12 phages. The efficacy of phage combinations increased with phage richness. However, complementarity between functionally diverse phages allowed efficacy to be maximized at lower levels of phage richness in functionally diverse combinations. These findings suggest that phage functional diversity is the key property of effective phage combinations, enabling the design of simple but effective phage therapies that overcome the practical and regulatory hurdles that limit development of more diverse phage therapy cocktails.

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Pseudomonas aeruginosa Resistance to Bacteriophages and Its Prevention by Strategic Therapeutic Cocktail Formulation

Antibiotics ◽

10.3390/antibiotics10020145 ◽

2021 ◽

Vol 10 (2) ◽

pp. 145

Author(s):

Andrew Vaitekenas ◽

Anna S. Tai ◽

Joshua P. Ramsay ◽

Stephen M. Stick ◽

Anthony Kicic

Keyword(s):

Pseudomonas Aeruginosa ◽

Bacterial Infections ◽

Phage Therapy ◽

Treatment Options ◽

Rapid Evolution ◽

Resistance Mechanisms ◽

Phage Resistance ◽

Strategic Development ◽

Promising Alternative ◽

Narrow Host Range

Antimicrobial resistance poses a significant threat to modern healthcare as it limits treatment options for bacterial infections, particularly impacting those with chronic conditions such as cystic fibrosis (CF). Viscous mucus accumulation in the lungs of individuals genetically predisposed to CF leads to recurrent bacterial infections, necessitating prolonged antimicrobial chemotherapy. Pseudomonas aeruginosa infections are the predominant driver of CF lung disease, and airway isolates are frequently resistant to multiple antimicrobials. Bacteriophages, or phages, are viruses that specifically infect bacteria and are a promising alternative to antimicrobials for CF P. aeruginosa infections. However, the narrow host range of P. aeruginosa-targeting phages and the rapid evolution of phage resistance could limit the clinical efficacy of phage therapy. A promising approach to overcome these issues is the strategic development of mixtures of phages (cocktails). The aim is to combine phages with broad host ranges and target multiple distinct bacterial receptors to prevent the evolution of phage resistance. However, further research is required to identify and characterize phage resistance mechanisms in CF-derived P. aeruginosa, which differ from their non-CF counterparts. In this review, we consider the mechanisms of P. aeruginosa phage resistance and how these could be overcome by an effective future phage therapy formulation.

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Application of bacteriophages

Microbiology Australia ◽

10.1071/ma17029 ◽

2017 ◽

Vol 38 (2) ◽

pp. 63 ◽

Cited By ~ 1

Author(s):

Rustam Aminov ◽

Jonathan Caplin ◽

Nina Chanishvili ◽

Aidan Coffey ◽

Ian Cooper ◽

...

Keyword(s):

Bacterial Infections ◽

Phage Therapy ◽

Round Table ◽

Resistant Bacteria ◽

Antibiotic Resistant ◽

Promising Alternative ◽

Nagoya Protocol ◽

Secondary Infections ◽

Recent Developments ◽

Novel Antibiotics

The emergence of antibiotic-resistant bacteria and decrease in the discovery rate of novel antibiotics takes mankind back to the ‘pre-antibiotic era' and search for alternative treatments. Bacteriophages have been one of promising alternative agents which can be utilised for medicinal and biological control purposes in agriculture and related fields. The idea to treat bacterial infections with phages came out of the pioneering work of Félix d‘Hérelle but this was overshadowed by the success of antibiotics. Recent renewed interest in phage therapy is dictated by its advantages most importantly by their specificity against the bacterial targets. This prevents complications such as antibiotic-induced dysbiosis and secondary infections. This article is compiled by the participants of the Expert Round Table conference ‘Bacteriophages as tools for therapy, prophylaxis and diagnostics' (19–21 October 2015) at the Eliava Institute of Bacteriophage, Microbiology and Virology, Tbilisi, Georgia. The first paper from the Round Table was published in the Biotechnology Journal1. This In Focus article expands from this paper and includes recent developments reported since then by the Expert Round Table participants, including the implementation of the Nagoya Protocol for the applications of bacteriophages.

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Pharmacodynamics of non-replicating viruses, bacteriocins and lysins

Proceedings of The Royal Society B Biological Sciences ◽

10.1098/rspb.2006.3640 ◽

2006 ◽

Vol 273 (1602) ◽

pp. 2703-2712 ◽

Cited By ~ 21

Author(s):

James J Bull ◽

Roland R Regoes

Keyword(s):

Mathematical Models ◽

Cancer Treatment ◽

Single Molecule ◽

Bacterial Infections ◽

Therapeutic Agent ◽

Phage Therapy ◽

Therapeutic Agents ◽

Chemotherapeutic Agents ◽

Adsorption Rates ◽

The Impact

The pharmacodynamics of antibiotics and many other chemotherapeutic agents is often governed by a ‘multi-hit’ kinetics, which requires the binding of several molecules of the therapeutic agent for the killing of their targets. In contrast, the pharmacodynamics of novel alternative therapeutic agents, such as phages and bacteriocins against bacterial infections or viruses engineered to target tumour cells, is governed by a ‘single-hit’ kinetics according to which the agent will kill once it is bound to its target. In addition to requiring only a single molecule for killing, these agents bind irreversibly to their targets. Here, we explore the pharmacodynamics of such ‘irreversible, single-hit inhibitors’ using mathematical models. We focus on agents that do not replicate, i.e. in the case of phage therapy, we deal only with non-lytic phages and in the case of cancer treatment, we restrict our analysis to replication of incompetent viruses. We study the impact of adsorption on dead cells, heterogeneity in adsorption rates and spatial compartmentalization.

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Phage Therapy of Pneumonia Is Not Associated with an Overstimulation of the Inflammatory Response Compared to Antibiotic Treatment in Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00379-19 ◽

2019 ◽

Vol 63 (8) ◽

Cited By ~ 10

Author(s):

Nicolas Dufour ◽

Raphaëlle Delattre ◽

Anne Chevallereau ◽

Jean-Damien Ricard ◽

Laurent Debarbieux

Keyword(s):

Inflammatory Response ◽

Antibiotic Treatment ◽

Bacterial Infections ◽

Phage Therapy ◽

Bacterial Load ◽

The United States ◽

Experimental Models ◽

Interleukin 12 ◽

The Impact

ABSTRACT Supported by years of clinical use in some countries and more recently by literature on experimental models, as well as its compassionate use in Europe and in the United States, bacteriophage (phage) therapy is providing a solution for difficult-to-treat bacterial infections. However, studies of the impact of such treatments on the host remain scarce. Murine acute pneumonia initiated by intranasal instillation of two pathogenic strains of Escherichia coli (536 and LM33) was treated by two specific bacteriophages (536_P1 and LM33_P1; intranasal) or antibiotics (ceftriaxone, cefoxitin, or imipenem-cilastatin; intraperitoneal). Healthy mice also received phages alone. The severity of pulmonary edema, acute inflammatory cytokine concentration (blood and lung homogenates), complete blood counts, and bacterial and bacteriophage counts were determined at early (≤12 h) and late (≥20 h) time points. The efficacy of bacteriophage to decrease bacterial load was faster than with antibiotics, but the two displayed similar endpoints. Bacteriophage treatment was not associated with overinflammation but in contrast tended to lower inflammation and provided a faster correction of blood cell count abnormalities than did antibiotics. In the absence of bacterial infection, bacteriophage 536_P1 promoted a weak increase in the production of antiviral cytokines (gamma interferon [IFN-γ] and interleukin-12 [IL-12]) and chemokines in the lungs but not in the blood. However, such variations were no longer observed when bacteriophage 536_P1 was administered to treat infected animals. The rapid lysis of bacteria by bacteriophages in vivo does not increase the innate inflammatory response compared to that with antibiotic treatment.

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Genetic and Chemical Engineering of Phages for Controlling Multidrug-Resistant Bacteria

Antibiotics ◽

10.3390/antibiotics10020202 ◽

2021 ◽

Vol 10 (2) ◽

pp. 202

Author(s):

Dingming Guo ◽

Jingchao Chen ◽

Xueyang Zhao ◽

Yanan Luo ◽

Menglu Jin ◽

...

Keyword(s):

Bacterial Infections ◽

Chemical Engineering ◽

Phage Therapy ◽

Public Health Problem ◽

Multidrug Resistant ◽

Host Recognition ◽

Resistant Bacteria ◽

Multidrug Resistant Bacteria ◽

Promising Alternative ◽

Review Reports

Along with the excessive use of antibiotics, the emergence and spread of multidrug-resistant bacteria has become a public health problem and a great challenge vis-à-vis the control and treatment of bacterial infections. As the natural predators of bacteria, phages have reattracted researchers’ attentions. Phage therapy is regarded as one of the most promising alternative strategies to fight pathogens in the post-antibiotic era. Recently, genetic and chemical engineering methods have been applied in phage modification. Among them, genetic engineering includes the expression of toxin proteins, modification of host recognition receptors, and interference of bacterial phage-resistant pathways. Chemical engineering, meanwhile, involves crosslinking phage coats with antibiotics, antimicrobial peptides, heavy metal ions, and photothermic matters. Those advances greatly expand the host range of phages and increase their bactericidal efficiency, which sheds light on the application of phage therapy in the control of multidrug-resistant pathogens. This review reports on engineered phages through genetic and chemical approaches. Further, we present the obstacles that this novel antimicrobial has incurred.

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Adjunct phage treatment enhances the effectiveness of low antibiotic concentration against Staphylococcus aureus biofilms in vitro

10.1101/358879 ◽

2018 ◽

Cited By ~ 2

Author(s):

James Dickey ◽

Véronique Perrot

Keyword(s):

Staphylococcus Aureus ◽

Bacterial Infections ◽

Phage Therapy ◽

Bacterial Biofilms ◽

High Concentration ◽

Antibiotic Concentration ◽

Treatment Regimens ◽

Resistant Strains ◽

Phage Treatment

AbstractPhage therapy is drawing more interest as antibiotic resistance becomes an ever more serious threat to public health. Bacterial biofilms represent a major obstacle in the fight against bacterial infections as they are inherently refractory to many types of antibiotics. Treating biofilms with phage has shown promise in a handful of experimental and case studies. However, quantification of the effect of phage combined with antibiotics is needed to pave the way for larger clinical trials. Here we explore the effect of using phage in combination with a total of nine antibiotics, applied simultaneously or as a pretreatment before antibiotics are applied to in vitro biofilms of Staphylococcus aureus. Most antibiotics alone were ineffective at low concentration (2×MIC), but the addition of phage to treatment regimens led to substantial improvements in efficacy. At high concentration (10×MIC), antibiotics alone were effective, and in most cases the addition of phage to treatment regimens did not improve efficacy. Using phage with rifampin was also very effective at reducing the outgrowth of resistant strains during the course of treatment.

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