scholarly journals Therapeutic Effects of Intravitreously Administered Bacteriophage in a Mouse Model of Endophthalmitis Caused by Vancomycin-Sensitive or -Resistant Enterococcus faecalis

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Tatsuma Kishimoto ◽  
Waka Ishida ◽  
Ken Fukuda ◽  
Isana Nakajima ◽  
Takashi Suzuki ◽  
...  
Keyword(s):  
Mouse Model ◽  
Enterococcus Faecalis ◽  
Structural Integrity ◽  
Vision Loss ◽  
Therapeutic Potential ◽  
Therapeutic Effects ◽  
Myeloperoxidase Activity ◽  
Content Type ◽  
Viable Bacteria ◽  
Vancomycin Resistant

ABSTRACT Endophthalmitis due to infection with Enterococcus spp. progresses rapidly and often results in substantial and irreversible vision loss. Given that the frequency of this condition caused by vancomycin-resistant Enterococcus faecalis has been increasing, the development of novel therapeutics is urgently required. We have demonstrated the therapeutic potential of bacteriophage ΦEF24C-P2 in a mouse model of endophthalmitis caused by vancomycin-sensitive (EF24) or vancomycin-resistant (VRE2) strains of E. faecalis. Phage ΦEF24C-P2 induced rapid and pronounced bacterial lysis in turbidity reduction assays with EF24, VRE2, and clinical isolates derived from patients with E. faecalis-related postoperative endophthalmitis. Endophthalmitis was induced in mice by injection of EF24 or VRE2 (1 × 104 cells) into the vitreous. The number of viable bacteria in the eye increased to >1 × 107 CFU, and neutrophil infiltration into the eye was detected as an increase in myeloperoxidase activity at 24 h after infection. A clinical score based on loss of visibility of the fundus as well as the number of viable bacteria and the level of myeloperoxidase activity in the eye were all significantly decreased by intravitreous injection of ΦEF24C-P2 6 h after injection of EF24 or VRE2. Whereas histopathologic analysis revealed massive infiltration of inflammatory cells and retinal detachment in vehicle-treated eyes, the number of these cells was greatly reduced and retinal structural integrity was preserved in phage-treated eyes. Our results thus suggest that intravitreous phage therapy is a potential treatment for endophthalmitis caused by vancomycin-sensitive or -resistant strains of E. faecalis.

scholarly journals In Vitro and In Vivo Evaluation of Three Newly Isolated Bacteriophage Candidates, phiEF7H, phiEF14H1, phiEF19G, for Treatment of Enterococcus faecalis Endophthalmitis

2021 ◽  
Vol 9 (2) ◽  
pp. 212
Author(s):  
Tatsuma Kishimoto ◽  
Waka Ishida ◽  
Tadahiro Nasukawa ◽  
Takako Ujihara ◽  
Isana Nakajima ◽  
...  
Keyword(s):  
Vision Loss ◽  
Therapeutic Potential ◽  
Vitreous Body ◽  
Bacteriophage Therapy ◽  
In Vivo Evaluation ◽  
Intravitreous Injection ◽  
Viable Bacteria ◽  
Vancomycin Resistant

Post-operative endophthalmitis caused by Enterococcus spp. progresses rapidly and often results in substantial and irreversible vision loss. Therefore, novel alternative treatments that are effective against enterococcal endophthalmitis are required. Bacteriophage therapy has the potential to be an optional therapy for infectious diseases. Therefore, we investigated the therapeutic potential of three newly isolated enterococcal phages, phiEF7H, phiEF14H1, and phiEF19G, in E. faecalis-induced endophthalmitis. These phages could lyse the broad-range E. faecalis, including strains derived from endophthalmitis and vancomycin-resistant E. faecalis in vitro, as determined by the streak test. Morphological and genomic analyses revealed that these phages were classified into the Herelleviridae genus Kochikohdavirus. The whole genomes of these phages contained 143,399, 143,280, and 143,400 bp, respectively. Endophthalmitis was induced in mice by injection of three strains of E. faecalis derived from post-operative endophthalmitis or vancomycin-resistant strains into the vitreous body. The number of viable bacteria and infiltration of neutrophils in the eye were both decreased by intravitreous injection of phiEF7H, phiEF14H1, and phiEF19G 6 h after injection of all E. faecalis strains. Thus, these results suggest that these newly isolated phages may serve as promising candidates for phage therapy against endophthalmitis.

scholarly journals Disarming Pore-Forming Toxins with Biomimetic Nanosponges in Intraocular Infections

mSphere ◽  
2019 ◽  
Vol 4 (3) ◽  
Author(s):  
Phillip S. Coburn ◽  
Frederick C. Miller ◽  
Austin L. LaGrow ◽  
Craig Land ◽  
Huzzatul Mursalin ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Streptococcus Pneumoniae ◽  
Bacillus Cereus ◽  
Enterococcus Faecalis ◽  
Vision Loss ◽  
Retinal Function ◽  
Bacterial Invasion ◽  
Methicillin Resistant ◽  
Content Type ◽  
Ocular Pathology

ABSTRACTIntraocular infections are prevalent after traumatic injuries or after common ocular surgeries. Infections cause inflammation that can damage the retina and architecture of the eye, often resulting in poor visual outcomes. Severe cases may result in blindness or require enucleation of the eye. Treatments for intraocular infections include intravitreal antibiotics and corticosteroids or surgical vitrectomy in serious cases. The increase in multidrug-resistant infections calls for novel treatment options. In the present study, a biomimetic erythrocyte-derived nanosponge was tested for the ability to neutralize pore-forming toxins from the most frequent Gram-positive bacterial causes of intraocular infections (Staphylococcus aureus,Enterococcus faecalis,Streptococcus pneumoniae, andBacillus cereus). Nanosponge pretreatment of supernatants reduced hemolytic activityin vitro.In a murine sterile endophthalmitis model, nanosponge pretreatment of injected supernatants resulted in greater retinal function and less ocular pathology compared to that in eyes injected with untreated supernatants from all pathogens except methicillin-resistantS. aureus. In a murine bacterial endophthalmitis model, treatment with gatifloxacin and gatifloxacin-nanosponges reduced intraocular bacterial burdens, except in the case of methicillin-sensitiveS. aureus. For all pathogens, eyes in both treatment groups showed decreased ocular pathology and inflammation. Overall, reductions in retinal function loss afforded by gatifloxacin-nanosponge treatment were significant forE. faecalis,S. pneumoniae, and methicillin-resistantS. aureusbut not forB. cereusand methicillin-sensitiveS. aureus. These results suggest that clinical improvements in intraocular infections following nanosponge treatment were dependent on the complexity and types of toxins produced. Nanosponges might serve as an adjunctive therapy for the treatment of ocular infections.IMPORTANCEEndophthalmitis is a blinding consequence of bacterial invasion of the interior of the eye. Because of increases in the numbers of ocular surgeries and intraocular injections, the incidence of endophthalmitis is steadily increasing.Staphylococcus aureus,Enterococcus faecalis,Streptococcus pneumoniae, andBacillus cereusare leading causes of infection following ocular procedures and trauma and are increasingly more difficult to treat due to multidrug resistance. Each of these pathogens produces pore-forming toxins that contribute to the pathogenesis of endophthalmitis. Treatment of these infections with antibiotics alone is insufficient to prevent damage to the retina and vision loss. Therefore, novel therapeutics are needed that include agents that neutralize bacterial pore-forming toxins. Here, we demonstrate that biomimetic nanosponges neutralize pore-forming toxins from these ocular pathogens and aid in preserving retinal function. Nanosponges may represent a new form of adjunct antitoxin therapy for serious potentially blinding intraocular infections.

scholarly journals Ampicillin in Combination with Ceftaroline, Cefepime, or Ceftriaxone Demonstrates Equivalent Activities in a High-Inoculum Enterococcus faecalis Infection Model

2016 ◽  
Vol 60 (5) ◽  
pp. 3178-3182 ◽  
Author(s):  
Megan K. Luther ◽  
Louis B. Rice ◽  
Kerry L. LaPlante
Keyword(s):  
Combination Therapy ◽  
Enterococcus Faecalis ◽  
Pharmacodynamic Model ◽  
Infection Model ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Time Profiles ◽  
Concentration Time ◽  
Vancomycin Resistant

ABSTRACTAmpicillin-ceftriaxone combination therapy has become a predominant treatment for seriousEnterococcus faecalisinfections, such as endocarditis. Unfortunately, ceftriaxone use is associated with future vancomycin-resistant enterococcus colonization. We evaluatedE. faecalisin anin vitropharmacodynamic model against simulated human concentration-time profiles of ampicillin plus ceftaroline, cefepime, ceftriaxone, or gentamicin. Ampicillin-cefepime and ampicillin-ceftaroline demonstrated activities similar to those of ampicillin-ceftriaxone againstE. faecalis.

scholarly journals Development of an imaging toolbox to assess the therapeutic potential and biodistribution of macrophages in a mouse model of multiple organ dysfunction

2018 ◽  
Author(s):  
Jack Sharkey ◽  
Lorenzo Ressel ◽  
Nathalie Brillant ◽  
Bettina Wilm ◽  
B. Kevin Park ◽  
...  
Keyword(s):  
Liver Function ◽  
Mouse Model ◽  
Organ Dysfunction ◽  
Therapeutic Potential ◽  
Cardiac Injury ◽  
Multiple Organ ◽  
Therapeutic Effects ◽  
M2 Macrophages ◽  
Optoacoustic Tomography ◽  
Kidney Liver

AbstractCell-based regenerative medicine therapies require robust preclinical safety, efficacy, biodistribution and engraftment data prior to clinical testing. To address these challenges, we have developed an imaging toolbox comprising multi-spectral optoacoustic tomography and ultrasonography, which allows the degree of kidney, liver and cardiac injury and the extent of functional recovery to be assessed non-invasively in a mouse model of multi-organ dysfunction. This toolbox allowed us to determine the therapeutic effects of adoptively transferred M2 macrophages. Using bioluminescence imaging, we could then investigate the association between amelioration and biodistribution. Macrophage therapy improved kidney and liver function to a limited extent, but did not ameliorate histological damage. No improvement in cardiac function was observed. Biodistribution analysis showed that macrophages homed and persisted in the injured kidneys and liver, but did not populate the heart. Our data suggest that the limited improvement observed in kidney and liver function could be mediated by M2 macrophages.

scholarly journals β-Lactams Enhance Daptomycin Activity against Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium inIn VitroPharmacokinetic/Pharmacodynamic Models

2015 ◽  
Vol 59 (5) ◽  
pp. 2842-2848 ◽  
Author(s):  
Jordan R. Smith ◽  
Katie E. Barber ◽  
Animesh Raut ◽  
Michael J. Rybak
Keyword(s):  
Body Weight ◽  
Combination Therapy ◽  
Enterococcus Faecalis ◽  
Enterococcus Faecium ◽  
Single Agent ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
Vancomycin Resistant ◽  
Combination Regimens

ABSTRACTEnterococcus faecalisandEnterococcus faeciumare frequently resistant to vancomycin and β-lactams. In enterococcal infections with reduced glycopeptide susceptibility, combination therapy is often administered. Our objective was to conduct pharmacokinetic/pharmacodynamic (PK/PD) models to evaluate β-lactam synergy with daptomycin (DAP) against resistant enterococci. OneE. faecalisstrain (R6981) and twoE. faeciumstrains (R6370 and 8019) were evaluated. DAP MICs were obtained. All strains were evaluated for response to LL37, an antimicrobial peptide, in the presence and absence of ceftaroline (CPT), ertapenem (ERT), and ampicillin (AMP). After 96 h,in vitromodels were run simulating 10 mg DAP/kg body weight/day, 600 mg CPT every 8 h (q8h), 2 g AMP q4h, and 1 g ERT q24h, both alone and in combination against all strains. DAP MICs were 2, 4, and 4 μg/ml for strains R6981, R6370, and 8019, respectively. PK/PD models demonstrated bactericidal activity with DAP-CPT, DAP-AMP, and DAP-ERT combinations against strain 8019 (P< 0.001 and log10CFU/ml reduction of >2 compared to any single agent). Against strains R6981 and R6370, the DAP-AMP combination demonstrated enhancement against R6370 but not R6981, while the combinations of DAP-CPT and DAP-ERT were bactericidal, demonstrated enhancement, and were statistically superior to all other regimens at 96 h (P< 0.001) against both strains. CPT, ERT, and AMP similarly augmented LL37 killing against strain 8019. In strains R6981 and R6370, CPT and ERT aided LL37 more than AMP (P< 0.001). Compared to DAP alone, combination regimens provide better killing and prevent resistance. Clinical research involving DAP combinations is warranted.

scholarly journals Intravitreal Injection of the Chimeric Phage Endolysin Ply187 Protects Mice from Staphylococcus aureus Endophthalmitis

2014 ◽  
Vol 58 (8) ◽  
pp. 4621-4629 ◽  
Author(s):  
Pawan Kumar Singh ◽  
David M. Donovan ◽  
Ashok Kumar
Keyword(s):  
Staphylococcus Aureus ◽  
Intravitreal Injection ◽  
Structural Integrity ◽  
Therapeutic Potential ◽  
Neutrophil Infiltration ◽  
Multidrug Resistant ◽  
Lytic Enzyme ◽  
Resistant Bacteria ◽  
Content Type ◽  
Mrsa Strains

ABSTRACTThe treatment of endophthalmitis is becoming very challenging due to the emergence of multidrug-resistant bacteria. Hence, the development of novel therapeutic alternatives for ocular use is essential. Here, we evaluated the therapeutic potential of Ply187AN-KSH3b, a chimeric phage endolysin derived from the Ply187 prophage, in a mouse model ofStaphylococcus aureusendophthalmitis. Our data showed that the chimeric Ply187 endolysin exhibited strong antimicrobial activity against both methicillin-sensitiveS. aureusand methicillin-resistantS. aureus(MRSA) strains, as evidenced by MIC determinations, reductions in turbidity, and disruption of biofilms. Moreover, exposure ofS. aureusto Ply187 for up to 10 generations did not lead to resistance development. The intravitreal injection of chimeric Ply187 (at 6 or 12 h postinfection) significantly improved the outcome of endophthalmitis, preserved retinal structural integrity, and maintained visual function as assessed by electroretinogram analysis. Furthermore, phage lysin treatment significantly reduced the bacterial burden and the levels of inflammatory cytokines and neutrophil infiltration in the eyes. These results indicate that the intravitreal administration of a phage lytic enzyme attenuates the development of bacterial endophthalmitis in mice. To the best of our knowledge, this is the first study demonstrating the therapeutic use of phage-based antimicrobials in ocular infections.

scholarly journals Comparison of the Clinical Characteristics and Outcomes Associated with Vancomycin-Resistant Enterococcus faecalis and Vancomycin-Resistant E. faecium Bacteremia

2012 ◽  
Vol 56 (5) ◽  
pp. 2452-2458 ◽  
Author(s):  
Kayoko Hayakawa ◽  
Dror Marchaim ◽  
Emily T. Martin ◽  
Namita Tiwari ◽  
Adnan Yousuf ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Lower Risk ◽  
Clinical Characteristics ◽  
Medical Center ◽  
Blood Cultures ◽  
Study Cohort ◽  
Vancomycin Resistant Enterococcus ◽  
Content Type ◽  
The Mean ◽  
Vancomycin Resistant

ABSTRACTIn published studies, cohorts of patients with bacteremia due to vancomycin-resistantEnterococcus(VRE) have predominantly been infected withEnterococcus faecium. Little is known about the epidemiology and outcomes associated with bacteremia due to VREnterococcus faecalis. A retrospective study of isolates obtained from January 2008 to October 2010 was conducted at Detroit Medical Center (DMC). Unique patients with blood cultures positive for VRE were reviewed. Outcomes were analyzed using logistic regression. During the study period, 105 cases of bacteremia due to VRE. faecalisand 197 cases of bacteremia due to VRE. faeciumwere identified. The mean age in the study cohort was 61.5 ± 15 years; 162 subjects (53.6%) were male. After controlling for a propensity score, bacteremia due to VRE. faecaliswas associated with >2-fold-lower in-hospital mortality than bacteremia due to VRE. faecium. Interestingly, bacteremia due to VRE. faecaliswas associated with longer hospital stay after VRE isolation, although total length of stay was similar for groups with VRE. faecalisand VRE. faecium. Bacteremia due to VRE. faecaliswas associated with a >2-fold-lower risk for mortality than bacteremia due to VRE. faecium, possibly due to the availability of β-lactam therapeutics for treatment of VRE. faecalis.

scholarly journals Perampanel Reduces Hyperthermia-Induced Seizures in Dravet Syndrome Mouse Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Shih-Yin Ho ◽  
Li Lin ◽  
I-Chun Chen ◽  
Che-Wen Tsai ◽  
Fang-Chia Chang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Therapeutic Potential ◽  
Treatment Options ◽  
Model Potential ◽  
Temperature Tolerance ◽  
Epileptic Activity ◽  
Dravet Syndrome ◽  
Therapeutic Effects ◽  
Discharge Duration ◽  
Spontaneous Recurrent Seizures

Treatment options for Dravet syndrome are limited. The aim of this study was to evaluate the antiepileptic effect of the AMPA receptor antagonist perampanel (PER) on a mouse model of Dravet syndrome (Scn1aE1099X/+). We report here that the PER (2 mg/kg) treatment inhibited the spontaneous recurrent seizures and attenuated epileptic activity in Scn1aE1099X/+ mice. In the hyperthermia-induced seizure experiment, PER clearly increased temperature tolerance and significantly ameliorated seizure frequency and discharge duration. PER also demonstrated antiepileptic effects in a cross-over study and a synergistic effect for attenuating heat-induced seizure when given in combination with stiripentol or valproic acid. The results showed that PER effectively decreased the occurrence of spontaneous recurrent seizures and showed significant therapeutic potential for hyperthermia-induced seizures with regard to both susceptibility and severity in a Dravet syndrome mouse model. Potential therapeutic effects of PER for treatment of Dravet syndrome were demonstrated.

scholarly journals Metformin modulates microbiota-derived inosine and ameliorates methamphetamine-induced anxiety and depression-like withdrawal symptoms in mice

2021 ◽  
Author(s):  
Jiqing Yang ◽  
Zunyue Zhang ◽  
Zhenrong Xie ◽  
Ling Bai ◽  
Pu Xiong ◽  
...  
Keyword(s):  
Mouse Model ◽  
Gut Microbiota ◽  
Relative Abundance ◽  
Therapeutic Potential ◽  
Withdrawal Symptoms ◽  
Anxiety And Depression ◽  
Therapeutic Effects ◽  
List Type ◽  
Psychiatric Manifestations ◽  
Behavioural Deficits

ABSTRACTObjectiveMetformin exhibits therapeutic potential in behavioural deficits induced by methamphetamine (METH) in rats. Emerging studies suggest gut microbiota may impact psychiatric symptoms, but there is no direct evidence supporting metformin’s participation in the pathophysiology of withdrawal symptoms via modulation of gut microbiota.MehodsIn order to define the functional contributions by gut microbiota and metformin to the behavioural deficits during METH withdrawal, we utilized a combination of fecal microbiota transplantation (FMT), high-throughput sequencing, and untargeted metabolomics technologies.ResultsFirst, METH addicts exhibited higher α diversity and distinct microbial structures compared to heathy controls. In particular, the relative abundance of Rikenellaceae was positively correlated with the severity of anxiety and depression. Second, both human-to-mouse and mouse-to-mouse FMTs confirmed that METH-altered-microbiota transplantation is sufficient to promote anxiety and depression-like behaviours in recipient germ-free mice, and these behavioural disturbances could be ameliorated by metformin. In-depth analysis revealed that METH significantly altered the bacterial composition and structure as well as relative abundance of several bacterial taxa and metabolites, including Rikenellaceae and inosine, respectively, whereas add-on metformin could remodel these alterations. Finally, the inosine complementation successfully restored METH-induced anxiety and depression-like behaviours in mice.DiscussionThis study demonstrates that METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model. The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota-derived metabolites, highlighting the role of the gut microbiota in substance use disorders and the pathophysiology of withdrawal symptoms.Study HighlightsWhat is known?There are no targeted therapies for substance withdrawal syndrome, but there is considerable evidence that withdrawal-associated psychiatric manifestations contribute to the poor adherence to rehabilitation treatment as well as the relapse rates.Metformin has shown its therapeutic potential against METH-induced neurobehavioural changes and neurodegeneration in rats through CREB/BDNF and Akt/GSK3 signaling pathways in the anxiety-related brain nuclei.What is new here?METH withdrawal-induced anxiety and depression-like behaviours are convertible and transmissible via gut microbiota in a mouse model.The therapeutic effects of metformin on psychiatric manifestations are associated with microbiota derived metabolites.Inosine complementation could restore METH withdrawal-induced anxiety and depression-like behaviours.

scholarly journals Epidemiology of Vancomycin-Resistant Enterococcus faecalis: a Case-Case-Control Study

2012 ◽  
Vol 57 (1) ◽  
pp. 49-55 ◽  
Author(s):  
Kayoko Hayakawa ◽  
Dror Marchaim ◽  
Mohan Palla ◽  
Uma Mahesh Gudur ◽  
Harish Pulluru ◽  
...  
Keyword(s):  
Enterococcus Faecalis ◽  
Case Control Study ◽  
Medical Center ◽  
Case Control ◽  
Study Cohort ◽  
Retrospective Case ◽  
Content Type ◽  
Skin Ulcers ◽  
Vancomycin Resistant ◽  
Control Study

ABSTRACTAlthough much is known about vancomycin-resistant (VR)Enterococcus faecium, little is known about the epidemiology of VREnterococcus faecalis. The predilection of VRE. faecalisto transfer the vancomycin resistance determinant toStaphylococcus aureusis much greater than that of VRE. faecium. The epidemiology of VRE. faecalishas important implications regarding the emergence of vancomycin-resistantS. aureus(VRSA); 8 of 13 reported VRSA cases have been from Michigan. A retrospective case-case-control study was conducted at the Detroit Medical Center, located in southeastern Michigan. Unique patients with VRE. faecalisinfection were matched to patients with strains of vancomycin-susceptible (VS)E. faecalisand to uninfected controls at a 1:1:1 ratio. Five hundred thirty-two VRE. faecaliscases were identified and were matched to 532 VSE. faecaliscases and 532 uninfected controls. The overall mean age of the study cohort (n= 1,596) was 63.0 ± 17.4 years, and 747 (46.8%) individuals were male. Independent predictors for the isolation of VRE. faecalis(but not VSE. faecalis) compared to uninfected controls were an age of ≥65 years, nonhome residence, diabetes mellitus, peripheral vascular disease, exposure to cephalosporins and fluoroquinolones in the prior 3 months, and immunosuppressive status. Invasive procedures and/or surgery, chronic skin ulcers, and indwelling devices were risk factors for both VRE. faecalisand VSE. faecalisisolation. Cephalosporin and fluoroquinolone exposures were unique, independent predictors for isolation of VRE. faecalis. A majority of case patients had VRE. faecalispresent at the time of admission. Control of VRE. faecalis, and ultimately VRSA, will likely require regional efforts focusing on infection prevention and antimicrobial stewardship.

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