scholarly journals Therapeutic Efficacy of Bacteriophage Therapy to Treat Carbapenem Resistant Klebsiella Pneumoniae in Mouse Model

2021 ◽  
Vol 19 (1) ◽  
pp. 76-82
Author(s):  
Gunaraj Dhungana ◽  
Madhav Regmi ◽  
Prashant Paudel ◽  
Apsara Parajuli ◽  
Elisha Upadhyay ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Mouse Model ◽  
Therapeutic Efficacy ◽  
Phage Therapy ◽  
Bacterial Load ◽  
Health Concern ◽  
Klebsiella Pneumonia ◽  
Lytic Bacteriophage ◽  
Bacteriophage Therapy ◽  
Carbapenem Resistant

Background: Global emergence of carbapenem-resistant Klebsiella pneumoniae is a major public health concern. Phage therapy – application of lytic phage to kill pathogenic bacteria – is considered as one of the promising alternatives to tackle this antibiotic crisis in recent days. This study aimed to isolate, characterize and evaluate therapeutic efficacy of a novel K. pneumoniae phage in mouse model.Methods: A novel lytic bacteriophage (phage) Kp_Pokalde_002 was isolated against carbapenem-resistant K. pneumoniae (Kp56) and characterized. Safety parameters of the phage were evaluated by bioinformatic analysis of its genome. A lethal dose (~1×107 CFU/mouse) of Kp56 was determined and administrated in the mice. The infected mice were treated with phage Kp_Pokalde_002 at a multiplicity of infection (MOI) 1.0 (~1×107 PFU/mouse) via both oral and intraperitoneal (IP) routes.Results: Isolated phage comprised an icosahedral capsid with a short tail. Based on genome analysis, the phage was strictly lytic belonging the Podoviridae family (T7-like viruses) and free from any virulent and antibiotic-resistant genes. The phage was stable up to 60 °C for 30 minutes and effective between pH 4 to 11 (optimum pH 9). The phage exhibited a short latent period (20 minutes) with burst size of 121 phage particles per infected cell. The infected mice were rescued with the phage therapy via both oral and IP route. Significant reduction of bacterial load (3-7 log10 CFU/ml) in the blood and lung was observed in the treatment group.Conclusions: We provide an evidence of successful phage therapy against carbapenem-resistant K. pneumoniae infected mouse model using locally isolated lytic phage.Keywords: Bacteriophage; klebsiella pneumonia; phage therapy

scholarly journals Advances in Bacteriophage Therapy against Relevant MultiDrug-Resistant Pathogens

Antibiotics ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 672
Author(s):  
Antonio Broncano-Lavado ◽  
Guillermo Santamaría-Corral ◽  
Jaime Esteban ◽  
Meritxell García-Quintanilla
Keyword(s):  
Clinical Trials ◽  
Phage Therapy ◽  
Case Reports ◽  
World Health ◽  
Health Concern ◽  
Bacteriophage Therapy ◽  
Promising Alternative ◽  
Carbapenem Resistant

The increase of multiresistance in bacteria and the shortage of new antibiotics in the market is becoming a major public health concern. The World Health Organization (WHO) has declared critical priority to develop new antimicrobials against three types of bacteria: carbapenem-resistant A. baumannii, carbapenem-resistant P. aeruginosa and carbapenem-resistant and ESBL-producing Enterobacteriaceae. Phage therapy is a promising alternative therapy with renewed research in Western countries. This field includes studies in vitro, in vivo, clinical trials and clinical cases of patients receiving phages as the last resource after failure of standard treatments due to multidrug resistance. Importantly, this alternative treatment has been shown to be more effective when administered in combination with antibiotics, including infections with biofilm formation. This review summarizes the most recent studies of this strategy in animal models, case reports and clinical trials to deal with infections caused by resistant A. baumannii, K. pneumoniae, E. coli, and P. aeruginosa strains, as well as discusses the main limitations of phage therapy.

scholarly journals Epigenomics, genomics, resistome, mobilome, virulome and evolutionary phylogenomics of carbapenem-resistant Klebsiella pneumoniae clinical strains

2020 ◽  
Vol 6 (12) ◽  
Author(s):  
Katlego Kopotsa ◽  
Nontombi M. Mbelle ◽  
John Osei Sekyere
Keyword(s):  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Type I ◽  
Bacteriophage Therapy ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Plasmid Replicon ◽  
Size Number ◽  
Plasmid Size ◽  
Epidemiological Trends

Carbapenem-resistant Klebsiella pneumoniae (CRKP) remains a major clinical pathogen and public health threat with few therapeutic options. The mobilome, resistome, methylome, virulome and phylogeography of CRKP in South Africa and globally were characterized. CRKP collected in 2018 were subjected to antimicrobial susceptibility testing, screening by multiplex PCR, genotyping by repetitive element palindromic (REP)-PCR, plasmid size, number, incompatibility and mobility analyses, and PacBio’s SMRT sequencing (n=6). There were 56 multidrug-resistant CRKP, having bla OXA-48-like and bla NDM-1/7 carbapenemases on self-transmissible IncF, A/C, IncL/M and IncX3 plasmids endowed with prophages, traT, resistance islands, and type I and II restriction modification systems (RMS). Plasmids and clades detected in this study were respectively related to globally established/disseminated plasmids clades/clones, evincing transboundary horizontal and vertical dissemination. Reduced susceptibility to colistin occurred in 23 strains. Common clones included ST307, ST607, ST17, ST39 and ST3559. IncFIIk virulent plasmid replicon was present in 56 strains. Whole-genome sequencing of six strains revealed least 41 virulence genes, extensive ompK36 mutations, and four different K- and O-loci types: KL2, KL25, KL27, KL102, O1, O2, O4 and O5. Types I, II and III RMS, conferring m6A (G A TC, G A TGNNNNNNTTG, CA A NNNNNNCATC motifs) and m4C (C C WGG) modifications on chromosomes and plasmids, were found. The nature of plasmid-mediated, clonal and multi-clonal dissemination of blaOXA-48-like and blaNDM-1 mirrors epidemiological trends observed for closely related plasmids and sequence types internationally. Worryingly, the presence of both bla OXA-48 and bla NDM-1 in the same isolates was observed. Plasmid-mediated transmission of RMS, virulome and prophages influence bacterial evolution, epidemiology, pathogenicity and resistance, threatening infection treatment. The influence of RMS on antimicrobial and bacteriophage therapy needs urgent investigation.

scholarly journals A public health concern: emergence of carbapenem-resistant Klebsiella pneumoniae in a public transportation environment

2020 ◽  
Vol 75 (10) ◽  
pp. 2769-2772
Author(s):  
Tingting Cao ◽  
Yuanyuan Liu ◽  
Yiming Li ◽  
Yang Wang ◽  
Zhangqi Shen ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Public Transportation ◽  
Genetic Relationships ◽  
Brain Heart Infusion ◽  
Health Concern ◽  
Resistant Bacteria ◽  
Carbapenem Resistant ◽  
Broth Microdilution Method ◽  
Carbapenem Resistant Enterobacteriaceae ◽  
Beijing Subway

Abstract Objectives This study was designed to understand the prevalence of antibiotic-resistant bacteria in the Beijing subway environment and the potential transmission of carbapenem-resistant Enterobacteriaceae in a public transportation environment. Methods Carbapenem-resistant isolates were selected on brain heart infusion agar supplemented with meropenem (0.5 mg/L) and antimicrobial susceptibility testing was conducted using the broth microdilution method. WGS analyses were conducted for 11 Klebsiella pneumoniae isolates to identify resistance genes. The genetic relationships among the isolates were evaluated by MLST and PFGE. Results We identified 11 carbapenem-resistant K. pneumoniae isolates from the Beijing subway environment. WGS revealed three STs among the 11 isolates, with 9 isolates classified as ST726 and containing a blaNDM-5-carrying IncX3 plasmid. The genetic environment of blaNDM-5 was very similar to that observed in other blaNDM-5-containing clinical isolates. Conclusions The presence of carbapenem-resistant Enterobacteriaceae in a public transportation environment is concerning and indicates that regular antimicrobial resistance surveillance is urgent and necessary.

scholarly journals In vivo efficacy of combination of colistin with fosfomycin or minocycline in a mouse model of multidrug-resistant Acinetobacter baumannii pneumonia

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Nam Su Ku ◽  
Su-Hyung Lee ◽  
Young- soun Lim ◽  
Heun Choi ◽  
Jin Young Ahn ◽  
...  
Keyword(s):  
Mouse Model ◽  
Acinetobacter Baumannii ◽  
Synergistic Effects ◽  
Bacterial Load ◽  
Multidrug Resistant ◽  
Therapeutic Options ◽  
Severance Hospital ◽  
Carbapenem Resistant ◽  
Combination Regimens

AbstractUnfortunately, the options for treating multidrug-resistant (MDR) Acinetobacter baumannii (A. baumannii) infections are extremely limited. Recently, fosfomycin and minocycline were newly introduced as a treatment option for MDR A. baumannii infection. Therefore, we investigated the efficacy of the combination of colistin with fosfomycin and minocycline, respectively, as therapeutic options in MDR A. baumannii pneumonia. We examined a carbapenem-resistant A. baumannii isolated from clinical specimens at Severance Hospital, Seoul, Korea. The effect of colistin with fosfomycin, and colistin with minocycline on the bacterial counts in lung tissue was investigated in a mouse model of pneumonia caused by MDR A. baumannii. In vivo, colistin with fosfomycin or minocycline significantly (p < 0.05) reduced the bacterial load in the lungs compared with the controls at 24 and 48 h. In the combination groups, the bacterial loads differed significantly (p < 0.05) from that with the more active antimicrobial alone. Moreover, the combination regimens of colistin with fosfomycin and colistin with minocycline showed bactericidal and synergistic effects compared with the more active antimicrobial alone at 24 and 48 h. This study demonstrated the synergistic effects of combination regimens of colistin with fosfomycin and minocycline, respectively, as therapeutic options in pneumonia caused by MDR A. baumannii.

scholarly journals Curcumin alone and in combination with augmentin protects against pulmonaryinflammation and acute lung injury generated during Klebsiella pneumoniae B5055-induced lung infection in BALB/c mice

2010 ◽  
Vol 59 (4) ◽  
pp. 429-437 ◽  
Author(s):  
Shruti Bansal ◽  
Sanjay Chhibber
Keyword(s):  
Klebsiella Pneumoniae ◽  
Mouse Model ◽  
Lung Tissue ◽  
Inflammatory Mediators ◽  
Bacterial Load ◽  
Neutrophil Infiltration ◽  
Lung Infection ◽  
Control Group ◽  
Intranasal Route ◽  
Anti Inflammatory

Acute lung injuries due to acute lung infections remain a major cause ofmortality. Thus a combination of an antibiotic and a compound with immunomodulatoryand anti-inflammatory activities can help to overcome acute lung infection-inducedinjuries. Curcumin derived from the rhizome of turmeric has been used fordecades and it exhibits anti-inflammatory, anti-carcinogenic, immunomodulatoryproperties by downregulation of various inflammatory mediators. Keeping theseproperties in mind, we investigated the anti-inflammatory properties of curcuminin a mouse model of acute inflammation by introducing Klebsiella pneumoniae B5055 into BALB/c mice via the intranasal route. Intranasal instillationof bacteria in this mouse model of acute pneumonia-induced inflammation resultedin a significant increase in neutrophil infiltration in the lungs along withincreased production of various inflammatory mediators [i.e. malondialdehyde (MDA),myeloperoxidase (MPO), nitric oxide (NO), tumour necrosisfactor (TNF)-α] in the lung tissue. The animalsthat received curcumin alone orally or in combination with augmentin, 15 daysprior to bacterial instillation into the lungs via the intranasal route, showeda significant (P <0.05) decrease in neutrophil influxinto the lungs and a significant (P <0.05) decreasein the production of MDA, NO, MPO activity and TNF-α levels.Augmentin treatment alone did not decrease the MDA, MPO, NO and TNF-α levels significantly (P >0.05) as compared tothe control group. We therefore conclude that curcumin ameliorates lung inflammationinduced by K. pneumoniae B5055 without significantly (P <0.05) decreasing the bacterial load in the lung tissue whereasaugmentin takes care of bacterial proliferation. Hence, curcumin can be usedas an adjunct therapy along with antibiotics as an anti-inflammatory or animmunomodulatory agent in the case of acute lung infection.

scholarly journals Piscidin is Highly Active against Carbapenem-Resistant Acinetobacter baumannii and NDM-1-Producing Klebsiella pneumonia in a Systemic Septicaemia Infection Mouse Model

Marine Drugs ◽  
2015 ◽  
Vol 13 (4) ◽  
pp. 2287-2305 ◽  
Author(s):  
Chieh-Yu Pan ◽  
Jian-Chyi Chen ◽  
Te-Li Chen ◽  
Jen-Leih Wu ◽  
Cho-Fat Hui ◽  
...  
Keyword(s):  
Mouse Model ◽  
Acinetobacter Baumannii ◽  
Klebsiella Pneumonia ◽  
Highly Active ◽  
Carbapenem Resistant

scholarly journals Bacteriophage Therapy To Reduce Campylobacter jejuni Colonization of Broiler Chickens

2005 ◽  
Vol 71 (11) ◽  
pp. 6554-6563 ◽  
Author(s):  
C. Loc Carrillo ◽  
R. J. Atterbury ◽  
A. El-Shibiny ◽  
P. L. Connerton ◽  
E. Dillon ◽  
...  
Keyword(s):  
Campylobacter Jejuni ◽  
Broiler Chickens ◽  
Phage Therapy ◽  
Experimental Models ◽  
Human Infection ◽  
Lytic Bacteriophage ◽  
Bacteriophage Therapy ◽  
Bacteriophage Infection ◽  
Low Passage

ABSTRACT Colonization of broiler chickens by the enteric pathogen Campylobacter jejuni is widespread and difficult to prevent. Bacteriophage therapy is one possible means by which this colonization could be controlled, thus limiting the entry of campylobacters into the human food chain. Prior to evaluating the efficacy of phage therapy, experimental models of Campylobacter colonization of broiler chickens were established by using low-passage C. jejuni isolates HPC5 and GIIC8 from United Kingdom broiler flocks. The screening of 53 lytic bacteriophage isolates against a panel of 50 Campylobacter isolates from broiler chickens and 80 strains isolated after human infection identified two phage candidates with broad host lysis. These phages, CP8 and CP34, were orally administered in antacid suspension, at different dosages, to 25-day-old broiler chickens experimentally colonized with the C. jejuni broiler isolates. Phage treatment of C. jejuni-colonized birds resulted in Campylobacter counts falling between 0.5 and 5 log10 CFU/g of cecal contents compared to untreated controls over a 5-day period postadministration. These reductions were dependent on the phage-Campylobacter combination, the dose of phage applied, and the time elapsed after administration. Campylobacters resistant to bacteriophage infection were recovered from phage-treated chickens at a frequency of <4%. These resistant types were compromised in their ability to colonize experimental chickens and rapidly reverted to a phage-sensitive phenotype in vivo. The selection of appropriate phage and their dose optimization are key elements for the success of phage therapy to reduce campylobacters in broiler chickens.

scholarly journals 995. A Murine Model of Klebsiella pneumoniae Gastrointestinal Colonization with Parenteral Vancomycin Administration

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S588-S588
Author(s):  
Bettina Cheung ◽  
Marine Lebrun-Corbin ◽  
Alan R Hauser
Keyword(s):  
Klebsiella Pneumoniae ◽  
Mouse Model ◽  
The United States ◽  
Post Inoculation ◽  
Fecal Shedding ◽  
Carbapenem Resistant ◽  
Human Dose ◽  
Colony Forming Units ◽  
Multiple Strains ◽  
Gastrointestinal Colonization

Abstract Background As a leading cause of nosocomial infections, Klebsiella pneumoniae poses a significant threat due to its propensity to acquire resistance to many classes of antibiotics, including carbapenems. Gastrointestinal (GI) colonization by K. pneumoniae is a risk factor for subsequent infection as well as transmission to other patients. To study this crucial step in pathogenesis, we developed a mouse model of K. pneumoniae GI colonization using a clinically relevant parenteral antibiotic regimen. Methods To improve the clinical relevance of our model, we elected to use intraperitoneal injections of vancomycin, one of the most highly utilized antibiotics in the United States. Results To optimize dosage in C57bl/6 mice, we injected 20mg/kg, 350mg/kg, or vehicle (PBS) for three days prior to gastric gavage with 108 colony forming units (CFU) of a low-resistance strain of K. pneumoniae. The mice who received 350mg/kg (a mouse equivalent of a human dose of 1g/day calculated through the FDA guidelines for estimating safe dosing) shed about 107 CFU/g of feces at Day 7 while those receiving the lower dose or vehicle shed 104 CFU/g. Next, we compared 3- or 5-day pre-treatments with vancomycin prior to inoculation with an ST258 (epidemic carbapenem-resistant) strain. At Day 7 post-inoculation, mice who received 5 days shed 1010 CFU/g feces while those who received vancomycin for 3 days or vehicle for 5 days (PBS) shed 106 or 104 CFU/g feces respectively. Thus, we chose 5 days of 350mg/kg vancomycin injection as our regimen for inducing robust GI colonization in mice. Finally, we tested the durability of colonization by following fecal shedding in mice up to Day 60 post-inoculation with a second ST258 strain. Shedding during the first 7 days occurs at about 1010 CFU/g feces, and from day 14 to day 60 fecal loads are stable around 107 CFU/g feces. Results are comparable between male and female mice. Conclusion In conclusion, we have developed a mouse model of robust, prolonged GI colonization with multiple strains of K. pneumoniae using controlled dosing of a clinically relevant antibiotic. This model may be used to study a key step in K. pneumoniae pathogenesis and infection prevention in the future. Disclosures All Authors: No reported disclosures

scholarly journals Phage therapy for treatment of virulent Klebsiella pneumoniae infection in a mouse model

2020 ◽  
Vol 21 ◽  
pp. 34-41 ◽  
Author(s):  
Taruna Anand ◽  
Nitin Virmani ◽  
Sudarshan Kumar ◽  
Ashok Kumar Mohanty ◽  
S. Pavulraj ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Mouse Model ◽  
Phage Therapy

Adjunctive Immunotherapeutic Efficacy of N-Formylated Internal Peptide of Mycobacterial Glutamine Synthetase in Mouse Model of Tuberculosis

2020 ◽  
Vol 27 (3) ◽  
pp. 236-242
Author(s):  
Shabir Ahmad Mir ◽  
Sadhna Sharma
Keyword(s):  
Reactive Oxygen Species ◽  
Glutamine Synthetase ◽  
Mouse Model ◽  
Therapeutic Efficacy ◽  
Bacterial Load ◽  
Oxygen Species ◽  
Colony Forming Units ◽  
Internal Peptide ◽  
Histopathological Results ◽  
Peptide Treatment

Background: Host-directed therapies are a comparatively new and promising method for the treatment of tuberculosis. A variety of host pathways, vaccines and drugs have the potential to provide novel adjunctive therapies for the treatment of tuberculosis. In this connection, we have earlier reported the immunotherapeutic potential of N-formylated N-terminal peptide of glutamine synthetase of Mycobacterim tuberculosis H37Rv (Mir SA and Sharma S, 2014). Now in the present study, we investigated the immunotherapeutic effect of N-terminally formylated internal-peptide 'f- MLLLPD' of mycobacterial glutamine synthetase (Rv2220) in mouse model of tuberculosis. Methods: The N-terminally formylated peptide, f-MLLLPD was tested for its potential to generate Reactive Oxygen Species (ROS) in murine neutrophils. Further, its therapeutic effect alone or in combination with anti-tubercular drugs was evaluated in mouse model of tuberculosis. Results: The f-MLLLPD peptide treatment alone and in combination with ATDs reduced the bacterial load (indicated as colony forming units) in lungs of infected mice by 0.58 (p<0.01) and 2.92 (p<0.001) log10 units respectively and in their spleens by 0.46 (p<0.05) and 2.46 (p<0.001) log10 units respectively. In addition, the observed histopathological results correlated well with the CFU data. Conclusion : The results of the current study show that f-MLLLPD peptide confers an additional therapeutic efficacy to the anti-tuberculosis drugs.

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