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1.
Vet Q ; 44(1): 1-9, 2024 Dec.
Article in English | MEDLINE | ID: mdl-38726795

ABSTRACT

Antibiotic-resistant pathogens are a growing global issue, leading to untreatable infectious diseases in both humans and animals. Personalized bacteriophage (phage) therapy, the use of specific anti-bacterial viruses, is currently a leading approach to combat antibiotic-resistant infections. The implementation of phage therapy has primarily been focused on humans, almost neglecting the impact of such infections on the health and welfare of companion animals. Pets also have the potential to spread resistant infections to their owners or the veterinary staff through zoonotic transmission. Here, we showcase personalized phage-antibiotic treatment of a cat with a multidrug-resistant Pseudomonas aeruginosa implant-associated infection post-arthrodesis surgery. The treatment encompassed a tailored combination of an anti-P. aeruginosa phage and ceftazidime, precisely matched to the pathogen. The phage was topically applied to the surgical wound while the antibiotic was administered intramuscularly. After two treatment courses spanning 7 and 3 weeks, the surgical wound, which had previously remained open for five months, fully closed. To the best of our knowledge, this is the first case of personalized phage therapy application in felines, which provides further evidence of the effectiveness of this approach. The successful outcome paves the way for personalized phage-antibiotic treatments against persistent infections therapy in veterinary practice.


Subject(s)
Anti-Bacterial Agents , Cat Diseases , Phage Therapy , Pseudomonas Infections , Pseudomonas aeruginosa , Animals , Cats , Phage Therapy/veterinary , Pseudomonas Infections/veterinary , Pseudomonas Infections/drug therapy , Pseudomonas Infections/therapy , Cat Diseases/therapy , Cat Diseases/drug therapy , Cat Diseases/microbiology , Pseudomonas aeruginosa/drug effects , Anti-Bacterial Agents/therapeutic use , Ceftazidime/therapeutic use , Drug Resistance, Multiple, Bacterial , Bacteriophages
2.
STAR Protoc ; 5(2): 102949, 2024 Apr 30.
Article in English | MEDLINE | ID: mdl-38691464

ABSTRACT

Phage therapy has re-emerged as a promising treatment for non-resolving infections. Given the lack of approved phage treatments, there is a need to establish a compassionate use pipeline. Here, we present a protocol for phage matching, treatment, and monitoring for compassionate bacteriophage use in non-resolving infections. We describe steps for consultation and request implementation, evaluating and comparing different aspects of phage activity, and phage production. We then detail procedures for multidisciplinary meetings, ethics approvals, phage therapy, and follow-up. For complete details on the use and execution of this protocol, please refer to Onallah et al.1,2.

3.
Med ; 4(9): 600-611.e4, 2023 09 08.
Article in English | MEDLINE | ID: mdl-37562400

ABSTRACT

BACKGROUND: A growing number of compassionate phage therapy cases were reported in the last decade, with a limited number of clinical trials conducted and few unsuccessful clinical trials reported. There is only a little evidence on the role of phages in refractory infections. Our objective here was to present the largest compassionate-use single-organism/phage case series in 16 patients with non-resolving Pseudomonas aeruginosa infections. METHODS: We summarized clinical phage microbiology susceptibility data, administration protocol, clinical data, and outcomes of all cases treated with PASA16 phage. In all intravenous phage administrations, PASA16 phage was manufactured and provided pro bono by Adaptive Phage Therapeutics. PASA16 was administered intravenously, locally to infection site, or by topical use to 16 patients, with data available for 15 patients, mainly with osteoarticular and foreign-device-associated infections. FINDINGS: A few minor side effects were noted, including elevated liver function enzymes and a transient reduction in white blood cell count. Good clinical outcome was documented in 13 out of 15 patients (86.6%). Two clinical failures were reported. The minimum therapy duration was 8 days with a once- to twice-daily regimen. CONCLUSIONS: PASA16 with antibiotics was found to be relatively successful in patients for whom traditional treatment approaches have failed previously. Such pre-phase-1 cohorts can outline potential clinical protocols and facilitate the design of future trials. FUNDING: The study was funded in part by The Israeli Science Foundation IPMP (ISF_1349/20), Rosetrees Trust (A2232), United States-Israel Binational Science Foundation (2017123), and the Milgrom Family Support Program.


Subject(s)
Bacteriophages , Pseudomonas Infections , Pseudomonas Phages , Humans , Pseudomonas Infections/drug therapy , Pseudomonas Infections/microbiology , Compassionate Use Trials , Anti-Bacterial Agents/therapeutic use
4.
Nat Commun ; 14(1): 1005, 2023 02 22.
Article in English | MEDLINE | ID: mdl-36813793

ABSTRACT

Acne vulgaris is a common neutrophil-driven inflammatory skin disorder in which Cutibacterium acnes (C. acnes) is known to play a key role. For decades, antibiotics have been widely employed to treat acne vulgaris, inevitably resulting in increased bacterial antibiotic resistance. Phage therapy is a promising strategy to combat the growing challenge of antibiotic-resistant bacteria, utilizing viruses that specifically lyse bacteria. Herein, we explore the feasibility of phage therapy against C. acnes. Eight novel phages, isolated in our laboratory, and commonly used antibiotics eradicate 100% of clinically isolated C. acnes strains. Topical phage therapy in a C. acnes-induced acne-like lesions mouse model affords significantly superior clinical and histological scores. Moreover, the decrease in inflammatory response was reflected by the reduced expression of chemokine CXCL2, neutrophil infiltration, and other inflammatory cytokines when compared with the infected-untreated group. Overall, these findings indicate the potential of phage therapy for acne vulgaris as an additional tool to conventional antibiotics.


Subject(s)
Acne Vulgaris , Phage Therapy , Animals , Mice , Anti-Bacterial Agents/pharmacology , Skin/microbiology , Drug Resistance, Bacterial , Propionibacterium acnes
5.
Phage (New Rochelle) ; 3(2): 85-94, 2022 Jun 01.
Article in English | MEDLINE | ID: mdl-36157284

ABSTRACT

The fascinating scientific history of phage therapy has been documented in numerous publications. In this study, however, we focus on an angle of the story that hitherto has remained relatively neglected, namely, phage therapy treatments, and the protagonists that conducted these in Mandatory-Palestine and subsequently the state of Israel, as part of a global trend. We complete the story by describing efforts in the new era of phage therapy in present-day Israel.

6.
Microbiol Resour Announc ; 11(4): e0009222, 2022 Apr 21.
Article in English | MEDLINE | ID: mdl-35258339

ABSTRACT

PASA16 is a Pseudomonas aeruginosa phage isolated from a soil sample and used to treat several patients suffering from persistent infections in various countries. PASA16's genome was sequenced, analyzed, and deposited in GenBank.

7.
ERJ Open Res ; 7(4)2021 Oct.
Article in English | MEDLINE | ID: mdl-34760998

ABSTRACT

Phage therapy is a promising antibacterial strategy for resistant respiratory tract infections. Phage inhalation may serve this goal; however, it requires a careful assessment of their delivery by this approach. Here we present an in vitro model to evaluate phage inhalation. Eight phages, most of which target pathogens common in cystic fibrosis, were aerosolised by jet nebuliser and administered to a real-scale computed tomography-derived 3D airways model with a breathing simulator. Viable phage loads reaching the output of the nebuliser and the tracheal level of the model were determined and compared to the loaded amount. Phage inhalation resulted in a diverse range of titre reduction, primarily associated with the nebulisation process. No correlation was found between phage delivery to the phage physical or genomic dimensions. These findings highlight the need for tailored simulations of phage delivery, ideally by a patient-specific model in addition to proper phage matching, to increase the potential of phage therapy success.

8.
Viruses ; 13(9)2021 09 07.
Article in English | MEDLINE | ID: mdl-34578366

ABSTRACT

Phage therapy is an experimental therapeutic approach used to target multidrug-resistant bacterial infections. A lack of reliable data with regard to its efficacy and regulatory hurdles hinders a broad application. Here we report, for the first time, a case of vancomycin-resistant Enterococcus faecium abdominal infection in a one-year-old, critically ill, and three times liver transplanted girl, which was successfully treated with intravenous injections (twice per day for 20 days) of a magistral preparation containing two Enterococcus phages. This correlated with a reduction in baseline C-reactive protein (CRP), successful weaning from mechanical ventilation and without associated clinical adverse events. Prior to clinical use, phage genome was sequenced to confirm the absence of genetic determinants conferring lysogeny, virulence or antibiotic resistance, and thus their safety. Using a phage neutralization assay, no neutralizing anti-phage antibodies in the patient's serum could be detected. Vancomycin-susceptible E. faecium isolates were identified in close relation to phage therapy and, by using whole-genome sequencing, it was demonstrated that vancomycin-susceptible E. faecium emerged from vancomycin-resistant progenitors. Covering a one year follow up, we provide further evidence for the feasibility of bacteriophage therapy that can serve as a basis for urgently needed controlled clinical trials.


Subject(s)
Anti-Bacterial Agents/pharmacology , Enterococcus faecium/drug effects , Gram-Positive Bacterial Infections/therapy , Liver Transplantation/adverse effects , Phage Therapy/methods , Vancomycin/pharmacology , Cross Infection , Drug Resistance, Multiple, Bacterial , Enterococcus faecium/genetics , Female , Genome, Bacterial , Gram-Positive Bacterial Infections/etiology , Humans , Infant , Microbial Sensitivity Tests , Treatment Outcome , Vancomycin-Resistant Enterococci , Whole Genome Sequencing
9.
Viruses ; 13(5)2021 05 02.
Article in English | MEDLINE | ID: mdl-34063251

ABSTRACT

Streptococcus mutans is a key bacterium in dental caries, one of the most prevalent chronic infectious diseases. Conventional treatment fails to specifically target the pathogenic bacteria, while tending to eradicate commensal bacteria. Thus, caries remains one of the most common and challenging diseases. Phage therapy, which involves the use of bacterial viruses as anti-bacterial agents, has been gaining interest worldwide. Nevertheless, to date, only a few phages have been isolated against S. mutans. In this study, we describe the isolation and characterization of a new S. mutans phage, termed SMHBZ8, from hundreds of human saliva samples that were collected, filtered, and screened. The SMHBZ8 genome was sequenced and analyzed, visualized by TEM, and its antibacterial properties were evaluated in various states. In addition, we tested the lytic efficacy of SMHBZ8 against S. mutans in a human cariogenic dentin model. The isolation and characterization of SMHBZ8 may be the first step towards developing a potential phage therapy for dental caries.


Subject(s)
Dental Caries/therapy , Phage Therapy , Streptococcus Phages/isolation & purification , Streptococcus mutans/virology , Dental Caries/microbiology , Dental Caries/virology , Genome, Viral , Humans , Saliva/virology , Streptococcus Phages/classification , Streptococcus Phages/genetics , Streptococcus Phages/physiology , Streptococcus mutans/physiology
10.
Microbiol Resour Announc ; 10(16)2021 Apr 22.
Article in English | MEDLINE | ID: mdl-33888497

ABSTRACT

EFGrKN and EFGrNG are new Enterococcus faecalis phages that were isolated from sewage samples as part of the Israeli Phage Bank (IPB). The complete genomes were sequenced, analyzed, and deposited in GenBank. According to their lytic activity in vitro, it seems that these phages have a potential to be used in future phage therapy treatments.

11.
Antibiotics (Basel) ; 10(4)2021 Apr 02.
Article in English | MEDLINE | ID: mdl-33918377

ABSTRACT

Providencia spp. are emerging pathogens mainly in nosocomial infections. Providencia stuartii in particular is involved in urinary tract infections and contributes significantly to the high incidence of biofilm-formation in catheterized patients. Furthermore, recent reports suggested a role for multiple drug resistant (MDR) P. stuartii in hospital-associated outbreaks which leads to excessive complications resulting in challenging treatments. Phage therapy is currently one of the most promising solutions to combat antibiotic-resistant infections. However, the number of available phages targeting Providencia spp. is extremely limited, restricting the use of phage therapy in such cases. In the present study, we describe the isolation and characterization of 17 lytic and temperate bacteriophages targeting clinical isolates of Providencia spp. as part of the Israeli Phage Bank (IPB). These phages, isolated from sewage samples, were evaluated for host range activity and effectively eradicated 95% of the tested bacterial strains isolated from different geographic locations and displaying a wide range of antibiotic resistance. Their lytic activity is demonstrated on agar plates, planktonic cultures, and biofilm formed in a catheter model. The results suggest that these bacteriophages can potentially be used for treatment of antibiotic-resistant Providencia spp. infections in general and of urinary tract infections in particular.

12.
Lancet Microbe ; 2(10): e555-e563, 2021 10.
Article in English | MEDLINE | ID: mdl-35544180

ABSTRACT

Phage therapy is a promising solution for bacterial infections that are not eradicated by conventional antibiotics. A crucial element of this approach is appropriate matching of bacteriophages and antibiotics to the bacterial target according to the clinical setting. However, there is currently little consistency in the protocols used for the laboratory evaluation of bacteriophages intended for antibacterial treatment. In this Personal View, we suggest a framework aimed to match appropriate bacteriophage-based treatments in clinical microbiology laboratories. This framework, which we have termed Clinical Phage Microbiology, is based on the current research on phage treatments. In addition, we discuss special cases that might require additional relevant evaluation, including bacteriophage interactions with the host immune response, biofilm-associated infections, and polymicrobial infections. The Clinical Phage Microbiology pipeline could serve as the basis for future standardisation of laboratory protocols for personalised phage therapy.


Subject(s)
Bacterial Infections , Bacteriophages , Phage Therapy , Anti-Bacterial Agents/therapeutic use , Bacterial Infections/therapy , Biofilms , Humans
13.
Acta Derm Venereol ; 100(17): adv00295, 2020 10 20.
Article in English | MEDLINE | ID: mdl-33021324

ABSTRACT

Antibiotic-resistant Cutibacterium acnes has been reported worldwide, but data from Israeli patients with acne is currently lacking. This study evaluated the antibiotic susceptibility of C. acnes, isolated from 50 Israeli patients with acne to commonly prescribed antibiotics, using the Epsilometer test (E-test). Matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) analysis, 16S rRNA sequencing and single locus sequence typing (SLST) molecular typing were used to identify and characterize C. acnes. Among 36 strains isolated, phylotype IA1 was most common. Resistance to at least one antibiotic was found in 30.6% of tested strains. Resistance rates were highest for erythromycin (25.0%), followed by doxycycline (19.4%), clindamycin (16.7%), minocycline (11.1%) and tetracycline (8.3%). Significant correlation was found between resistance to multiple antibiotics, with 5.6% of isolates resistant to all antibiotics tested. When reviewing resistances rate worldwide antibiotic resistance was found to be prevalent in Israel. Measures to limit the emergence of antibiotic-resistant strains of Cutibacterium acnes should be taken and alternative treatments should be sought.


Subject(s)
Acne Vulgaris , Propionibacterium acnes , Acne Vulgaris/diagnosis , Acne Vulgaris/drug therapy , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Humans , Israel/epidemiology , Microbial Sensitivity Tests , Propionibacterium acnes/genetics , RNA, Ribosomal, 16S/genetics
14.
Antibiotics (Basel) ; 9(5)2020 May 21.
Article in English | MEDLINE | ID: mdl-32455557

ABSTRACT

A key element in phage therapy is the establishment of large phage collections, termed herein "banks", where many well-characterized phages, ready to be used in the clinic, are stored. These phage banks serve for both research and clinical purposes. Phage banks are also a key element in clinical phage microbiology, the prior treatment matching of phages and antibiotics to specific bacterial targets. A worldwide network of phage banks can promote a phage-based solution for any isolated bacteria. Herein, we describe the Israeli Phage Bank (IPB) established in the Hebrew University, Jerusalem, which currently has over 300 phages matching 16 bacteria, mainly pathogens. The phage bank is constantly isolating new phages and developing methods for phage isolation and characterization. The information on the phages and bacteria stored in the bank is available online.

15.
Bio Protoc ; 10(1): e3473, 2020 Jan 05.
Article in English | MEDLINE | ID: mdl-33654708

ABSTRACT

Ancient fermented food has been studied mainly based on residue analysis and recipes and reconstruction attempts were performed using modern domesticated yeast. Furthermore, microorganisms which participated in fermentation were studied using ancient-DNA techniques. In a recent paper, we presented a novel approach based on the hypothesis that enriched yeast populations in fermented beverages could have become the dominant species in storage vessels and their descendants could be isolated and studied today. Here we present a pipeline for isolation of yeast from clay vessels uncovered in archeological sites and transferred to the microbiology lab where they can be isolated and characterized. This method opens new avenues for experimental archeology and enables attempts to recreate ancient food and beverages using the original microorganisms.

16.
Viruses ; 11(10)2019 10 16.
Article in English | MEDLINE | ID: mdl-31623253

ABSTRACT

Currently, effective options are needed to fight vancomycin-resistant Enterococcus faecalis (VRE). The present study shows that combinations of phage and vancomycin are highly efficient against VRE, despite being resistant to the antibiotic. Vancomycin-phage EFLK1 (anti-E. faecalis phage) synergy was assessed against VRE planktonic and biofilm cultures. The effect of the combined treatment on VRE biofilms was determined by evaluating the viable counts and biomass and then visualized using scanning electron microscopy (SEM). The cell wall peptidoglycan was stained after phage treatment, visualized by confocal microscopy and quantified by fluorescence activated cell sorting (FACS) analysis. The combined treatment was synergistically effective compared to treatment with phage or antibiotic alone, both in planktonic and biofilm cultures. Confocal microscopy and FACS analysis showed that fluorescence intensity of phage-treated bacteria increased eight-fold, suggesting a change in the peptidoglycan of the cell wall. Our results indicate that with combined treatment, VRE strains are not more problematic than sensitive strains and thus give hope in the continuous struggle against the current emergence of multidrug resistant pathogens.


Subject(s)
Anti-Bacterial Agents/pharmacology , Bacteriophages/physiology , Biofilms/drug effects , Vancomycin-Resistant Enterococci/drug effects , Vancomycin-Resistant Enterococci/virology , Vancomycin/pharmacology , Colony Count, Microbial , Drug Resistance, Multiple, Bacterial , Microbial Sensitivity Tests
17.
Microbiol Resour Announc ; 8(38)2019 Sep 19.
Article in English | MEDLINE | ID: mdl-31537666

ABSTRACT

We report the genomic sequences of phages KpCHEMY26 and KpGranit, isolated in Israel during a worldwide effort against a multidrug- and phage-resistant strain of Klebsiella pneumoniae from a patient in Finland. These results demonstrate the importance of an efficient worldwide network for collaborating in personalized therapy for infectious diseases.

18.
mBio ; 10(2)2019 04 30.
Article in English | MEDLINE | ID: mdl-31040238

ABSTRACT

Ancient fermented food has been studied based on recipes, residue analysis, and ancient-DNA techniques and reconstructed using modern domesticated yeast. Here, we present a novel approach based on our hypothesis that enriched yeast populations in fermented beverages could have become the dominant species in storage vessels and their descendants could be isolated and studied today. We developed a pipeline of yeast isolation from clay vessels and screened for yeast cells in beverage-related and non-beverage-related ancient vessels and sediments from several archaeological sites. We found that yeast cells could be successfully isolated specifically from clay containers of fermented beverages. The findings that genotypically the isolated yeasts are similar to those found in traditional African beverages and phenotypically they grow similar to modern beer-producing yeast strongly suggest that they are descendants of the original fermenting yeast. These results demonstrate that modern microorganisms can serve as a new tool in bio-archaeology research.IMPORTANCE So far, most of the study of ancient organisms has been based mainly on the analysis of ancient DNA. Here we show that it is possible to isolate and study microorganisms-yeast in this case-from ancient pottery vessels used for fermentation. We demonstrate that it is highly likely that these cells are descendants of the original yeast strains that participated in the fermentation process and were absorbed into the clay matrix of the pottery vessels. Moreover, we characterized the isolated yeast strains, their genomes, and the beer they produced. These results open new and exciting avenues in the study of domesticated microorganisms and contribute significantly to the fields of bio- and experimental archaeology that aim to reconstruct ancient artifacts and products.


Subject(s)
Archaeology/methods , Fossils/microbiology , Geologic Sediments/microbiology , Microbiological Techniques/methods , Yeasts/isolation & purification , Genotype
19.
Clin Infect Dis ; 69(11): 2015-2018, 2019 11 13.
Article in English | MEDLINE | ID: mdl-30869755

ABSTRACT

A patient with a trauma-related left tibial infection associated with extensively drug-resistant Acinetobacter baumannii and multidrug-resistant Klebsiella pneumoniae was treated with bacteriophages and antibiotics. There was rapid tissue healing and positive culture eradication. As a result, the patient's leg did not have to be amputated and he is undergoing rehabilitation.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacteriophages/physiology , Wound Infection/drug therapy , Wound Infection/therapy , Acinetobacter Infections/drug therapy , Acinetobacter Infections/therapy , Acinetobacter baumannii/drug effects , Acinetobacter baumannii/pathogenicity , Adult , Drug Resistance, Multiple, Bacterial/drug effects , Humans , Klebsiella pneumoniae/pathogenicity , Male
20.
Res Microbiol ; 169(9): 531-539, 2018 Nov.
Article in English | MEDLINE | ID: mdl-29777835

ABSTRACT

Clinical applications of bacteriophage therapy have been recently gathering significant attention worldwide, used mostly as rescue therapy in cases of near-fatal antibiotic failure. Thus, clinically relevant in-vivo models presenting both short- and long-term implications of phage therapy given as rescue treatment for fulminant infections are of highest importance. In this study, a cocktail consisting of two lytic bacteriophages was used to evaluate the therapeutic efficacy of phage therapy as a rescue treatment for severe septic peritonitis in a mouse model. We established that a single injection of the bacteriophage cocktail was sufficient to completely reverse a 100% mortality trend caused by Vancomycin-Resistant Enterococcus faecalis, with significant improvement in both the clinical state and laboratory test results, and without harmful effects on the microbiome. The combination of bacteriophages with a suboptimal antibiotic regimen imparts an additional beneficial effect on the treatment success.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Bacteriophages/physiology , Enterococcus faecalis/drug effects , Gram-Positive Bacterial Infections/therapy , Phage Therapy/methods , Animals , Anti-Bacterial Agents/administration & dosage , Disease Models, Animal , Drug Therapy, Combination/methods , Enterococcus faecalis/growth & development , Female , Gastrointestinal Microbiome/drug effects , Mice , Peritonitis/microbiology , Peritonitis/therapy , Phage Therapy/adverse effects , Stem Cells
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