Intrastromal Injections in the Management of Infectious Keratitis
Abstract
1. Introduction
2. Materials and Methods
3. Results
3.1. Bacterial Keratitis
3.2. Fungal Keratitis
3.2.1. General Management Guidelines
3.2.2. Antifungal Drugs
Voriconazole
Amphotericin B
Natamycin
Author | Year | Intervention | Indication | n | Healing Rate | Main Cultures | Mean Healing Duration | Special Comments |
---|---|---|---|---|---|---|---|---|
Prakash et al. [37] | 2008 | IS VCZ as an adjuvant to topical NTM and VCZ | Deep recalcitrant fungal keratitis | 3 | 100% | Fusarium spp. and Aspergillus | 18.6 ± 4 days | Targeted delivery of VCZ is safe and effective |
Tu [45] | 2009 | IS VCZ with topical capsofungin or topical fluconazole | Alternaria keratitis not responding to standard therapy | 3 | 100% | Alternaria | 1 case needed IS VCZ with topical capsofungin | |
Sharma et al. [40] | 2011 | IS VCZ after topical NTM, VCZ and oral VCZ | Recalcitrant fungal keratitis | 12 | 83% healed, all of them received >1 injection | Aspergillus and Fusarium | 39.7567.62 days | IS VCZ is effective in recalcitrant fungal keratitis |
Sharma et al. [38] | 2013 | Topical vs. IS VCZ as an adjuvant to topical NTM | Recalcitrant fungal keratitis | 40 | 95% in topical VCZ vs. 80% in IS VCZ (p = 0.34) | Aspergillus (30%), Fusarium (17.5%) | 28.9 ± 19.1 days in topical VCZ vs. 36.1 ± 20.2 days in IS VCZ | IS injections with VCZ are not superior to topical VCZ |
Tu and Hu et al. [43] | 2014 | IS VCZ and IS AMB | Late-onset post-DSAEK interface fungal keratitis | 2 | 100% | Candida species | 3 weeks | IS antifungal therapy is useful in preserving graft viability. |
Kalaiselvi et al. [42] | 2015 | IS VCZ after topical NTM and VCZ | Deep recalcitrant fungal keratitis | 25 | 72%, of which 4 patients needed >1 injection | Fusarium (52%), Aspergillus (16%) | 45.68 ± 11.49 days | IS VCZ is safe and effective in treating deep recalcitrant fungal keratitis |
Nada et al. [48] | 2017 | IS AMB and topical FCZ (group A) vs. topical AMB (group B) | Fungal keratitis | 68 |
| Candida and Aspergillus | 24 ± 6.42 days vs. 39.66 ± 13.6 days | |
Konar et al. [41] | 2019 | IS VCZ after topical NTM and VCZ | Recalcitrant mycotic keratitis | 20 | 70% healed and 15 patients required more than 1 injection (between 2 and 7 injections) | Fusarium (30%) | 35.5 ± 9.22 days | IS VCZ is proven to be safe in recalcitrant mycotic keratitis |
Narayana et al. [39] | 2019 | IS VCZ + topical NTM vs. topical NTM alone | Primary treatment of severe filamentous fungal ulcers | 70 |
| Fusarium (27%), Aspergillus (24%) | IS VCZ shows no benefit as an adjuvant to NTM in primary treatment | |
Saluja et al. [55] | 2021 | IS NTM after 2 weeks of topical NTM | Recalcitrant fungal keratitis | 20 | 95% healed and 30% needed >1 injection | Aspergillus (60%) and Fusarium (40%) | 35.3 ± 6.4 days | IS of novel formulation of NTM plays a promising role in management of recalcitrant fungal keratitis |
Saluja et al. [54] | 2021 | IS VCZ vs. IS AMB vs. IS NTM after two weeks of topical NTM | Recalcitrant fungal keratitis | 60 |
| Aspergillus (53%) and Fusarium (40%) |
| All three antifungal agents show good therapeutic response in recalcitrant fungal keratitis |
3.3. Viral Keratitis
3.4. The Technique of Intrastromal Injection
3.4.1. Preparation of Intrastromal Drug Concentration
Amphotericin B
Voriconazole
3.4.2. Injection Procedure
3.4.3. Limitations and Complications of the Procedure
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Whitcher, J.P.; Srinivasan, M.; Upadhyay, M.P. Corneal blindness—A globalperspective. Bull. World Health Organ. 2001, 79, 214–221. Available online: https://apps.who.int/iris/handle/10665/268284 (accessed on 19 February 2023). [PubMed]
- Ung, L.; Bispo, P.J.; Shanbhag, S.S.; Gilmore, M.S.; Chodosh, J. The persistent dilemma of microbial keratitis: Global burden, diagnosis, and antimicrobial resistance. Surv. Ophthalmol. 2018, 64, 255–271. [Google Scholar] [CrossRef]
- Cabrera-Aguas, M.; Khoo, P.; Watson, S.L. Infectious keratitis: A review. Clin. Exp. Ophthalmol. 2022, 50, 543–562. [Google Scholar] [CrossRef] [PubMed]
- Patel, A.; Cholkar, K.; Agrahari, V.; Mitra, A.K. Ocular drug delivery systems: An overview. World J. Pharmacol. 2013, 2, 47–64. [Google Scholar] [CrossRef]
- Ghate, D.; Edelhauser, H.F. Ocular drug delivery. Expert Opin. Drug Deliv. 2006, 3, 275–287. [Google Scholar] [CrossRef] [PubMed]
- Sahay, P.; Singhal, D.; Nagpal, R.; Maharana, P.K.; Farid, M.; Gelman, R.; Sinha, R.; Agarwal, T.; Titiyal, J.S.; Sharma, N. Pharmacologic therapy of mycotic keratitis. Surv. Ophthalmol. 2019, 64, 380–400. [Google Scholar] [CrossRef] [PubMed]
- Said, D.G.; Rallis, K.I.; Al-Aqaba, M.A.; Ting, D.S.; Dua, H.S. Surgical management of infectious keratitis. Ocul. Surf. 2021; in press. [Google Scholar] [CrossRef]
- Austin, A.; Lietman, T.; Rose-Nussbaumer, J. Update on the Management of Infectious Keratitis. Ophthalmology 2017, 124, 1678–1689. [Google Scholar] [CrossRef] [PubMed]
- Khoo, P.; Cabrera-Aguas, M.; Nguyen, V.; Lahra, M.M.; Watson, S.L. Microbial keratitis in Sydney, Australia: Risk factors, patient outcomes, and seasonal variation. Graefe’s Arch. Clin. Exp. Ophthalmol. 2020, 258, 1745–1755. [Google Scholar] [CrossRef]
- Miller, D.; Cavuoto, K.M.; Alfonso, E.C. Bacterial Keratitis. In Infections of the Cornea and Conjunctiva; Das, S., Jhanji, V., Eds.; Springer: Singapore, 2021; pp. 85–104. [Google Scholar]
- Lin, A.; Rhee, M.K.; Akpek, E.K.; Amescua, G.; Farid, M.; Garcia-Ferrer, F.J.; Varu, D.M.; Musch, D.; Dunn, S.P.; Mah, F.S.; et al. American Academy of Ophthalmology Preferred Practice Pattern Cornea and External Disease Panel. Bacterial Keratitis Preferred Practice Pattern®. Ophthalmology 2019, 126, P1–P55. [Google Scholar] [CrossRef] [PubMed]
- Khan, I.J.; Hamada, S.; Rauz, S. Infectious Crystalline Keratopathy Treated with Intrastromal Antibiotics. Cornea 2010, 29, 1186–1188. [Google Scholar] [CrossRef] [PubMed]
- Martinez-Velazquez, L.; Ma, K.K.; Patel, N.S.; Luo, Z.K. Successful Management of Infectious Crystalline Keratopathy with Intrastromal Antibiotic Injections. Case Rep. Ophthalmol. Med. 2022, 2022, 5830617. [Google Scholar] [CrossRef] [PubMed]
- Grzybowski, A.; Brona, P.; Zeman, L.; Stewart, M.W. Commonly used intracameral antibiotics for endophthalmitis prophylaxis: A literature review. Surv. Ophthalmol. 2020, 66, 98–108. [Google Scholar] [CrossRef]
- Porter, A.J.; Lee, G.A.; Jun, A.S. Infectious crystalline keratopathy. Surv. Ophthalmol. 2018, 63, 480–499. [Google Scholar] [CrossRef] [PubMed]
- Meisler, D.M.; Langston, R.H.; Naab, T.J.; Aaby, A.A.; McMahon, J.T.; Tubbs, R.R. Infectious Crystalline Keratopathy. Am. J. Ophthalmol. 1984, 97, 337–343. [Google Scholar] [CrossRef] [PubMed]
- Matoba, A.Y.; O’Brien, T.P.; Wilhelmus, K.R.; Jones, D.B. Infectious Crystalline Keratopathy due to Streptococcus pneumoniae. Possible association with serotype. Ophthalmology 1994, 101, 1000–1004. [Google Scholar] [CrossRef]
- Groden, L.R.; Pascucci, S.E.; Brinser, J.H. Haemophilus aphrophilus as a Cause of Crystalline Keratopathy. Am. J. Ophthalmol. 1987, 104, 89–90. [Google Scholar] [CrossRef]
- Sridhar, M.S.; Sharma, S.; Garg, P.; Rao, G.N. Epithelial infectious crystalline keratopathy. Am. J. Ophthalmol. 2001, 131, 255–257. [Google Scholar] [CrossRef]
- Khater, T.T.; Jones, D.B.; Wilhelmus, K.R. Infectious Crystalline Keratopathy Caused by Gram-negative Bacteria. Am. J. Ophthalmol. 1997, 124, 19–23. [Google Scholar] [CrossRef]
- Davis, R.M.; Schroeder, R.P.; Rowsey, J.J.; Jensen, H.G.; Tripathi, R.C. Acanthamoeba Keratitis and Infectious Crystalline Keratopathy. Arch. Ophthalmol. 1987, 105, 1524–1527. [Google Scholar] [CrossRef]
- Stewart, P.S.; Costerton, J.W. Antibiotic resistance of bacteria in biofilms. Lancet 2001, 358, 135–138. [Google Scholar] [CrossRef] [PubMed]
- Mah, T.-F.C.; O’Toole, G.A. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol. 2001, 9, 34–39. [Google Scholar] [CrossRef] [PubMed]
- Hall-Stoodley, L.; Stoodley, P. Evolving concepts in biofilm infections. Cell. Microbiol. 2009, 11, 1034–1043. [Google Scholar] [CrossRef] [PubMed]
- Stewart, P.S. Diffusion in Biofilms. J. Bacteriol. 2003, 185, 1485–1491. [Google Scholar] [CrossRef]
- Agahan, A.; Regalado, R. Infectious Crystalline Keratopathy Caused by Diphtheroids Treated with Intrastromal Antibiotics in a Post-corneal Transplant Patient. Ophthalmol. Res. Int. J. 2016, 5, 1–5. [Google Scholar] [CrossRef]
- Liang, S.Y.-W.; Lee, G.A. Intrastromal injection of antibiotic agent in the management of recalcitrant bacterial keratitis. J. Cataract. Refract. Surg. 2011, 37, 960–962. [Google Scholar] [CrossRef]
- Ha, B.J.; Lee, S.H.; Kim, Y.M.; Kwon, H.S.; Chu, Y.K.; Seo, K.Y. A Case of Inadvertent Anterior Chamber and Corneal Stromal Injection with Antibiotics during Cataract Operation. Korean J. Ophthalmol. 2006, 20, 241–245. [Google Scholar] [CrossRef]
- Medhi, J.; Bhattacharjee, H.; Bhattacharjee, K.; Altaf, A. Descemet′s membrane detachment caused by inadvertent vancomycin injection. Indian J. Ophthalmol. 2008, 56, 241–243. [Google Scholar] [CrossRef]
- Pak, C.M.; Savage, D.E.; Plotnik, R.; Wozniak, R.A. Intrastromal Antibiotic Injection in Polymicrobial Keratitis: Case Report and Literature Review. Case Rep. Ophthalmol. 2022, 13, 550–555. [Google Scholar] [CrossRef]
- Garg, P. Fungal, Mycobacterial, and Nocardia infections and the eye: An update. Eye 2011, 26, 245–251. [Google Scholar] [CrossRef]
- Chang, H.-Y.P.; Chodosh, J. Diagnostic and Therapeutic Considerations in Fungal Keratitis. Int. Ophthalmol. Clin. 2011, 51, 33–42. [Google Scholar] [CrossRef] [PubMed]
- Vajpayee, R.B.; Maharana, P.K.; Sharma, N.; Nagpal, R.; Jhanji, V.; Das, S. Recent advances in diagnosis and management of Mycotic Keratitis. Indian J. Ophthalmol. 2016, 64, 346–357. [Google Scholar] [CrossRef] [PubMed]
- Brown, L.; Leck, A.K.; Gichangi, M.; Burton, M.J.; Denning, D.W. The global incidence and diagnosis of fungal keratitis. Lancet Infect. Dis. 2020, 21, e49–e57. [Google Scholar] [CrossRef] [PubMed]
- Lalitha, P.; Prajna, N.V.; Kabra, A.; Mahadevan, K.; Srinivasan, M. Risk Factors for Treatment Outcome in Fungal Keratitis. Ophthalmology 2006, 113, 526–530. [Google Scholar] [CrossRef] [PubMed]
- Watson, S.L.; Cabrera-Aguas, M.; Keay, L.; Khoo, P.; McCall, D.; Lahra, M.M. The clinical and microbiological features and outcomes of fungal keratitis over 9 years in Sydney, Australia. Mycoses 2019, 63, 43–51. [Google Scholar] [CrossRef]
- Sharma, N.; Sahay, P.; Maharana, P.K.; Singhal, D.; Saluja, G.; Bandivadekar, P.; Chako, J.; Agarwal, T.; Sinha, R.; Titiyal, J.S.; et al. Management Algorithm for Fungal Keratitis: The TST (Topical, Systemic, and Targeted Therapy) Protocol. Cornea 2018, 38, 141–145. [Google Scholar] [CrossRef]
- Ansari, Z.; Miller, D.; Galor, A. Current Thoughts in Fungal Keratitis: Diagnosis and Treatment. Curr. Fungal Infect. Rep. 2013, 7, 209–218. [Google Scholar] [CrossRef]
- Raj, N.; Vanathi, M.; Ahmed, N.H.; Gupta, N.; Lomi, N.; Tandon, R. Recent Perspectives in the Management of Fungal Keratitis. J. Fungi 2021, 7, 907. [Google Scholar] [CrossRef]
- Parchand, S.; Gupta, A.; Ram, J.; Gupta, N.; Chakrabarty, A. Voriconazole for Fungal Corneal Ulcers. Ophthalmology 2012, 119, 1083–1083.e3. [Google Scholar] [CrossRef]
- Prakash, G.; Sharma, N.; Goel, M.; Titiyal, J.S.; Vajpayee, R.B. Evaluation of Intrastromal Injection of Voriconazole as a Therapeutic Adjunctive for the Management of Deep Recalcitrant Fungal Keratitis. Am. J. Ophthalmol. 2008, 146, 56–59.e2. [Google Scholar] [CrossRef]
- Sharma, N.; Chacko, J.; Velpandian, T.; Titiyal, J.S.; Sinha, R.; Satpathy, G.; Tandon, R.; Vajpayee, R.B. Comparative Evaluation of Topical versus Intrastromal Voriconazole as an Adjunct to Natamycin in Recalcitrant Fungal Keratitis. Ophthalmology 2013, 120, 677–681. [Google Scholar] [CrossRef] [PubMed]
- Narayana, S.; Krishnan, T.; Ramakrishnan, S.; Samantaray, P.P.; Austin, A.; Pickel, J.; Porco, T.; Lietman, T.; Rose-Nussbaumer, J. Mycotic Antimicrobial Localized Injection: A Randomized Clinical Trial Evaluating Intrastromal Injection of Voriconazole. Ophthalmology 2019, 126, 1084–1089. [Google Scholar] [CrossRef] [PubMed]
- Sharma, N.; Agarwal, P.; Sinha, R.; Titiyal, J.S.; Velpandian, T.; Vajpayee, R.B. Evaluation of intrastromal voriconazole injection in recalcitrant deep fungal keratitis: Case series. Br. J. Ophthalmol. 2011, 95, 1735–1737. [Google Scholar] [CrossRef] [PubMed]
- Konar, P.; Joshi, S.; Mandhare, S.J.; Thakur, R.; Deshpande, M.; Dayal, A. Intrastromal voriconazole: An adjuvant approach for recalcitrant mycotic keratitis. Indian J. Ophthalmol. 2020, 68, 35–38. [Google Scholar] [CrossRef] [PubMed]
- Kalaiselvi, G.; Narayana, S.; Krishnan, T.; Sengupta, S. Intrastromal voriconazole for deep recalcitrant fungal keratitis: A case series. Br. J. Ophthalmol. 2014, 99, 195–198. [Google Scholar] [CrossRef]
- Tu, E.; Hou, J. Intrastromal Antifungal Injection with Secondary Lamellar Interface Infusion for Late-Onset Infectious Keratitis After DSAEK. Cornea 2014, 33, 990–993. [Google Scholar] [CrossRef]
- Haddad, R.S.; El-Mollayess, G.M. Combination of intracameral and intrastromal voriconazole in the treatment of recalcitrant Acremonium fungal keratitis. Middle East Afr. J. Ophthalmol. 2012, 19, 265–268. [Google Scholar] [CrossRef]
- Tu, E.Y. Alternaria Keratitis: Clinical Presentation and Resolution with Topical Fluconazole or Intrastromal Voriconazole and Topical Caspofungin. Cornea 2009, 28, 116–119. [Google Scholar] [CrossRef]
- Cavallini, G.M.; Ducange, P.; Volante, V.; Benatti, C. Successful treatment of Fusarium keratitis after photo refractive keratectomy. Indian J. Ophthalmol. 2013, 61, 669–671. [Google Scholar] [CrossRef]
- Jain, V.; Borse, N.; Shome, D.; Natarajan, S. Recalcitrant fungal tunnel infection treated with intrastromal injection of voriconazole. Int. Ophthalmol. 2010, 30, 723–725. [Google Scholar] [CrossRef]
- Nada, W.M.; Al Aswad, M.A.; El-Haig, W.M. Combined intrastromal injection of amphotericin B and topical fluconazole in the treatment of resistant cases of keratomycosis: A retrospective study. Clin. Ophthalmol. 2017, 11, 871–874. [Google Scholar] [CrossRef] [PubMed]
- Aydin, B.; Cubuk, M.O.; Ucgul, A.; Ertop, M.; Ozmen, M.C.; Atalay, T.; Akata, F. Combined Intrastromal Voriconazole and Amphotericin B Treatment for Persistent Fungal Keratitis. Eye Contact Lens Sci. Clin. Pr. 2020, 46, 269–273. [Google Scholar] [CrossRef] [PubMed]
- Garcia-Valenzuela, E.; Song, C.D. Intracorneal Injection of Amphothericin B for Recurrent Fungal Keratitis and Endophthalmitis. Arch. Ophthalmol. 2005, 123, 1721–1723. [Google Scholar] [CrossRef]
- Hu, J.; Zhang, J.; Li, Y.; Han, X.; Zheng, W.; Yang, J.; Xu, G. A Combination of Intrastromal and Intracameral Injections of Amphotericin B in the Treatment of Severe Fungal Keratitis. J. Ophthalmol. 2016, 2016, 3436415. [Google Scholar] [CrossRef]
- Hoffman, J.J.; Arunga, S.; Ahmed, A.H.A.M.; Hu, V.H.; Burton, M.J. Management of Filamentous Fungal Keratitis: A Pragmatic Approach. J. Fungi 2022, 8, 1067. [Google Scholar] [CrossRef] [PubMed]
- Prajna, N.V.; Krishnan, T.; Mascarenhas, J.; Rajaraman, R.; Prajna, L.; Srinivasan, M.; Raghavan, A.; Oldenburg, C.E.; Ray, K.J.; Zegans, M.E.; et al. The Mycotic Ulcer Treatment Trial: A randomized trial comparing natamycin vs voriconazole. JAMA Ophthalmol. 2013, 131, 422–429. [Google Scholar] [CrossRef]
- Saluja, G.; Sharma, N.; Agarwal, R.; Sharma, H.P.; Singhal, D.; Kumar Maharana, P.; Sinha, R.; Agarwal, T.; Velpandian, T.; Titiyal, J.S.; et al. Comparison of Safety and Efficacy of Intrastromal Injections of Voriconazole, Amphotericin B and Natamycin in Cases of Recalcitrant Fungal Keratitis: A Randomized Controlled Trial. Clin. Ophthalmol. 2021, 15, 2437–2446. [Google Scholar] [CrossRef]
- Sharma, N.; Saluja, G.; Agarwal, R.; Sharma, H.; Maharana, P.; Satpathy, G.; Titiyal, J.; Velpandian, T. Determination of surgical outcomes with a novel formulation of intrastromal natamycin in recalcitrant fungal keratitis: A pilot study. Indian J. Ophthalmol. 2021, 69, 2670. [Google Scholar] [CrossRef]
- Liesegang, T.J.; Melton, L.J.; Daly, P.J.; Ilstrup, D.M. Epidemiology of Ocular Herpes Simplex. Incidence in Rochester, Minn, 1950 through 1982. Arch. Ophthalmol. 1989, 107, 1155–1159. [Google Scholar] [CrossRef]
- Chou, T.Y.; Hong, B.Y. Ganciclovir ophthalmic gel 0.15% for the treatment of acute herpetic keratitis: Background, effectiveness, tolerability, safety, and future applications. Ther. Clin. Risk Manag. 2014, 10, 665–681. [Google Scholar] [CrossRef]
- Arenas, E.; Mieth, A.; Muñoz, D. Combined intrastromal injection of ganciclovir and depot betamethasone for the management of nummular keratitis: Case series. Arch. Soc. Esp. Oftalmol. 2019, 94, 347–351. [Google Scholar] [CrossRef] [PubMed]
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Zemba, M.; Radu, M.; Istrate, S.; Dumitrescu, O.-M.; Ionescu, M.A.; Vatafu, A.; Barac, I.R. Intrastromal Injections in the Management of Infectious Keratitis. Pharmaceutics 2023, 15, 1091. https://doi.org/10.3390/pharmaceutics15041091
Zemba M, Radu M, Istrate S, Dumitrescu O-M, Ionescu MA, Vatafu A, Barac IR. Intrastromal Injections in the Management of Infectious Keratitis. Pharmaceutics. 2023; 15(4):1091. https://doi.org/10.3390/pharmaceutics15041091
Chicago/Turabian StyleZemba, Mihail, Madalina Radu, Sinziana Istrate, Otilia-Maria Dumitrescu, Mihai Alexandru Ionescu, Andrei Vatafu, and Ileana Ramona Barac. 2023. "Intrastromal Injections in the Management of Infectious Keratitis" Pharmaceutics 15, no. 4: 1091. https://doi.org/10.3390/pharmaceutics15041091
APA StyleZemba, M., Radu, M., Istrate, S., Dumitrescu, O.-M., Ionescu, M. A., Vatafu, A., & Barac, I. R. (2023). Intrastromal Injections in the Management of Infectious Keratitis. Pharmaceutics, 15(4), 1091. https://doi.org/10.3390/pharmaceutics15041091