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

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. 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.

[1]  G. Barrett,et al.  Intracameral antibiotics for prophylaxis of postoperative endophthalmitis in Australia: Response , 2019, Clinical & experimental ophthalmology.

[2]  M. S. Hakim,et al.  Interaction of phages, bacteria, and the human immune system: Evolutionary changes in phage therapy , 2019, Reviews in medical virology.

[3]  G. Barrett,et al.  Intracameral antibiotics for prophylaxis of postoperative endophthalmitis in Australia: a review , 2018, Clinical & experimental ophthalmology.

[4]  A. R. Costa,et al.  Functional Analysis and Antivirulence Properties of a New Depolymerase from a Myovirus That Infects Acinetobacter baumannii Capsule K45 , 2018, Journal of Virology.

[5]  J. Bull,et al.  Antibiotic Therapy Using Phage Depolymerases: Robustness Across a Range of Conditions , 2018, Viruses.

[6]  S. Beyth,et al.  Combined bacteriophages and antibiotics as an efficient therapy against VRE Enterococcus faecalis in a mouse model. , 2018, Research in microbiology.

[7]  George A. Williams,et al.  Vancomycin-Associated Hemorrhagic Occlusive Retinal Vasculitis: A Clinical-Pathophysiological Analysis. , 2018, American journal of ophthalmology.

[8]  Y. Tanji,et al.  Characterization of the Lytic Capability of a LysK-Like Endolysin, Lys-phiSA012, Derived from a Polyvalent Staphylococcus aureus Bacteriophage , 2018, Pharmaceuticals.

[9]  A. Palestine,et al.  Trends in treatment strategies for suspected bacterial endophthalmitis , 2018, Graefe's Archive for Clinical and Experimental Ophthalmology.

[10]  Forest Rohwer,et al.  Development and Use of Personalized Bacteriophage-Based Therapeutic Cocktails To Treat a Patient with a Disseminated Resistant Acinetobacter baumannii Infection , 2017, Antimicrobial Agents and Chemotherapy.

[11]  H. Tomita,et al.  Postoperative Enterococcus faecalis endophthalmitis: virulence factors leading to poor visual outcome , 2017, Japanese Journal of Ophthalmology.

[12]  C. Wykoff,et al.  Vancomycin-Associated Hemorrhagic Occlusive Retinal Vasculitis: Clinical Characteristics of 36 Eyes. , 2017, Ophthalmology.

[13]  M. Hartnett,et al.  Successful management of post-traumatic vancomycin-resistant enterococcus endophthalmitis , 2017, American journal of ophthalmology case reports.

[14]  T. Nakazawa,et al.  Measurement of Electroretinograms and Visually Evoked Potentials in Awake Moving Mice , 2016, PloS one.

[15]  H. Yener,et al.  Daptomycin versus Vancomycin in an Enterococcus faecalis Endophthalmitis Rabbit Model , 2016, Current eye research.

[16]  A. Fadlallah,et al.  Corneal Infection Therapy with Topical Bacteriophage Administration , 2015, The open ophthalmology journal.

[17]  L. Sobrin,et al.  Postoperative Hemorrhagic Occlusive Retinal Vasculitis: Expanding the Clinical Spectrum and Possible Association with Vancomycin. , 2015, Ophthalmology.

[18]  H. Flynn,et al.  Endophthalmitis caused by Enterococcus faecalis: clinical features, antibiotic sensitivities, and outcomes. , 2014, American journal of ophthalmology.

[19]  S. Reardon.  Phage therapy gets revitalized , 2014, Nature.

[20]  P. Singh,et al.  Intravitreal Injection of the Chimeric Phage Endolysin Ply187 Protects Mice from Staphylococcus aureus Endophthalmitis , 2014, Antimicrobial Agents and Chemotherapy.

[21]  M. Osanai,et al.  Experimental phage therapy against lethal lung-derived septicemia caused by Staphylococcus aureus in mice. , 2014, Microbes and infection.

[22]  Jumpei Uchiyama,et al.  Perspective: The age of the phage , 2014, Nature.

[23]  C. Sotozono,et al.  [Postcataract endophthalmitis caused by Enterococcus faecalis]. , 2014, Nippon Ganka Gakkai zasshi.

[24]  T. Bae,et al.  Emergence of Enterococcus species in the infectious microorganisms cultured from patients with endophthalmitis in South Korea , 2014, Infection.

[25]  H. Flynn,et al.  Vancomycin-resistant Gram-positive bacterial endophthalmitis: epidemiology, treatment options, and outcomes , 2013, Journal of Ophthalmic Inflammation and Infection.

[26]  M. Ostrowski,et al.  Post-traumatic vancomycin-resistant enterococcal endophthalmitis , 2013, Journal of Ophthalmic Inflammation and Infection.

[27]  U. Stenevi,et al.  Six‐year incidence of endophthalmitis after cataract surgery: Swedish national study , 2013, Journal of cataract and refractive surgery.

[28]  V. Aleksić,et al.  Phage-antibiotic synergism: a possible approach to combatting Pseudomonas aeruginosa. , 2013, Research in microbiology.

[29]  K. Fukuda,et al.  Pseudomonas aeruginosa Keratitis in Mice: Effects of Topical Bacteriophage KPP12 Administration , 2012, PloS one.

[30]  A. Navas,et al.  Delayed-Onset Post-Keratoplasty Endophthalmitis Caused by Vancomycin-Resistant Enterococcus faecium , 2012, Case Reports in Ophthalmology.

[31]  Jumpei Uchiyama,et al.  Improved Adsorption of an Enterococcus faecalis Bacteriophage ΦEF24C with a Spontaneous Point Mutation , 2011, PloS one.

[32]  M. Gilmore,et al.  Role of wall teichoic acids in Staphylococcus aureus endophthalmitis. , 2011, Investigative ophthalmology & visual science.

[33]  R. U. Desai,et al.  Vancomycin-resistant enterococcal endophthalmitis. , 2010, Archives of ophthalmology.

[34]  内山 淳平.  In silico and in vivo evaluation of bacteriophage φEF24C, a candidate for treatment of Enterococcus faecalis infections , 2009 .

[35]  B. Cairns,et al.  Bacteriophage Therapy and the Mutant Selection Window , 2008, Antimicrobial Agents and Chemotherapy.

[36]  Jumpei Uchiyama,et al.  In Silico and In Vivo Evaluation of Bacteriophage φEF24C, a Candidate for Treatment of Enterococcus faecalis Infections , 2008, Applied and Environmental Microbiology.

[37]  E. Wawrousek,et al.  αB-Crystallin Protects Retinal Tissue during Staphylococcus aureus- Induced Endophthalmitis , 2008, Infection and Immunity.

[38]  Jumpei Uchiyama,et al.  Isolation and characterization of a novel Enterococcus faecalis bacteriophage φEF24C as a therapeutic candidate , 2008 .

[39]  Jumpei Uchiyama,et al.  Isolation and characterization of a novel Enterococcus faecalis bacteriophage phiEF24C as a therapeutic candidate. , 2008, FEMS microbiology letters.

[40]  G. Noskin,et al.  Postoperative vancomycin-resistant Enterococcus faecium endophthalmitis. , 2007, Archives of ophthalmology.

[41]  Cheng-Kuo Cheng,et al.  Community-acquired bleb-related endophthalmitis caused by vancomycin-resistant enterococci. , 2007, Canadian journal of ophthalmology. Journal canadien d'ophtalmologie.

[42]  H. Brüssow,et al.  Phage therapy: the Escherichia coli experience. , 2005, Microbiology.

[43]  H. Flynn,et al.  Endophthalmitis caused by enterococcus faecalis: antibiotic selection and treatment outcomes. , 2003, Ophthalmology.

[44]  B. Esmaeli,et al.  Endogenous endophthalmitis secondary to vancomycin-resistant enterococci infection. , 2003, Retina.

[45]  R. Stone.  Stalin's Forgotten Cure , 2002, Science.

[46]  F. Schade,et al.  Effects of antimicrobial agents on spontaneous and endotoxin-induced cytokine release of human peripheral blood mononuclear cells , 2002, Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy.

[47]  D. Roth,et al.  Antibiotic selection in the treatment of endophthalmitis: the significance of drug combinations and synergy. , 1997, Survey of ophthalmology.

[48]  M. Zembala,et al.  Vancomycin down-regulates lipopolysaccharide-induced tumour necrosis factor alpha (TNFα) production and TNFa-mRNA accumulation in human blood monocytes , 1997 .

[49]  M. Zembala,et al.  Vancomycin down-regulates lipopolysaccharide-induced tumour necrosis factor alpha (TNF alpha) production and TNF alpha-mRNA accumulation in human blood monocytes. , 1997, Immunopharmacology.

[50]  M. Durand.  Microbiologic factors and visual outcome in the endophthalmitis vitrectomy study. , 1997, American journal of ophthalmology.

[51]  Jennifer I. Lim,et al.  Microbiologic factors and visual outcome in the endophthalmitis vitrectomy study , 1996 .

[52]  The Age of Phage , 2022 .