Double-masked, sham and placebo-controlled trial of corneal cross-linking and topical difluprednate in the treatment of bacterial keratitis: Steroids and Cross-linking for Ulcer Treatment Trial (SCUT II) study protocol

Naveen Radhakrishnan, Venkatesh N Prajna, Lalitha S Prajna, Anitha Venugopal, Shivanandha Narayana, Revathi Rajaraman, Guillermo Amescua, Travis C Porco, Thomas M Lietman, Jennifer Rose-Nussbaumer, Naveen Radhakrishnan, Venkatesh N Prajna, Lalitha S Prajna, Anitha Venugopal, Shivanandha Narayana, Revathi Rajaraman, Guillermo Amescua, Travis C Porco, Thomas M Lietman, Jennifer Rose-Nussbaumer

Abstract

Introduction: Although antibiotics are successful at achieving microbiological cure in infectious keratitis, outcomes are often poor due to corneal scarring. Ideal treatment of corneal ulcers would address both the infection and the inflammation. Adjunctive topical steroid treatment may improve outcomes by reducing inflammation. Corneal cross-linking (CXL) is a novel prospective therapy that may simultaneously reduce both inflammatory cells and bacterial pathogens. The purpose of this study is to determine differences in 6-month visual acuity between standard medical therapy with antibiotics versus antibiotics with adjunctive early topical steroid therapy versus antibiotic treatment plus CXL and early topical steroids.

Methods and analysis: This international, randomised, sham and placebo-controlled, three-arm clinical trial randomises patients with smear positive bacterial ulcers in a 1:1:1 fashion to one of three treatment arms: (1) topical 0.5% moxifloxacin plus topical placebo plus sham CXL; (2) topical 0.5% moxifloxacin plus difluprednate 0.05% plus sham CXL; or (3) the CXL group: topical 0.5% moxifloxacin plus difluprednate 0.05% plus CXL.

Ethics and dissemination: We anticipate that both adjunctive topical steroids and CXL will improved best spectacle corrected visual acuity and also reduce complications such as corneal perforation and the need for therapeutic penetrating keratoplasty. This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Our results will be disseminated via ClinicalTrials.gov website, meetings and journal publications. Our data will also be available on reasonable request.

Trial registration number: NCT04097730.

Keywords: clinical trial; cornea; infection; inflammation.

Conflict of interest statement

Competing interests: None declared.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Enrolment schema for the Steroids and Cross-linking for Ulcer Treatment Trial. AS-OCT, anterior segment optical coherence tomography; BSCVA, best spectacle corrected visual acuity; CXL, corneal cross-linking;VFQ, Visual Function Questionnaire.

References

    1. McDonald EM, Ram FSF, Patel DV, et al. . Topical antibiotics for the management of bacterial keratitis: an evidence-based review of high quality randomised controlled trials. Br J Ophthalmol 2014;98:1470–7. 10.1136/bjophthalmol-2013-304660
    1. Tan DTH, Janardhanan P, Zhou H, et al. . Penetrating keratoplasty in Asian eyes: the Singapore corneal transplant study. Ophthalmology 2008;115:e971:975–82. 10.1016/j.ophtha.2007.08.049
    1. Hobden JA. Pseudomonas aeruginosa proteases and corneal virulence. DNA Cell Biol 2002;21:391–6. 10.1089/10445490260099674
    1. Matsumoto K. Role of bacterial proteases in pseudomonal and serratial keratitis. Biol Chem 2004;385:1007–16. 10.1515/BC.2004.131
    1. Ray KJ, Srinivasan M, Mascarenhas J, et al. . Early addition of topical corticosteroids in the treatment of bacterial keratitis. JAMA Ophthalmol 2014;132:737–41. 10.1001/jamaophthalmol.2014.292
    1. Palioura S, Henry CR, Amescua G, et al. . Role of steroids in the treatment of bacterial keratitis. Clin Ophthalmol 2016;10:179–86. 10.2147/OPTH.S80411
    1. Alio JL, Abbouda A, Valle DD, et al. . Corneal cross linking and infectious keratitis: a systematic review with a meta-analysis of reported cases. J Ophthalmic Inflamm Infect 2013;3:47. 10.1186/1869-5760-3-47
    1. Sand D, She R, Shulman IA, et al. . Microbial keratitis in Los Angeles: the doheny eye Institute and the Los Angeles County Hospital experience. Ophthalmology 2015;122:918–24. 10.1016/j.ophtha.2014.11.027
    1. Papaioannou L, Miligkos M, Papathanassiou M. Corneal collagen cross-linking for infectious keratitis: a systematic review and meta-analysis. Cornea 2016;35:62–71. 10.1097/ICO.0000000000000644
    1. Martins SAR, Combs JC, Noguera G, et al. . Antimicrobial efficacy of riboflavin/UVA combination (365 nm) in vitro for bacterial and fungal isolates: a potential new treatment for infectious keratitis. Invest Ophthalmol Vis Sci 2008;49:3402–8. 10.1167/iovs.07-1592
    1. Panda A, Krishna SN, Kumar S. Photo-activated riboflavin therapy of refractory corneal ulcers. Cornea 2012;31:1210–3. 10.1097/ICO.0b013e31823f8f48
    1. Iseli HP, Thiel MA, Hafezi F, et al. . Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts. Cornea 2008;27:590–4. 10.1097/ICO.0b013e318169d698
    1. Makdoumi K, Mortensen J, Crafoord S. Infectious keratitis treated with corneal crosslinking. Cornea 2010;29:1353–8. 10.1097/ICO.0b013e3181d2de91
    1. Shetty R, Nagaraja H, Jayadev C, et al. . Collagen crosslinking in the management of advanced non-resolving microbial keratitis. Br J Ophthalmol 2014;98:1033–5. 10.1136/bjophthalmol-2014-304944
    1. Makdoumi K, Mortensen J, Sorkhabi O, et al. . UVA-riboflavin photochemical therapy of bacterial keratitis: a pilot study. Graefes Arch Clin Exp Ophthalmol 2012;250:95–102. 10.1007/s00417-011-1754-1
    1. Ray KJ, Lalitha P, Prajna NV, et al. . The utility of repeat culture in fungal corneal ulcer management: a secondary analysis of the MUTT-I randomized clinical trial. Am J Ophthalmol 2017;178:157–62. 10.1016/j.ajo.2017.03.032
    1. Bhadange Y, Das S, Kasav MK, et al. . Comparison of culture-negative and culture-positive microbial keratitis: cause of culture negativity, clinical features and final outcome. Br J Ophthalmol 2015;99:1498–502. 10.1136/bjophthalmol-2014-306414
    1. McLeod SD, Kolahdouz-Isfahani A, Rostamian K, et al. . The role of smears, cultures, and antibiotic sensitivity testing in the management of suspected infectious keratitis. Ophthalmology 1996;103:23–8. 10.1016/S0161-6420(96)30738-0
    1. Vemuganti GK, Garg P, Gopinathan U, et al. . Evaluation of agent and host factors in progression of mycotic keratitis: a histologic and microbiologic study of 167 corneal buttons. Ophthalmology 2002;109:1538–46. 10.1016/s0161-6420(02)01088-6
    1. Whitcher JP, Srinivasan M, Upadhyay MP. Corneal blindness: a global perspective. Bull World Health Organ 2001;79:214–21.
    1. ABKP . Bacterial keratitis preferred practice pattern (ppp) guideline. 2013. In: American Academy of Ophthalmology, 2013.
    1. Jeng BH, Gritz DC, Kumar AB, et al. . Epidemiology of ulcerative keratitis in Northern California. Arch Ophthalmol 2010;128:1022–8. 10.1001/archophthalmol.2010.144
    1. Gonzales CA, Srinivasan M, Whitcher JP, et al. . Incidence of corneal ulceration in Madurai district, South India. Ophthalmic Epidemiol 1996;3:159–66. 10.3109/09286589609080122
    1. Rose-Nussbaumer J, Prajna NV, Krishnan KT, et al. . Vision-Related quality-of-life outcomes in the mycotic ulcer treatment trial I: a randomized clinical trial. JAMA Ophthalmol 2015;133:642–6. 10.1001/jamaophthalmol.2015.0319
    1. Austin A, Schallhorn J, Geske M, et al. . Empirical treatment of bacterial keratitis: an international survey of corneal specialists. BMJ Open Ophthalmol 2017;2. 10.1136/bmjophth-2016-000047. [Epub ahead of print: 16 08 2017].
    1. Acharya NR, Srinivasan M, Mascarenhas J, et al. . The steroid controversy in bacterial keratitis. Arch Ophthalmol 2009;127:1231. 10.1001/archophthalmol.2009.221
    1. Cohen EJ. The case against the use of steroids in the treatment of bacterial keratitis. Arch Ophthalmol 2009;127:103–4. 10.1001/archophthalmol.2008.503
    1. Hindman HB, Patel SB, Jun AS. Rationale for adjunctive topical corticosteroids in bacterial keratitis. Arch Ophthalmol 2009;127:97–102. 10.1001/archophthalmol.2008.504
    1. Den S, Sotozono C, Kinoshita S, et al. . Efficacy of early systemic betamethasone or cyclosporin A after corneal alkali injury via inflammatory cytokine reduction. Acta Ophthalmol Scand 2004;82:195–9. 10.1111/j.1600-0420.2004.00229.x
    1. Yi K, Chung TY, Hyon JY. Combined treatment with antioxidants and immunosuppressants on cytokine release by human peripheral blood mononuclear cells - chemically injured keratocyte reaction. Mol Vis 2011;17:2665–71.
    1. Williams RN, Paterson CA. The influence of topical corticosteroid therapy upon polymorphonuclear leukocyte distribution, vascular integrity and ascorbate levels in endotoxin-induced inflammation of the rabbit eye. Exp Eye Res 1987;44:191–8. 10.1016/S0014-4835(87)80003-9
    1. Chung J-H, Kang Y-G, Kim H-J. Effect of 0.1% dexamethasone on epithelial healing in experimental corneal alkali wounds: morphological changes during the repair process. Graefes Arch Clin Exp Ophthalmol 1998;236:537–45. 10.1007/s004170050118
    1. Tomas-Barberan S, Fagerholm P. Influence of topical treatment on epithelial wound healing and pain in the early postoperative period following photorefractive keratectomy. Acta Ophthalmol Scand 1999;77:135–8. 10.1034/j.1600-0420.1999.770203.x
    1. Gritz DC, Kwitko S, Trousdale MD, et al. . Recurrence of microbial keratitis concomitant with antiinflammatory treatment in an animal model. Cornea 1992;11:404–8. 10.1097/00003226-199209000-00008
    1. Gritz DC, Lee TY, Kwitko S, et al. . Topical anti-inflammatory agents in an animal model of microbial keratitis. Arch Ophthalmol 1990;108:1001–5. 10.1001/archopht.1990.01070090103049
    1. Blair J, Hodge W, Al-Ghamdi S, et al. . Comparison of antibiotic-only and antibiotic-steroid combination treatment in corneal ulcer patients: double-blinded randomized clinical trial. Can J Ophthalmol 2011;46:40–5. 10.3129/i10-054
    1. Carmichael TR, Gelfand Y, Welsh NH. Topical steroids in the treatment of central and paracentral corneal ulcers. Br J Ophthalmol 1990;74:528–31. 10.1136/bjo.74.9.528
    1. Srinivasan M, Lalitha P, Mahalakshmi R, et al. . Corticosteroids for bacterial corneal ulcers. Br J Ophthalmol 2009;93:198–202. 10.1136/bjo.2008.147298
    1. Srinivasan M, Mascarenhas J, Rajaraman R, et al. . Corticosteroids for bacterial keratitis: the steroids for corneal ulcers trial (SCUT). Arch Ophthalmol 2012;130:143–50. 10.1001/archophthalmol.2011.315
    1. Srinivasan M, Mascarenhas J, Rajaraman R, et al. . The steroids for corneal ulcers trial (SCUT): secondary 12-month clinical outcomes of a randomized controlled trial. Am J Ophthalmol 2014;157:e323:327–33. 10.1016/j.ajo.2013.09.025
    1. Cherfan D, Verter EE, Melki S, et al. . Collagen cross-linking using rose Bengal and green light to increase corneal stiffness. Invest Ophthalmol Vis Sci 2013;54:3426–33. 10.1167/iovs.12-11509
    1. Kamaev P, Friedman MD, Sherr E, et al. . Photochemical kinetics of corneal cross-linking with riboflavin. Invest Ophthalmol Vis Sci 2012;53:2360–7. 10.1167/iovs.11-9385
    1. Vatansever F, de Melo WCMA, Avci P, et al. . Antimicrobial strategies centered around reactive oxygen species--bactericidal antibiotics, photodynamic therapy, and beyond. FEMS Microbiol Rev 2013;37:955–89. 10.1111/1574-6976.12026
    1. Arafat SN, Robert M-C, Shukla AN, et al. . UV cross-linking of donor corneas confers resistance to keratolysis. Cornea 2014;33:955–9. 10.1097/ICO.0000000000000185
    1. Keating A, Pineda R. 2Nd, Colby K. corneal cross linking for keratoconus. Semin Ophthalmol 2010;25:249–55.
    1. Lamy R, Netto CF, Reis RG, et al. . Effects of corneal cross-linking on contrast sensitivity, visual acuity, and corneal topography in patients with keratoconus. Cornea 2013;32:591–6. 10.1097/ICO.0b013e31826672e2
    1. Raiskup-Wolf F, Hoyer A, Spoerl E, et al. . Collagen crosslinking with riboflavin and ultraviolet-A light in keratoconus: long-term results. J Cataract Refract Surg 2008;34:796–801. 10.1016/j.jcrs.2007.12.039
    1. Vinciguerra P, Albè E, Trazza S, et al. . Intraoperative and postoperative effects of corneal collagen cross-linking on progressive keratoconus. Arch Ophthalmol 2009;127:1258–65. 10.1001/archophthalmol.2009.205
    1. Mazzotta C, Hafezi F, Kymionis G, et al. . In vivo confocal microscopy after corneal collagen crosslinking. Ocul Surf 2015;13:298–314. 10.1016/j.jtos.2015.04.007
    1. Sharma N, Suri K, Sehra SV, et al. . Collagen cross-linking in keratoconus in Asian eyes: visual, refractive and confocal microscopy outcomes in a prospective randomized controlled trial. Int Ophthalmol 2015;35:827–32. 10.1007/s10792-015-0054-x
    1. Bamdad S, Malekhosseini H, Khosravi A. Ultraviolet A/riboflavin collagen cross-linking for treatment of moderate bacterial corneal ulcers. Cornea 2015;34:402–6. 10.1097/ICO.0000000000000375
    1. Said DG, Elalfy MS, Gatzioufas Z, et al. . Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting. Ophthalmology 2014;121:1377–82. 10.1016/j.ophtha.2014.01.011
    1. Mittal R, Garg P. Re: Said et al.: Collagen cross-linking with photoactivated riboflavin (PACK-CXL) for the treatment of advanced infectious keratitis with corneal melting (Ophthalmology 2014;121:1377-82). Ophthalmology 2014;121:e67–8. 10.1016/j.ophtha.2014.06.043
    1. Marasini S, Zhang AC, Dean SJ, et al. . Safety and efficacy of UV application for superficial infections in humans: a systematic review and meta-analysis. Ocul Surf 2021;21:331–44. 10.1016/j.jtos.2021.03.002
    1. El Rami H, Chelala E, Dirani A, et al. . An update on the safety and efficacy of corneal collagen cross-linking in pediatric keratoconus. Biomed Res Int 2015;2015:1–7. 10.1155/2015/257927
    1. Lalitha P, Srinivasan M, Manikandan P, et al. . Relationship of in vitro susceptibility to moxifloxacin and in vivo clinical outcome in bacterial keratitis. Clin Infect Dis 2012;54:1381–7. 10.1093/cid/cis189

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner