The Association of Intracameral Bacteriophage Administration with Tumor Necrosis Factor Alpha (TNF-α) Expression and Bacterial Viability as a Prophylactic Strategy Against Staphylococcus aureus-Induced Endophthalmitis Following Lens Extraction Surgery : A
Keywords:
bacteriophage therapy,, Staphylococcus aureus, TNF-α, bacterial viability, lens extractionAbstract
Postoperative infections remain a critical concern following lens extraction procedures, often linked to the presence of Staphylococcus aureus. Conventional antibiotic treatments are increasingly challenged by the rise of resistant bacterial strains. This literature review explores the therapeutic potential of Staphylococcus aureus-specific bacteriophages in modulating immune response—particularly the expression of Tumor Necrosis Factor-α (TNF-α)—and reducing bacterial viability in ocular surgical contexts. Drawing from a range of peer-reviewed sources, the review examines the dual role of bacteriophages as antimicrobial agents and as modulators of inflammation. Evidence suggests that phage therapy may suppress Staphylococcus aureus viability while attenuating pro-inflammatory cytokine production, potentially improving clinical outcomes and minimizing reliance on antibiotics. These findings underscore the need for further in vivo studies and clinical trials to validate phage application as a safe and effective adjunct in ophthalmic surgery.
Downloads
References
Nowak, M. S., Grzybowski, A., Michalska-Małecka, K., Szaflik, J. P., Kozioł, M., Niemczyk, W., & Grabska-Liberek, I. (2019). Incidence and characteristics of endophthalmitis after cataract surgery in Poland, during 2010–2015. International Journal of Environmental Research and Public Health, 16(12), 1–10. https://doi.org/10.3390/ijerph16122188
Siahaan, & Christina, N. (2014). Karakteristik klinis pasien endoftalmitis pasca bedah katarak di Pusat Mata Nasional Rumah Sakit Mata Cicendo.
Gentile, R. C., Shukla, S., Shah, M., Ritterband, D. C., Engelbert, M., Davis, A., & Hu, D. N. (2014). Microbiological spectrum and antibiotic sensitivity in endophthalmitis: A 25-year review. Ophthalmology, 121(8), 1634–1642. https://doi.org/10.1016/j.ophtha.2014.02.001
Kishimoto, T., Ishida, W., Nakajima, I., Ujihara, T., Suzuki, T., Uchiyama, J., Matsuzaki, S., & Fukuda, K. (2022). Intracameral bacteriophage injection as postoperative prophylaxis for Enterococcus faecalis–induced endophthalmitis after cataract surgery in rabbits. Translational Vision Science and Technology, 11(4), 1–8. https://doi.org/10.1167/tvst.11.4.2
McChanel, C. A., Berrocal, A. M., Holder, G. E., Kim, S. J., Leonard, B. C., Rosen, R. B., Spaide, R. F., & Sun, J. K. (2022). Retina and Vitreous BCSC 2021–2022 (2021st–2022nd ed.). American Academy of Ophthalmology.
Kishimoto, T., Ishida, W., Fukuda, K., Nakajima, I., Suzuki, T., Uchiyama, J., Matsuzaki, S., Todokoro, D., Daibata, M., & Fukushimaa, A. (2019). Therapeutic effects of intravitreously administered bacteriophage in a mouse model of endophthalmitis caused by vancomycin-sensitive or -resistant Enterococcus faecalis. Antimicrobial Agents and Chemotherapy, 63(11), 1–12. https://doi.org/10.1128/AAC.01088-19
Zhang, S., & Xu, J. (2025). Impact of patient characteristics and surgery-related risk factors on endophthalmitis after cataract surgery: A meta-analysis. Ophthalmic Research, 68(1), 117–136. https://doi.org/10.1159/000543353
Beigi, B., Westlake, W., Mangelschots, E., Chang, B., Rich, W., & Riordan, T. (1997). Peroperative microbial contamination of anterior chamber aspirates during extracapsular cataract extraction and phacoemulsification. British Journal of Ophthalmology, 81(11), 953–955. https://doi.org/10.1136/bjo.81.11.953
Feys, J., Emond, J. P., Salvanet-Bouccara, A., & Dublanchet, A. (2003). Épidémiologie de la contamination bactérienne oculaire en chirurgie de la cataracte [Bacterial contamination: Epidemiology in cataract surgery]. Journal Français d’Ophtalmologie, 26(3), 255–258.
Meisler, D. M., & Mandelbaum, S. (1989). Propionibacterium-associated endophthalmitis after extracapsular cataract extraction: Review of reported cases. Ophthalmology, 96(1), 54–61. https://doi.org/10.1016/s0161-6420(89)32939-3
Kim, Y. C., & Kim, K. S. (2012). A case of postoperative endophthalmitis by extended-spectrum beta-lactamase-producing Escherichia coli. Korean Journal of Ophthalmology, 26(4), 306–308. https://doi.org/10.3341/kjo.2012.26.4.306
Grady, M., & Cullen, J. J. (2003). Preventing postoperative Staphylococcus infections: An update. Surgical Technology International, 11, 57–60.
Dreyfus, J., Yu, H., Begier, E., Gayle, J., & Olsen, M. A. (2021). Incidence of Staphylococcus aureus infections after elective surgeries in US hospitals. Clinical Infectious Diseases, 73(9), e2635–e2646. https://doi.org/10.1093/cid/ciaa913
Troeman, D. P. R., Hazard, D., Timbermont, L., Malhotra-Kumar, S., van Werkhoven, C. H., Wolkewitz, M., Ruzin, A., Goossens, H., Bonten, M. J. M., Harbarth, S., Sifakis, F., Kluytmans, J. A. J. W., … Van den Abeele, A. M. (2023). Postoperative Staphylococcus aureus infections in patients with and without preoperative colonization. JAMA Network Open, 6(10), e2339793. https://doi.org/10.1001/jamanetworkopen.2023.39793
Allen, K. B., Fowler, V. G., Jr., Gammie, J. S., Hartzel, J. S., Onorato, M. T., DiNubile, M. J., & Sobanjo-Ter Meulen, A. (2014). Staphylococcus aureus infections after elective cardiothoracic surgery: Observations from an international randomized placebo-controlled trial of an investigational S. aureus vaccine. Open Forum Infectious Diseases, 1(2), ofu071. https://doi.org/10.1093/ofid/ofu071
O'Brien, W. J., Gupta, K., & Itani, K. M. F. (2019). A longitudinal study of S. aureus infection in a national cohort of surgical patients. Open Forum Infectious Diseases, 6(10), ofz350. https://doi.org/10.1093/ofid/ofz350
Althiabi, S., Aljbreen, A. J., Alshutily, A., & Althwiny, F. A. (2022). Postoperative endophthalmitis after cataract surgery: An update. Cureus, 14(2), e22003. https://doi.org/10.7759/cureus.22003
Wadbudhe, A. M., Tidke, S. C., & Tidake, P. K. (2022). Endophthalmitis after cataract surgery: A postoperative complication. Cureus, 14(10), e30110. https://doi.org/10.7759/cureus.30110
Verma, L., & Chakravarti, A. (2017). Prevention and management of postoperative endophthalmitis: A case-based approach. Indian Journal of Ophthalmology, 65(12), 1396–1402. https://doi.org/10.4103/ijo.IJO_1058_17
Kernt, M., & Kampik, A. (2010). Endophthalmitis: Pathogenesis, clinical presentation, management, and perspectives. Clinical Ophthalmology, 4, 121–135. https://doi.org/10.2147/opth.s6461
Maalouf, F., Abdulaal, M., & Hamam, R. N. (2012). Chronic postoperative endophthalmitis: A review of clinical characteristics, microbiology, treatment strategies, and outcomes. International Journal of Inflammation, 2012, 313248. https://doi.org/10.1155/2012/313248
Doft, B. H., & Barza, M. (1996). Optimal management of postoperative endophthalmitis and results of the Endophthalmitis Vitrectomy Study. Current Opinion in Ophthalmology, 7(3), 84–94. https://doi.org/10.1097/00055735-199606000-00015
Panahi, P., Mirzakouchaki-Borujeni, N., Pourdakan, O., & Arévalo, J. F. (2023). Early vitrectomy for endophthalmitis: Are EVS guidelines still valid? Ophthalmic Research, 66(1), 1318–1326. https://doi.org/10.1159/000534650
Loh, G. K., Mishra, A. V., Seamone, M., & Tennant, M. (2024). Unified approach to treating exogenous endophthalmitis with immediate vitrectomy. Journal of Vitreoretinal Diseases. Advance online publication. https://doi.org/10.1177/24741264241275246
Negretti, G. S., Chan, W., Pavesio, C., & Muqit, M. M. K. (2020). Vitrectomy for endophthalmitis: 5-year study of outcomes and complications. BMJ Open Ophthalmology, 5(1), e000423. https://doi.org/10.1136/bmjophth-2019-000423
Hibstu, Z., Belew, H., Akelew, Y., & Mengist, H. M. (2022). Phage therapy: A different approach to fight bacterial infections. Biologics: Targets & Therapy, 16, 173–186. https://doi.org/10.2147/BTT.S381237
Subramanian, A. (2024). Emerging roles of bacteriophage-based therapeutics in combating antibiotic resistance. Frontiers in Microbiology, 15, 1384164. https://doi.org/10.3389/fmicb.2024.1384164
Olawade, D. B., Fapohunda, O., Egbon, E., Ebiesuwa, O. A., Usman, S. O., Faronbi, A. O., & Fidelis, S. C. (2024). Phage therapy: A targeted approach to overcoming antibiotic resistance. Microbial Pathogenesis, 197, 107088. https://doi.org/10.1016/j.micpath.2024.107088
Bashabsheh, R. H. F., Al-Fawares, O., Natsheh, I., Bdeir, R., Al-Khreshieh, R. O., & Bashabsheh, H. H. F. (2024). Staphylococcus aureus epidemiology, pathophysiology, clinical manifestations and application of nano-therapeutics as a promising approach to combat methicillin resistant Staphylococcus aureus. Pathogens and Global Health, 118(3), 209–231. https://doi.org/10.1080/20477724.2023.2285187
Tong, S. Y., Davis, J. S., Eichenberger, E., Holland, T. L., & Fowler, V. G., Jr. (2015). Staphylococcus aureus infections: Epidemiology, pathophysiology, clinical manifestations, and management. Clinical Microbiology Reviews, 28(3), 603–661. https://doi.org/10.1128/CMR.00134-14
Kwiecinski, J. M., & Horswill, A. R. (2020). Staphylococcus aureus bloodstream infections: Pathogenesis and regulatory mechanisms. Current Opinion in Microbiology, 53, 51–60. https://doi.org/10.1016/j.mib.2020.02.005
Thomer, L., Schneewind, O., & Missiakas, D. (2016). Pathogenesis of Staphylococcus aureus bloodstream infections. Annual Review of Pathology, 11, 343–364. https://doi.org/10.1146/annurev-pathol-012615-044351
Foster, T. (1996). Staphylococcus. In S. Baron (Ed.), Medical Microbiology (4th ed., Chap. 12). University of Texas Medical Branch at Galveston. https://www.ncbi.nlm.nih.gov/books/NBK8448/
Ho, D., Clayton, N. A., Silverstein, B., & Koff, A. (2022). Endogenous endophthalmitis from methicillin-resistant Staphylococcus aureus bacteremia treated with ceftaroline. Cureus, 14(2), e22216. https://doi.org/10.7759/cureus.22216
Shenoy, S. B., Thotakura, M., Kamath, Y., & Bekur, R. (2016). Endogenous endophthalmitis in patients with MRSA septicemia: A case series and review of literature. Ocular Immunology and Inflammation, 24(5), 515–520. https://doi.org/10.3109/09273948.2015.1020173
Flynn, E., Lesche, S., Ittoop, S., Mansour, T., Barak, S., & Wroblewski, K. J. (2023). MRSA panophthalmitis in a brittle diabetic. Journal of Ophthalmic Inflammation and Infection, 13(1), 19. https://doi.org/10.1186/s12348-023-00344-3
Blomquist, P. H. (2006). Methicillin-resistant Staphylococcus aureus infections of the eye and orbit (An American Ophthalmological Society thesis). Transactions of the American Ophthalmological Society, 104, 322–345.
Jang, D. I., Lee, A. H., Shin, H. Y., Song, H. R., Park, J. H., Kang, T. B., Lee, S. R., & Yang, S. H. (2021). The role of tumor necrosis factor alpha (TNF-α) in autoimmune disease and current TNF-α inhibitors in therapeutics. International Journal of Molecular Sciences, 22(5), 2719. https://doi.org/10.3390/ijms22052719
Idriss, H. T., & Naismith, J. H. (2000). TNF alpha and the TNF receptor superfamily: Structure-function relationship(s). Microscopy Research and Technique, 50(3), 184–195. https://doi.org/10.1002/1097-0029(20000801)50:3<184::AID-JEMT2>3.0.CO;2-H
Chu, W. M. (2013). Tumor necrosis factor. Cancer Letters, 328(2), 222–225. https://doi.org/10.1016/j.canlet.2012.10.014
Ghorbaninezhad, F., Leone, P., Alemohammad, H., Najafzadeh, B., Nourbakhsh, N. S., Prete, M., Malerba, E., Saeedi, H., Tabrizi, N. J., Racanelli, V., & Baradaran, B. (2022). Tumor necrosis factor α in systemic lupus erythematosus: Structure, function and therapeutic implications (Review). International Journal of Molecular Medicine, 49(4), 43. https://doi.org/10.3892/ijmm.2022.5098
Karampetsou, M. P., Liossis, S. N., & Sfikakis, P. P. (2010). TNF-α antagonists beyond approved indications: Stories of success and prospects for the future. QJM: Monthly Journal of the Association of Physicians, 103(12), 917–928. https://doi.org/10.1093/qjmed/hcq152
Jung, Y., Ohn, K., Shin, H., Oh, S. E., Park, C. K., & Park, H. L. (2022). Factors associated with elevated tumor necrosis factor-α in aqueous humor of patients with open-angle glaucoma. Journal of Clinical Medicine, 11(17), 5232. https://doi.org/10.3390/jcm11175232
Paschalis, E. I., Zhou, C., Sharma, J., Dohlman, T. H., Kim, S., Lei, F., Chodosh, J., Vavvas, D., Urtti, A., Papaliodis, G., & Dohlman, C. H. (2024). The prophylactic value of TNF-α inhibitors against retinal cell apoptosis and optic nerve axon loss after corneal surgery or trauma. Acta Ophthalmologica, 102(3), e381–e394. https://doi.org/10.1111/aos.15786
Zhou, C., Lei, F., Sharma, J., Hui, P. C., Wolkow, N., Dohlman, C. H., Vavvas, D. G., Chodosh, J., & Paschalis, E. I. (2023). Sustained inhibition of VEGF and TNF-α achieves multi-ocular protection and prevents formation of blood vessels after severe ocular trauma. Pharmaceutics, 15(8), 2059. https://doi.org/10.3390/pharmaceutics15082059
O'Callaghan, R. J. (2018). The pathogenesis of Staphylococcus aureus eye infections. Pathogens, 7(1), 9. https://doi.org/10.3390/pathogens7010009
Singh, S. R., Bhattacharyya, A., Dogra, M. R., Singh, R., & Dogra, M. (2020). Endogenous endophthalmitis due to Staphylococcus aureus in a lactating woman. Indian Journal of Ophthalmology, 68(11), 2595–2597. https://doi.org/10.4103/ijo.IJO_740_20
Ho, D., Clayton, N. A., Silverstein, B., & Koff, A. (2022). Endogenous endophthalmitis from methicillin-resistant Staphylococcus aureus bacteremia treated with ceftaroline. Cureus, 14(2), e22216. https://doi.org/10.7759/cureus.22216
Sugi, N., Whiston, E. A., Ksander, B. R., & Gregory, M. S. (2013). Increased resistance to Staphylococcus aureus endophthalmitis in BALB/c mice: Fas ligand is required for resolution of inflammation but not for bacterial clearance. Infection and Immunity, 81(6), 2217–2225. https://doi.org/10.1128/IAI.00405-12
Parrott, A. C., Coburn, P. S., Miller, F. C., LaGrow, A. L., Mursalin, M. H., & Callegan, M. C. (2024). The role of CCL chemokines in experimental Staphylococcus aureus endophthalmitis. Investigative Ophthalmology & Visual Science, 65(6), 12. https://doi.org/10.1167/iovs.65.6.12
Mao, L. K., Flynn, H. W., Jr., Miller, D., & Pflugfelder, S. C. (1993). Endophthalmitis caused by Staphylococcus aureus. American Journal of Ophthalmology, 116(5), 584–589. https://doi.org/10.1016/s0002-9394(14)73200-3
Simakurthy, S., & Tripathy, K. (2023). Endophthalmitis. In StatPearls [Internet]. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK559079/
Coburn, P. S., Parrott, A. C., Miller, F. C., LaGrow, A. L., Mursalin, M. H., & Callegan, M. C. (2023). The role of CXC chemokines in Staphylococcus aureus endophthalmitis. Investigative Ophthalmology & Visual Science, 64(3), 10. https://doi.org/10.1167/iovs.64.3.10
Nishida, T., Ishida, K., Niwa, Y., Kawakami, H., Mochizuki, K., & Ohkusu, K. (2015). An eleven‐year retrospective study of endogenous bacterial endophthalmitis. Journal of Ophthalmology, 2015, 261310. https://doi.org/10.1155/2015/261310
Lefèvre, S., Saleh, M., Marcellin, L., Subilia, A., Bourcier, T., Prévost, G., & Jehl, F. (2012). Daptomycin versus vancomycin in a methicillin-resistant Staphylococcus aureus endophthalmitis rabbit model: Bactericidal effect, safety, and ocular pharmacokinetics. Antimicrobial Agents and Chemotherapy, 56(5), 2485–2492. https://doi.org/10.1128/AAC.05745-11
Kumar, A., & Kumar, A. (2015). Role of Staphylococcus aureus virulence factors in inducing inflammation and vascular permeability in a mouse model of bacterial endophthalmitis. PLOS ONE, 10(6), e0128423. https://doi.org/10.1371/journal.pone.0128423
Rajamani, D., Singh, P. K., Rottmann, B. G., Singh, N., Bhasin, M. K., & Kumar, A. (2016). Temporal retinal transcriptome and systems biology analysis identifies key pathways and hub genes in Staphylococcus aureus endophthalmitis. Scientific Reports, 6, 21502. https://doi.org/10.1038/srep21502
Strathdee, S. A., Hatfull, G. F., Mutalik, V. K., & Schooley, R. T. (2023). Phage therapy: From biological mechanisms to future directions. Cell, 186(1), 17–31. https://doi.org/10.1016/j.cell.2022.11.017
Ibrahim, R., Aranjani, J. M., Kalikot Valappil, V., & Nair, G. (2025). Unveiling the potential of bacteriophage therapy: A systematic review. Future Science OA, 11(1), 2468114. https://doi.org/10.1080/20565623.2025.2468114
Wittebole, X., De Roock, S., & Opal, S. M. (2014). A historical overview of bacteriophage therapy as an alternative to antibiotics for the treatment of bacterial pathogens. Virulence, 5(1), 226–235. https://doi.org/10.4161/viru.25991
Perez-Lopez, A., Hernandez-Galicia, G., Lopez-Bailon, L. U., Gonzalez-Telona, A. D., Rosales-Reyes, R., Alpuche-Aranda, C. M., Santos-Preciado, J. I., & Ortiz-Navarrete, V. (2025). Pro-inflammatory and anti-inflammatory responses in B cells during Salmonella infection. European Journal of Microbiology & Immunology, 15(1), 32–41. https://doi.org/10.1556/1886.2024.00088
Gross, J. L., Basu, R., Bradfield, C. J., et al. (2024). Bactericidal antibiotic treatment induces damaging inflammation via TLR9 sensing of bacterial DNA. Nature Communications, 15, 10359. https://doi.org/10.1038/s41467-024-54497-3
Chen, Y. T., Lohia, G. K., Chen, S., & Riquelme, S. A. (2024). Immunometabolic regulation of bacterial infection, biofilms, and antibiotic susceptibility. Journal of Innate Immunity, 16(1), 143–158. https://doi.org/10.1159/000536649
Hao, H., Nie, Z., Wu, Y., Liu, Z., Luo, F., Deng, F., & Zhao, L. (2024). Probiotic characteristics and anti-inflammatory effects of Limosilactobacillus fermentum 664 isolated from Chinese fermented pickles. Antioxidants, 13(6), 703. https://doi.org/10.3390/antiox13060703
Amoroso, C., Perillo, F., Strati, F., Fantini, M. C., Caprioli, F., & Facciotti, F. (2020). The role of gut microbiota biomodulators on mucosal immunity and intestinal inflammation. Cells, 9(5), 1234. https://doi.org/10.3390/cells9051234
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
You are free to:
- Share — copy and redistribute the material in any medium or format
- Adapt — remix, transform, and build upon the material for any purpose, even commercially.
Terms:
- Attribution — You must give appropriate credit, provide a link to the license, and indicate if changes were made. You may do so in any reasonable manner, but not in any way that suggests the licensor endorses you or your use.
- No additional restrictions — You may not apply legal terms or technological measures that legally restrict others from doing anything the license permits.
