Update on the Management of Infectious Keratitis
2017; Elsevier BV; Volume: 124; Issue: 11 Linguagem: Inglês
10.1016/j.ophtha.2017.05.012
ISSN1549-4713
AutoresAriana Austin, Tom Lietman, Jennifer Rose‐Nussbaumer,
Tópico(s)Corneal surgery and disorders
ResumoInfectious keratitis is a major global cause of visual impairment and blindness, often affecting marginalized populations. Proper diagnosis of the causative organism is critical, and although culture remains the prevailing diagnostic tool, newer techniques such as in vivo confocal microscopy are helpful for diagnosing fungus and Acanthamoeba. Next-generation sequencing holds the potential for early and accurate diagnosis even for organisms that are difficult to culture by conventional methods. Topical antibiotics remain the best treatment for bacterial keratitis, and a recent review found all commonly prescribed topical antibiotics to be equally effective. However, outcomes remain poor secondary to corneal melting, scarring, and perforation. Adjuvant therapies aimed at reducing the immune response associated with keratitis include topical corticosteroids. The large, randomized, controlled Steroids for Corneal Ulcers Trial found that although steroids provided no significant improvement overall, they did seem beneficial for ulcers that were central, deep or large, non-Nocardia, or classically invasive Pseudomonas aeruginosa; for patients with low baseline vision; and when started early after the initiation of antibiotics. Fungal ulcers often have worse clinical outcomes than bacterial ulcers, with no new treatments since the 1960s when topical natamycin was introduced. The randomized controlled Mycotic Ulcer Treatment Trial (MUTT) I showed a benefit of topical natamycin over topical voriconazole for fungal ulcers, particularly among those caused by Fusarium. MUTT II showed that oral voriconazole did not improve outcomes overall, although there may have been some effect among Fusarium ulcers. Given an increase in nonserious adverse events, the authors concluded that they could not recommend oral voriconazole. Viral keratitis differs from bacterial and fungal cases in that it is often recurrent and is common in developed countries. The Herpetic Eye Disease Study (HEDS) I showed a significant benefit of topical corticosteroids and oral acyclovir for stromal keratitis. HEDS II showed that oral acyclovir decreased the recurrence of any type of herpes simplex virus keratitis by approximately half. Future strategies to reduce the morbidity associated with infectious keratitis are likely to be multidimensional, with adjuvant therapies aimed at modifying the immune response to infection holding the greatest potential to improve clinical outcomes. Infectious keratitis is a major global cause of visual impairment and blindness, often affecting marginalized populations. Proper diagnosis of the causative organism is critical, and although culture remains the prevailing diagnostic tool, newer techniques such as in vivo confocal microscopy are helpful for diagnosing fungus and Acanthamoeba. Next-generation sequencing holds the potential for early and accurate diagnosis even for organisms that are difficult to culture by conventional methods. Topical antibiotics remain the best treatment for bacterial keratitis, and a recent review found all commonly prescribed topical antibiotics to be equally effective. However, outcomes remain poor secondary to corneal melting, scarring, and perforation. Adjuvant therapies aimed at reducing the immune response associated with keratitis include topical corticosteroids. The large, randomized, controlled Steroids for Corneal Ulcers Trial found that although steroids provided no significant improvement overall, they did seem beneficial for ulcers that were central, deep or large, non-Nocardia, or classically invasive Pseudomonas aeruginosa; for patients with low baseline vision; and when started early after the initiation of antibiotics. Fungal ulcers often have worse clinical outcomes than bacterial ulcers, with no new treatments since the 1960s when topical natamycin was introduced. The randomized controlled Mycotic Ulcer Treatment Trial (MUTT) I showed a benefit of topical natamycin over topical voriconazole for fungal ulcers, particularly among those caused by Fusarium. MUTT II showed that oral voriconazole did not improve outcomes overall, although there may have been some effect among Fusarium ulcers. Given an increase in nonserious adverse events, the authors concluded that they could not recommend oral voriconazole. Viral keratitis differs from bacterial and fungal cases in that it is often recurrent and is common in developed countries. The Herpetic Eye Disease Study (HEDS) I showed a significant benefit of topical corticosteroids and oral acyclovir for stromal keratitis. HEDS II showed that oral acyclovir decreased the recurrence of any type of herpes simplex virus keratitis by approximately half. Future strategies to reduce the morbidity associated with infectious keratitis are likely to be multidimensional, with adjuvant therapies aimed at modifying the immune response to infection holding the greatest potential to improve clinical outcomes. Corneal disease remains the leading cause of monocular blindness worldwide, especially affecting marginalized populations.1Whitcher J.P. Srinivasan M. Upadhyay M.P. Corneal blindness: a global perspective.Bull World Health Organ. 2001; 79: 214-221PubMed Google Scholar Corneal opacities, which are largely caused by infectious keratitis, are the fourth leading cause of blindness globally and are responsible for 10% of avoidable visual impairment in the world's least developed countries.2Pascolini D. Mariotti S.P. Global estimates of visual impairment: 2010.Br J Ophthalmol. 2012; 96: 614-618Crossref PubMed Scopus (799) Google Scholar, 3World Health OrganizationCauses of blindness and visual impairment.http://www.who.int/blindness/causes/enGoogle Scholar Approximately 2 million people develop a corneal ulcer every year in India alone.4Gupta N. Tandon R. Gupta S.K. et al.Burden of corneal blindness in India.Indian J Community Med. 2013; 38: 198-206Crossref PubMed Scopus (1) Google Scholar, 5Gonzales C.A. Srinivasan M. Whitcher J.P. Smolin G. Incidence of corneal ulceration in Madurai district, South India.Ophthalmic Epidemiol. 1996; 3: 159-166Crossref PubMed Google Scholar In the United States, infectious keratitis often is associated with contact lens wear,6Dart J.K. Stapleton F. Minassian D. Contact lenses and other risk factors in microbial keratitis.Lancet. 1991; 338: 650-653Abstract PubMed Scopus (296) Google Scholar, 7Green M. Apel A. Stapleton F. Risk factors and causative organisms in microbial keratitis.Cornea. 2008; 27: 22-27Crossref PubMed Scopus (0) Google Scholar, 8Keay L. Stapleton F. Schein O. Epidemiology of contact lens-related inflammation and microbial keratitis: a 20-year perspective.Eye Contact Lens. 2007; 33 (discussion 362-363): 346-353Crossref PubMed Scopus (35) Google Scholar but in developing countries it is more commonly caused by ocular trauma sustained during agricultural work.9Thylefors B. Epidemiological patterns of ocular trauma.Aust N Z J Ophthalmol. 1992; 20: 95-98Crossref PubMed Google Scholar, 10Sheng X.L. Li H.P. Liu Q.X. et al.Prevalence and associated factors of corneal blindness in Ningxia in northwest China.Int J Ophthalmol. 2014; 7: 557-562PubMed Google Scholar, 11Saha S. Banerjee D. Khetan A. Sengupta J. Epidemiological profile of fungal keratitis in urban population of West Bengal, India.Oman J Ophthalmol. 2009; 2: 114-118Crossref PubMed Google Scholar, 12Nirmalan P.K. Katz J. Tielsch J.M. et al.Ocular trauma in a rural south Indian population: the Aravind Comprehensive Eye Survey.Ophthalmology. 2004; 111: 1778-1781Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In this review, we explore the current literature and future directions of the diagnosis and treatment of infectious keratitis. Proper diagnosis of keratitis is essential to determining treatment and achieving resolution of infection. The mainstay in diagnosis is still Gram stain and culture of corneal samples despite imperfect sensitivity.13McLeod S.D. 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: 23-28Abstract Full Text PDF PubMed Google Scholar, 14Kim E. Chidambaram J.D. Srinivasan M. et al.Prospective comparison of microbial culture and polymerase chain reaction in the diagnosis of corneal ulcer.Am J Ophthalmol. 2008; 146 (723.e711): 714-723Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 15Chang H.Y. Chodosh J. Diagnostic and therapeutic considerations in fungal keratitis.Int Ophthalmol Clin. 2011; 51: 33-42Crossref PubMed Scopus (0) Google Scholar Gram and Giemsa stains are advantageous because they provide instant results, with Gram stain accurately detecting the causative organism 60% to 75% of the time in bacterial cases and 35% to 90% in fungal cases. Giemsa has a sensitivity of 40% to 85% for diagnosing fungal cases.16Badiee P. Nejabat M. Alborzi A. et al.Comparative study of Gram stain, potassium hydroxide smear, culture and nested PCR in the diagnosis of fungal keratitis.Ophthalmic Res. 2010; 44: 251-256Crossref PubMed Scopus (0) Google Scholar, 17Zhang W. Yang H. Jiang L. et al.Use of potassium hydroxide, Giemsa and calcofluor white staining techniques in the microscopic evaluation of corneal scrapings for diagnosis of fungal keratitis.J Int Med Res. 2010; 38: 1961-1967Crossref PubMed Google Scholar, 18Gopinathan U. Sharma S. Garg P. Rao G.N. Review of epidemiological features, microbiological diagnosis and treatment outcome of microbial keratitis: experience of over a decade.Indian J Ophthalmol. 2009; 57: 273-279Crossref PubMed Scopus (121) Google Scholar Blood and chocolate agar are most commonly used to culture bacteria, whereas Sabouraud's agar or potato dextrose are best for isolating fungus, and non-nutrient agar with Escherichia coli overlay can be used to culture Acanthamoeba. Thioglycollate broth is another option to identify aerobic or facultatively anaerobic bacteria, but contamination is a problem, and often it is difficult to determine whether isolated organisms are the cause of infection.19American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern GuidelinesBacterial Keratitis. American Academy of Ophthalmology, San Francisco, CA2013Google Scholar Viral keratitis is diagnosed largely on clinical examination because of its characteristic dendritic appearance,20Darougar S. Wishart M.S. Viswalingam N.D. Epidemiological and clinical features of primary herpes simplex virus ocular infection.Br J Ophthalmol. 1985; 69: 2-6Crossref PubMed Google Scholar but polymerase chain reaction is sometimes used to confirm diagnosis with high sensitivity.21El-Aal A.M. El Sayed M. Mohammed E. et al.Evaluation of herpes simplex detection in corneal scrapings by three molecular methods.Curr Microbiol. 2006; 52: 379-382Crossref PubMed Scopus (0) Google Scholar There is still substantial room for exploration of novel methods of diagnosing infectious keratitis. In vivo confocal microscopy has grown in popularity in recent years because of its rapidity and high sensitivity in detecting larger organisms, such as filamentous fungus, acanthamoeba, and Nocardia bacteria (Fig 1).22Nielsen E. Heegaard S. Prause J.U. et al.Fungal keratitis—improving diagnostics by confocal microscopy.Case Rep Ophthalmol. 2013; 4: 303-310Crossref PubMed Scopus (0) Google Scholar, 23Avunduk A.M. Beuerman R.W. Varnell E.D. Kaufman H.E. Confocal microscopy of Aspergillus fumigatus keratitis.Br J Ophthalmol. 2003; 87: 409-410Crossref PubMed Scopus (0) Google Scholar, 24Das S. Samant M. Garg P. et al.Role of confocal microscopy in deep fungal keratitis.Cornea. 2009; 28: 11-13Crossref PubMed Scopus (19) Google Scholar, 25Kanavi M.R. Javadi M. Yazdani S. Mirdehghanm S. Sensitivity and specificity of confocal scan in the diagnosis of infectious keratitis.Cornea. 2007; 26: 782-786Crossref PubMed Scopus (58) Google Scholar, 26Vaddavalli P.K. Garg P. Sharma S. et al.Role of confocal microscopy in the diagnosis of fungal and acanthamoeba keratitis.Ophthalmology. 2011; 118: 29-35Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar Anterior segment optical coherence tomography has been used more recently to provide an objective measure of corneal infiltrate or scar size or to monitor corneal thinning during treatment.27Konstantopoulos A. Kuo J. Anderson D. Hossain P. Assessment of the use of anterior segment optical coherence tomography in microbial keratitis.Am J Ophthalmol. 2008; 146: 534-542Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 28Martone G. Pichierri P. Franceschini R. et al.In vivo confocal microscopy and anterior segment optical coherence tomography in a case of alternaria keratitis.Cornea. 2011; 30: 449-453Crossref PubMed Scopus (0) Google Scholar In the United States, bacterial keratitis is most associated with contact lens use.19American Academy of Ophthalmology Cornea/External Disease Panel. Preferred Practice Pattern GuidelinesBacterial Keratitis. American Academy of Ophthalmology, San Francisco, CA2013Google Scholar Severe cases can progress rapidly and cause permanent vision loss requiring corneal transplantation. Topical antibiotics remain the first-line treatment for bacterial keratitis. Clinicians weigh many factors when choosing an antibiotic regimen, including broad-spectrum coverage, toxicity, availability and cost, and region-specific epidemiology of pathogens and resistance patterns. Indeed, a recent international survey of cornea specialists found that concerns over several of these factors were predictive of antibiotic choice.29Austin A, Schallhorn J, Geske M, et al. Empiric treatment of bacterial keratitis: an international survey of corneal specialists. Br J Ophthalmol Open. [Accepted for publication].Google Scholar A recent Cochrane-style review of high-quality, randomized, controlled, clinical trials on the management of bacterial keratitis with topical antibiotics identified 16 trials comparing 2 or more topical antibiotics over at least 7 days. McDonald et al30McDonald E.M. Ram F.S. Patel D.V. McGhee C.N. Topical antibiotics for the management of bacterial keratitis: an evidence-based review of high quality randomised controlled trials.Br J Ophthalmol. 2014; 98: 1470-1477Crossref PubMed Scopus (0) Google Scholar found no significant difference in the relative risk of treatment success defined as complete re-epithelialization of the cornea or on time to cure. Although there was an increase in the relative risk of minor adverse events, such as ocular discomfort or chemical conjunctivitis with aminoglycoside-cephalosporin compared with fluoroquinolones, there was no difference in serious complications.30McDonald E.M. Ram F.S. Patel D.V. McGhee C.N. Topical antibiotics for the management of bacterial keratitis: an evidence-based review of high quality randomised controlled trials.Br J Ophthalmol. 2014; 98: 1470-1477Crossref PubMed Scopus (0) Google Scholar, 31Constantinou M. Daniell M. Snibson G.R. et al.Clinical efficacy of moxifloxacin in the treatment of bacterial keratitis: a randomized clinical trial.Ophthalmology. 2007; 114: 1622-1629Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 32O'Brien T.P. Maguire M.G. Fink N.E. et al.Efficacy of ofloxacin vs. cefazolin and tobramycin in the therapy for bacterial keratitis. Report from the Bacterial Keratitis Study Research Group.Arch Ophthalmol. 1995; 113: 1257-1265Crossref PubMed Google Scholar, 33Hyndiuk R.A. Eiferman R.A. Caldwell D.R. et al.Comparison of ciprofloxacin ophthalmic solution 0.3% to fortified tobramycin-cefazolin in treating bacterial corneal ulcers. Ciprofloxacin Bacterial Keratitis Study Group.Ophthalmology. 1996; 103: 1854-1863Abstract Full Text PDF PubMed Google Scholar, 34Ofloxacin monotherapy for the primary treatment of microbial keratitis: a double-masked, randomized, controlled trial with conventional dual therapy.Ophthalmology. 1997; 104 (The Ofloxacin Study Group.): 1902-1909Abstract Full Text PDF PubMed Google Scholar Bacterial ulcers are usually responsive to treatment with available topical antibiotic drops, an increase in the rates of antibiotic-resistant infections such as methicillin-resistant Staphylococcus aureus in North America has caused concern. The US Centers for Disease Control and Prevention estimates that 2 million people are infected with drug-resistant microbes each year.35Team E.E. CDC publishes report on antibiotic resistance threats in the United States for the first time.Eurosurveillance. 2013; 18 (28-28)Google Scholar Approximately 80% of ocular isolates of methicillin-resistant Staphylococcus aureus in the United States have been reported to be resistant to the most commonly prescribed antibiotic class, the fluoroquinolones.36Asbell P.A. Colby K.A. Deng S. et al.Ocular TRUST: nationwide antimicrobial susceptibility patterns in ocular isolates.Am J Ophthalmol. 2008; 145: 951-958Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar, 37Haas W. Pillar C.M. Torres M. et al.Monitoring antibiotic resistance in ocular microorganisms: results from the Antibiotic Resistance Monitoring in Ocular micRorganisms (ARMOR) 2009 surveillance study.Am J Ophthalmol. 2011; 152: 567-574.e563Abstract Full Text Full Text PDF PubMed Scopus (69) Google Scholar, 38Alster Y. Herlin L. Lazar M. Loewenstein A. Intraocular penetration of vancomycin eye drops after application to the medial canthus with closed lids.Br J Ophthalmol. 2000; 84: 300-302Crossref PubMed Scopus (0) Google Scholar In the Steroids for Corneal Ulcer Trial (SCUT), in vitro susceptibility was correlated with clinical outcomes.39Ray K.J. Prajna L. Srinivasan M. et al.Fluoroquinolone treatment and susceptibility of isolates from bacterial keratitis.JAMA Ophthalmol. 2013; 131: 310-313Crossref PubMed Scopus (0) Google Scholar, 40Oldenburg C.E. Lalitha P. Srinivasan M. et al.Moxifloxacin susceptibility mediates the relationship between causative organism and clinical outcome in bacterial keratitis.Invest Ophthalmol Vis Sci. 2013; 54: 1522-1526Crossref PubMed Scopus (0) Google Scholar, 41Lalitha 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: 1381-1387Crossref PubMed Scopus (0) Google Scholar Therefore, corneal culture and sensitivity testing are recommended for all corneal ulcers. Assessing response to treatment is critical, and if the patient appears to be worsening on treatment, one can consider switching to fortified broad-spectrum antibiotics if the initial therapy was fluoroquinolone monotherapy. However, if initial therapy was with a broad-spectrum fortified antibiotic, toxicity from the drops can become the most important factor affecting healing, and reducing therapy is often advised. Even when bacterial ulcer pathogens are susceptible to available topical antibiotics, clinical outcomes can be poor secondary to irregular astigmatism and corneal opacity. Therefore, investigating factors that mitigate the inflammatory response to infection, which results in corneal melting and subsequent scarring, may be the way to have the greatest impact on clinical outcomes in bacterial keratitis. During acute infection fibroblasts, keratocytes and other inflammatory cells secrete enzymes, such as collagenases and matrix metalloproteinases, that are involved in protein degradation and keratolysis. Directing therapy toward stabilization of corneal melting may reduce the incidence of severe complications of infectious keratitis, such as corneal perforation and the need for therapeutic penetrating keratoplasty. Tetracyclines have been shown to inhibit collagenase and have demonstrated antimetalloproteinase activity in vitro.42Burns F.R. Stack M.S. Gray R.D. Paterson C.A. Inhibition of purified collagenase from alkali-burned rabbit corneas.Invest Ophthalmol Vis Sci. 1989; 30: 1569-1575PubMed Google Scholar, 43Golub L.M. Sorsa T. Lee H.M. et al.Doxycycline inhibits neutrophil (PMN)-type matrix metalloproteinases in human adult periodontitis gingiva.J Clin Periodontol. 1995; 22: 100-109Crossref PubMed Google Scholar, 44Dursun D. Kim M.C. Solomon A. Pflugfelder S.C. Treatment of recalcitrant recurrent corneal erosions with inhibitors of matrix metalloproteinase-9, doxycycline and corticosteroids.Am J Ophthalmol. 2001; 132: 8-13Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar In one laboratory study, alkali-induced corneal ulceration in rabbits was dramatically reduced from 85% to 9% in those randomized to high-dose systemic tetracycline administration.45Seedor J.A. Perry H.D. McNamara T.F. et al.Systemic tetracycline treatment of alkali-induced corneal ulceration in rabbits.Arch Ophthalmol. 1987; 105: 268-271Crossref PubMed Google Scholar In another rabbit study, systemic doxycycline reduced the rate of corneal perforation in pseudomonas ulcers by approximately 50%.46Levy J.H. Katz H.R. Effect of systemic tetracycline on progression of Pseudomonas aeruginosa keratitis in the rabbit.Ann Ophthalmol. 1990; 22: 179-183PubMed Google Scholar Unfortunately, there are no high-quality randomized controlled trials in humans to guide clinicians in the use of adjuvant doxycycline for the treatment of corneal ulceration despite its widespread use among corneal specialists. The use of adjuvant corticosteroids has long been debated in the treatment of bacterial keratitis.47Acharya N.R. Srinivasan M. Mascarenhas J. et al.The steroid controversy in bacterial keratitis.Arch Ophthalmol. 2009; 127: 1231Crossref PubMed Scopus (0) Google Scholar, 48Cohen E.J. The case against the use of steroids in the treatment of bacterial keratitis.Arch Ophthalmol. 2009; 127: 103-104Crossref PubMed Scopus (0) Google Scholar, 49Hindman H.B. Patel S.B. Jun A.S. Rationale for adjunctive topical corticosteroids in bacterial keratitis.Arch Ophthalmol. 2009; 127: 97-102Crossref PubMed Scopus (0) Google Scholar Proponents of the use of corticosteroids argue that they improve outcomes by decreasing inflammation, thereby reducing scarring, neovascularization, and stromal melt.49Hindman H.B. Patel S.B. Jun A.S. Rationale for adjunctive topical corticosteroids in bacterial keratitis.Arch Ophthalmol. 2009; 127: 97-102Crossref PubMed Scopus (0) Google Scholar, 50Den S. Sotozono C. Kinoshita S. Ikeda T. Efficacy of early systemic betamethasone or cyclosporin A after corneal alkali injury via inflammatory cytokine reduction.Acta Ophthalmol Scand. 2004; 82: 195-199Crossref PubMed Scopus (20) Google Scholar, 51Yi K. Chung T.Y. Hyon J.Y. et al.Combined treatment with antioxidants and immunosuppressants on cytokine release by human peripheral blood mononuclear cells—chemically injured keratocyte reaction.Mol Vis. 2011; 17: 2665-2671PubMed Google Scholar, 52Williams R.N. Paterson C.A. 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: 191-198Crossref PubMed Google Scholar However, others argue that corticosteroids delay epithelial healing and may even worsen infection.53Chung 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: 537-545Crossref PubMed Scopus (0) Google Scholar, 54Tomas-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: 135-138Crossref PubMed Google Scholar, 55Gritz D.C. Kwitko S. Trousdale M.D. et al.Recurrence of microbial keratitis concomitant with antiinflammatory treatment in an animal model.Cornea. 1992; 11: 404-408Crossref PubMed Google Scholar, 56Gritz D.C. Lee T.Y. Kwitko S. McDonnell P.J. Topical anti-inflammatory agents in an animal model of microbial keratitis.Arch Ophthalmol. 1990; 108: 1001-1005Crossref PubMed Google Scholar A recent Cochrane review of adjuvant topical steroids for bacterial keratitis identified 4 randomized controlled trials comparing adjuvant steroids with topical antibiotics alone.57Herretes S. Wang X. Reyes J.M. Topical corticosteroids as adjunctive therapy for bacterial keratitis.Cochrane Database Syst Rev. 2014; : CD005430PubMed Google Scholar Three small randomized controlled trials examining the benefit of adjuvant topical steroids for the treatment of corneal ulcers found no difference in visual acuity outcomes or healing times between those randomized to topical antibiotic alone and those randomized to topical antibiotic plus topical steroid.58Blair 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: 40-45Abstract Full Text PDF PubMed Scopus (0) Google Scholar, 59Carmichael T.R. Gelfand Y. Welsh N.H. Topical steroids in the treatment of central and paracentral corneal ulcers.Br J Ophthalmol. 1990; 74: 528-531Crossref PubMed Google Scholar, 60Srinivasan M. Lalitha P. Mahalakshmi R. et al.Corticosteroids for bacterial corneal ulcers.Br J Ophthalmol. 2009; 93: 198-202Crossref PubMed Scopus (0) Google Scholar The fourth and largest randomized controlled trial to investigate the role of steroids in the treatment of bacterial ulcers to date was SCUT. SCUT was a randomized, double-masked, placebo-controlled clinical trial that compared adjunctive topical corticosteroids with placebo in the treatment of bacterial corneal ulcers.61Srinivasan M. Mascarenhas J. Rajaraman R. et al.Corticosteroids for bacterial keratitis: the Steroids for Corneal Ulcers Trial (SCUT).Arch Ophthalmol. 2012; 130: 143-150Crossref PubMed Scopus (0) Google Scholar A total of 500 study participants with culture-positive bacterial ulcers were enrolled at Aravind Eye Hospitals in Madurai, Coimbatore, and Tirunelveli, India, the University of California, San Francisco, and the Dartmouth-Hitchcock Medical Center in New Hampshire. Patients were randomized to receive topical prednisolone sodium phosphate 1.0% or topical placebo starting after a 48-hour course of topical moxifloxacin 0.5%. Despite the overall data showing no difference in outcomes such as 3-month visual acuity, 3-month scar size, or rate of perforation between the corticosteroid and placebo groups, subgroup analyses suggested that corticosteroids are beneficial in certain subgroups. Patients with low vision (counting fingers or worse) at baseline had 1.7 lines better vision at 3 months in the corticosteroid group compared with the placebo group (P = 0.03). Central ulcers, covering the central 4-mm pupil, that were treated with corticosteroids also had better 3-month best spectacle-corrected visual acuity (BSCVA) compared with placebo (∼2 lines better; P = 0.02). Likewise, patients with deep ulcers at baseline fared better with topical steroids (1.5 lines better; P = 0.07). Timing of steroid administration also proved to be a significant factor, with patients randomized to corticosteroids after only 2 to 3 days of antibiotics having better BSCVA at 3 months than those randomized to placebo (∼1 line better BSCVA; P = 0.01).62Ray K.J. Srinivasan M. Mascarenhas J. et al.Early addition of topical corticosteroids in the treatment of bacterial keratitis.JAMA Ophthalmol. 2014; 132: 737-741Crossref PubMed Scopus (8) Google Scholar Evidence from SCUT subgroup analyses also revealed organism subtype to be an important factor to consider when initiating adjuvant topical steroids in bacterial ulcers. Nocardia, a partially acid-fast atypical bacteria, represented 10% of all ulcers in SCUT. Nocardia ulcers randomized to corticosteroids had 0.40 mm larger infiltrate or scar size at 3 months compared with placebo (P = 0.03), although this did not result in worse 3-month BSCVA (P = 0.21) (Fig 2).63Lalitha P. Srinivasan M. Rajaraman R. et al.Nocardia keratitis: clinical course and effect of corticosteroids.Am J Ophthalmol. 2012; 154: 934-939.e931Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar This trend continued at 12 months, with non-Nocardia ulcers faring better with corticosteroids (1 line improvement of BSCVA; P = 0.02) and Nocardia ulcers faring worse (average scar size increased by 0.47 mm; P = 0.02; no difference in BSCVA).64Srinivasan 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: 327-333.e323Abstract Full Text Full Text PDF PubMed Google Scholar Overall, Pseudomonas aeruginosa ulcers did not benefit from the addition of corticosteroids; however, the classically invasive subtype of P. aeruginosa demonstrated 2.5 lines of visual acuity improvement at 3-month BSCVA when randomized to steroids versus placebo (Fig 3).65Borkar D.S. Fleiszig S.M. Leong C. et al.Association between cytotoxic and invasive Pseudomonas aeruginosa and clinical outcomes in bacterial keratitis.JAMA Ophthalmol. 2013; 131: 147-153Crossref PubMed Scopus (0) Google ScholarFigure 3A 67-year-old male manual laborer enrolled in the Steroids for Corneal Ulcer Trial (SCUT) whose ulcer was culture positive for Pseudomonas aeruginosa was randomized to adjuvant corticosteroids. A, At enrollment, his visual acuity was logMAR 1.7 (Snellen counting fingers). B, At 3 weeks, his visual acuity was logMAR 0.62 (Snellen ∼20/83). C, At 12 months, his visual acuity further improved to 0.24 logMAR (Snellen ∼20/35) with contact lens over refraction.View Large Image Figure ViewerDownload Hi-res
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