Meenakshi Ravindran

Corticosteroids for Bacterial Keratitis: The Steroids for Corneal Ulcers Trial (SCUT)

OBJECTIVE To determine whether there is a benefit in clinical outcomes with the use of topical corticosteroids as adjunctive therapy in the treatment of bacterial corneal ulcers. METHODS Randomized, placebo-controlled, double-masked, multicenter clinical trial comparing prednisolone sodium phosphate, 1.0%, to placebo as adjunctive therapy for the treatment of bacterial corneal ulcers. Eligible patients had a culture-positive bacterial corneal ulcer and received topical moxifloxacin for at least 48 hours before randomization. MAIN OUTCOME MEASURES The primary outcome was best spectacle-corrected visual acuity (BSCVA) at 3 months from enrollment. Secondary outcomes included infiltrate/scar size, reepithelialization, and corneal perforation. RESULTS Between September 1, 2006, and February 22, 2010, 1769 patients were screened for the trial and 500 patients were enrolled. No significant difference was observed in the 3-month BSCVA (-0.009 logarithm of the minimum angle of resolution [logMAR]; 95% CI, -0.085 to 0.068; P = .82), infiltrate/scar size (P = .40), time to reepithelialization (P = .44), or corneal perforation (P > .99). A significant effect of corticosteroids was observed in subgroups of baseline BSCVA (P = .03) and ulcer location (P = .04). At 3 months, patients with vision of counting fingers or worse at baseline had 0.17 logMAR better visual acuity with corticosteroids (95% CI, -0.31 to -0.02; P = .03) compared with placebo, and patients with ulcers that were completely central at baseline had 0.20 logMAR better visual acuity with corticosteroids (-0.37 to -0.04; P = .02). CONCLUSIONS We found no overall difference in 3-month BSCVA and no safety concerns with adjunctive corticosteroid therapy for bacterial corneal ulcers. APPLICATION TO CLINICAL PRACTICE Adjunctive topical corticosteroid use does not improve 3-month vision in patients with bacterial corneal ulcers. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00324168.

Pseudomonas aeruginosa Keratitis: Outcomes and Response to Corticosteroid Treatment

PURPOSE To compare the clinical course and effect of adjunctive corticosteroid therapy in Pseudomonas aeruginosa with those of all other strains of bacterial keratitis. METHODS Subanalyses were performed on data collected in the Steroids for Corneal Ulcers Trial (SCUT), a large randomized controlled trial in which patients were treated with moxifloxacin and were randomly assigned to 1 of 2 adjunctive treatment arms: corticosteroid or placebo (4 times a day with subsequent reduction). Multivariate analysis was used to determine the effect of predictors, organism, and treatment on outcomes, 3-month best-spectacle-corrected visual acuity (BSCVA), and infiltrate/scar size. The incidence of adverse events over a 3-month follow-up period was compared using Fishers exact test. RESULTS SCUT enrolled 500 patients. One hundred ten patients had P. aeruginosa ulcers; 99 of 110 (90%) enrolled patients returned for follow-up at 3 months. Patients with P. aeruginosa ulcers had significantly worse visual acuities than patients with other bacterial ulcers (P = 0.001) but showed significantly more improvement in 3-month BSCVA than those with other bacterial ulcers, adjusting for baseline characteristics (-0.14 logMAR; 95% confidence interval, -0.23 to -0.04; P = 0.004). There was no significant difference in adverse events between P. aeruginosa and other bacterial ulcers. There were no significant differences in BSCVA (P = 0.69), infiltrate/scar size (P = 0.17), and incidence of adverse events between patients with P. aeruginosa ulcers treated with adjunctive corticosteroids and patients given placebo. CONCLUSIONS Although P. aeruginosa corneal ulcers have a more severe presentation, they appear to respond better to treatment than other bacterial ulcers. The authors did not find a significant benefit with corticosteroid treatment, but they also did not find any increase in adverse events. (ClinicalTrials.gov number, NCT00324168.).

The Steroids for Corneal Ulcers Trial: Study Design and Baseline Characteristics

OBJECTIVES To provide comprehensive trial methods and baseline data for the Steroids for Corneal Ulcers Trial and to present epidemiological characteristics such as risk factors, causative organisms, and ulcer severity. METHODS Baseline data from a 1:1 randomized, placebo-controlled, double-masked clinical trial comparing prednisolone phosphate, 1%, with placebo as adjunctive therapy for the treatment of bacterial corneal ulcers. Eligible patients had a culture-positive bacterial corneal ulcer and had been taking moxifloxacin for 48 hours. The primary outcome for the trial is best spectacle-corrected visual acuity at 3 months from enrollment. This report provides comprehensive baseline data, including best spectacle-corrected visual acuity, infiltrate size, microbiological results, and patient demographics, for patients enrolled in the trial. RESULTS Of 500 patients enrolled, 97% were in India. Two hundred twenty patients (44%) were agricultural workers. Median baseline visual acuity was 0.84 logMAR (Snellen, 20/125) (interquartile range, 0.36-1.7; Snellen, 20/50 to counting fingers). Baseline visual acuity was not significantly different between the United States and India. Ulcers in India had larger infiltrate/scar sizes (P = .04) and deeper infiltrates (P = .04) and were more likely to be localized centrally (P = .002) than ulcers enrolled in the United States. Gram-positive bacteria were the most common organisms isolated from the ulcers (n = 366, 72%). CONCLUSIONS The Steroids for Corneal Ulcers Trial will compare the use of a topical corticosteroid with placebo as adjunctive therapy for bacterial corneal ulcers. Patients enrolled in this trial had diverse ulcer severity and on average significantly reduced visual acuity at presentation. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00324168.

Relationship of In Vitro Susceptibility to Moxifloxacin and In Vivo Clinical Outcome in Bacterial Keratitis

BACKGROUND For bacterial infections, the susceptibility to antibiotics in vitro has been associated with clinical outcomes in vivo, although the importance of minimum inhibitory concentration (MIC) has been debated. In this study, we analyzed the association of MIC on clinical outcomes in bacterial corneal ulcers, while controlling for organism and severity of disease at presentation. METHODS Data were collected as part of a National Eye Institute-funded, randomized, controlled trial (the Steroids for Corneal Ulcers Trial [SCUT]). All cases enrolled in SCUT had a culture-positive bacterial corneal ulcer and received moxifloxacin. The MIC to moxifloxacin was measured by E test. Outcomes included best spectacle-corrected visual acuity, infiltrate/scar size, time to re-epithelialization, and corneal perforation. RESULTS Five hundred patients with corneal ulcers were enrolled in the trial, and 480 were included in this analysis. The most commonly isolated organisms were Streptococcus pneumoniae and Pseudomonas aeruginosa. A 2-fold increase in MIC was associated with an approximately 0.02 logMAR decrease in visual acuity at 3 weeks, approximately 1 letter of vision loss on a Snellen chart (0.019 logMAR; 95% confidence interval [CI], .0040-.033; P = .01). A 2-fold increase in MIC was associated with an approximately 0.04-mm larger infiltrate/scar size at 3 weeks (0.036 mm; 95% CI, .010-.061; P = .006). After controlling for organism, a higher MIC was associated with slower time to re-epithelialization (hazards ratio, 0.92; 95% CI, .86-.97; P = .005). CONCLUSIONS In bacterial keratitis, a higher MIC to the treating antibiotic is significantly associated with worse clinical outcomes, with approximately 1 line of vision loss per 32-fold increase in MIC. CLINICAL TRIALS REGISTRATION NCT00324168.

Rubella serosurveys at three Aravind Eye Hospitals in Tamil Nadu, India

OBJECTIVE To determine the susceptibility of female eye hospital staff to rubella infection and the potential risk for hospital-based rubella outbreaks. METHODS A prospective cohort study on the seroprevalence of rubella IgG antibodies was conducted at three large eye hospitals in Coimbatore, Madurai and Tirunelveli, Tamil Nadu, India, where young children with eye abnormalities attributable to congenital rubella are treated. A total of 1000 female hospital employees aged 18-40 years agreed to participate and gave written informed consent. FINDINGS The proportions of rubella-seronegative women were: 11.7% at Coimbatore, with a 95% confidence interval (CI) of 8.1-16.5; 15% at Madurai (95% CI = 12.3-18.1), and 20.8 at Tirunelveli (95% CI = 14.7-28.6). For the entire cohort the proportion seronegative was significantly higher among married women (21.5%) than among single women (14.0%) (P = 0.02). Rates of seronegativity were highest among physicians and lowest among housekeepers. All 150 seronegative women in the study sample accepted a dose of rubella vaccine. CONCLUSION These are the first rubella serosurveys to have been reported from eye hospitals in any country. The relatively high rate of susceptibility indicated a risk of a rubella outbreak, and this was reduced by vaccinating all seronegative women. A policy has been established at all three hospitals for the provision of rubella vaccine to new employees. Other hospitals, especially eye hospitals and hospitals in countries without routine rubella immunization, should consider the rubella susceptibility of staff and the risk of hospital-based rubella outbreaks.

Nocardia Keratitis: Clinical Course and Effect of Corticosteroids

PURPOSE To compare the clinical course of Nocardia species keratitis with keratitis resulting from other bacterial organisms and to assess the effect of corticosteroids as adjunctive therapy using data collected from the Steroids for Corneal Ulcers Trial. DESIGN Subgroup analysis of a randomized controlled trial. METHODS setting: Multicenter randomized controlled trial. study population: Five hundred patients with bacterial keratitis randomized 1:1 to topical corticosteroid or placebo who had received at least 48 hours of topical moxifloxacin. intervention/observation procedure: Topical prednisolone phosphate 1% or placebo and clinical course of Nocardia keratitis. main outcome measures: Best spectacle-corrected visual acuity and infiltrate or scar size at 3 months from enrollment. RESULTS Of 500 patients enrolled in the trial, 55 (11%) had a Nocardia corneal ulcer. Patients with Nocardia ulcers had better presentation visual acuity compared with non-Nocardia ulcers (median Snellen visual acuity, 20/45, compared with 20/145; P < .001) and comparable 3-month visual acuity (median, 20/25, vs 20/40; P = .25). Nocardia ulcers had approximately 2 lines less of improvement in visual acuity compared with non-Nocardia ulcers (0.21 logarithm of the minimal angle of resolution; 95% confidence interval, 0.09 to 0.33 logarithm of the minimal angle of resolution; P = .001). This difference may reflect the better starting visual acuity in patients with Nocardia ulcers. In Nocardia ulcers, corticosteroids were associated with an average 0.4-mm increase in 3-month infiltrate or scar size (95% confidence interval, 0.03 to 0.77 mm; P = .03). CONCLUSIONS Nocardia ulcers responded well to treatment. They showed less overall improvement in visual acuity than non-Nocardia ulcers, but had better presentation acuity. Corticosteroids may be associated with worse outcomes.

The Steroids for Corneal Ulcers Trial (SCUT): Secondary 12-Month Clinical Outcomes of a Randomized Controlled Trial

PURPOSE To determine whether topical corticosteroids as adjunctive therapy for bacterial keratitis improves long-term clinical outcomes. DESIGN Randomized, placebo-controlled, double-masked clinical trial. METHODS This multicenter trial compared 1.0% prednisolone sodium phosphate to placebo in the treatment of bacterial keratitis among 500 patients with culture-positive ulcers receiving 48 hours of moxifloxacin before randomization. The primary endpoint was 3 months from enrollment, and 399 patients were evaluated at 12 months. The outcomes examined were best spectacle-corrected visual acuity (BSCVA) and scar size at 12 months. Based on previous results, regression models with adjustments for baseline status and/or causative organism were used for analysis. RESULTS No significant differences in clinical outcomes by treatment group were seen with the prespecified regression models (BSCVA: -0.04 logMAR, 95% CI, -0.12 to 0.05, P = .39; scar size: 0.03 mm, 95% CI, -0.12 to 0.18, P = .69). A regression model including a Nocardia-treatment arm interaction found corticosteroid use associated with a mean 1-line improvement in BSCVA at 12 months among patients with non-Nocardia ulcers (-0.10 logMAR, 95% CI, -0.19 to -0.02, P = .02). No significant difference was observed in 12-month BSCVA for Nocardia ulcers (0.18 logMAR, 95% CI, -0.04 to 0.41, P = .16). Corticosteroids were associated with larger mean scar size at 12 months among Nocardia ulcers (0.47 mm, 95% CI, 0.06-0.88, P = .02) and no significant difference was identified by treatment for scar size for non-Nocardia ulcers (-0.06 mm, 95% CI, -0.21 to 0.10, P = .46). CONCLUSIONS Adjunctive topical corticosteroid therapy may be associated with improved long-term clinical outcomes in bacterial corneal ulcers not caused by Nocardia species.

Early Addition of Topical Corticosteroids in the Treatment of Bacterial Keratitis

IMPORTANCE Scarring from bacterial keratitis remains a leading cause of visual loss. OBJECTIVE To determine whether topical corticosteroids are beneficial as an adjunctive therapy for bacterial keratitis if given early in the course of infection. DESIGN, SETTING, AND PARTICIPANTS The Steroids for Corneal Ulcers Trial (SCUT) was a randomized, double-masked, placebo-controlled trial that overall found no effect of adding topical corticosteroids to topical moxifloxacin hydrochloride in bacterial keratitis. Here, we assess the timing of administration of corticosteroids in a subgroup analysis of the SCUT. We define earlier administration of corticosteroids (vs placebo) as addition after 2 to 3 days of topical antibiotics and later as addition after 4 or more days of topical antibiotics. MAIN OUTCOMES AND MEASURES We assess the effect of topical corticosteroids (vs placebo) on 3-month best spectacle-corrected visual acuity in patients who received corticosteroids or placebo earlier vs later. Further analyses were performed for subgroups of patients with non-Nocardia keratitis and those with no topical antibiotic use before enrollment. RESULTS Patients treated with topical corticosteroids as adjunctive therapy within 2 to 3 days of antibiotic therapy had approximately 1-line better visual acuity at 3 months than did those given placebo (-0.11 logMAR; 95% CI, -0.20 to -0.02 logMAR; P = .01). In patients who had 4 or more days of antibiotic therapy before corticosteroid treatment, the effect was not significant; patients given corticosteroids had 1-line worse visual acuity at 3 months compared with those in the placebo group (0.10 logMAR; 95% CI, -0.02 to 0.23 logMAR; P = .14). Patients with non-Nocardia keratitis and those having no topical antibiotic use before the SCUT enrollment showed significant improvement in best spectacle-corrected visual acuity at 3 months if corticosteroids were administered earlier rather than later. CONCLUSIONS AND RELEVANCE There may be a benefit with adjunctive topical corticosteroids if application occurs earlier in the course of bacterial corneal ulcers.

Emerging Moxifloxacin Resistance in Pseudomonas aeruginosa Keratitis Isolates in South India

ABSTRACT Purpose: To describe temporal trends in Pseudomonas aeruginosa resistance to moxifloxacin in keratitis isolates from South India. Methods: The Steroids for Corneal Ulcers Trial (SCUT) was a randomized, double-masked, placebo-controlled trial assessing outcomes in patients with culture positive bacterial corneal ulcers randomized to receive prednisolone phosphate or placebo. All patients received moxifloxacin, and susceptibility to moxifloxacin was measured at baseline using Etest. We investigated trends in moxifloxacin susceptibility of P. aeruginosa during 2007, 2008, and 2009 isolated in SCUT in South India. Results: There were 89 P. aeruginosa isolates during 2007, 2008, and 2009 in SCUT that were eligible for this study. There was an increase in the proportion of resistant isolates from 19% in 2007 to 52% in 2009 (p = 0.02, χ2 test for trend). Logistic regression showed that there was a 2-fold increase in odds of resistance per 1 year increase during the study period (odds ratio 2.16, 95% confidence interval 1.09–4.26, p = 0.027). Conclusions: We found a sharp increase in the proportion of isolates that were resistant to moxifloxacin from 2007 to 2009. Further work needs to be done to characterize the nature of this increase.

Differences in Clinical Outcomes in Keratitis Due to Fungus and Bacteria

Retrospective studies have suggested that, compared with bacterial keratitis, fungal keratitis has particularly poor outcomes.1 An unbiased analysis would ideally be performed in a prospective, standardized fashion. Herein, we compare clinical outcomes in ulcers due to bacteria and fungus using data collected from 2 similarly structured prospective clinical trials.2,3