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.

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.

Emerging moxifloxacin resistance in Pseudomonas aeruginosa keratitis isolates in South India.

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, χ(2) 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.

Moxifloxacin susceptibility mediates the relationship between causative organism and clinical outcome in bacterial keratitis.

PURPOSE: Bacterial keratitis is a sight-threatening infection of the cornea that is one of the leading causes of blindness globally. In this report, we analyze the role of moxifloxacin susceptibility in the relationship between causative organisms and clinical outcome in bacteria keratitis. METHODS: A mediation analysis is used to assess the role of moxifloxacin susceptibility in the relationship between causative organisms and clinical outcome in bacterial keratitis using data collected in a randomized, controlled trial. RESULTS: In the Steroids for Corneal Ulcers Trial (SCUT), 500 corneal infections were treated with topical moxifloxacin. The outcome of 3-week best spectacle-corrected visual acuity was significantly associated with an organism (Streptococcus pneumoniae, Pseudomonas aeruginosa, etc., P = 0.008). An indirect effects mediation model suggests that MIC accounted for approximately 13% (95% confidence interval, 3%-24%, P = 0.015) of the effect of the organism on 3-week visual acuity. CONCLUSIONS: Moxifloxacin mediates the relationship between causative organisms and clinical outcome in bacterial keratitis, and is likely on the causal pathway between the organism and outcome. (ClinicalTrials.gov number, NCT00324168.).

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.

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.

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.

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 Fisher's 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.).