Nisha R. Acharya

Comparison of natamycin and voriconazole for the treatment of fungal keratitis.

OBJECTIVE To conduct a therapeutic exploratory clinical trial comparing clinical outcomes of treatment with topical natamycin vs topical voriconazole for fungal keratitis. METHODS The multicenter, double-masked, clinical trial included 120 patients with fungal keratitis at Aravind Eye Hospital in India who were randomized to receive either topical natamycin or topical voriconazole and either had repeated scraping of the epithelium or not. MAIN OUTCOME MEASURES The primary outcome was best spectacle-corrected visual acuity (BSCVA) at 3 months. Other outcomes included scar size, perforations, and a subanalysis of BSCVA at 3 months in patients with an enrollment visual acuity of 20/40 to 20/400. RESULTS Compared with those who received natamycin, voriconazole-treated patients had an approximately 1-line improvement in BSCVA at 3 months after adjusting for scraping in a multivariate regression model but the difference was not statistically significant (P = .29). Scar size at 3 months was slightly greater with voriconazole after adjusting for scraping (P = .48). Corneal perforations in the voriconazole group (10 of 60 patients) were not significantly different than in the natamycin-treated group (9 of 60 patients) (P >.99). Scraping was associated with worse BSCVA at 3 months after adjusting for drug (P = .06). Patients with baseline BSCVA of 20/40 to 20/400 showed a trend toward a 2-line improvement in visual acuity with voriconazole (P = .07). CONCLUSIONS Overall, there were no significant differences in visual acuity, scar size, and perforations between voriconazole- and natamycin-treated patients. There was a trend toward scraping being associated with worse outcomes. Application to Clinical Practice The benefit seen with voriconazole in the subgroup of patients with baseline visual acuity of 20/40 to 20/400 needs to be validated in a confirmatory clinical trial. Trial Registration clinicaltrials.gov Identifier: NCT00557362.

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.

Incidence and Prevalence of Uveitis: Results From the Pacific Ocular Inflammation Study

IMPORTANCE Uveitis is responsible for a significant proportion of legal blindness in the United States. Currently, there are few population-based reports characterizing the epidemiology of uveitis. OBJECTIVE To ascertain the incidence and prevalence of uveitis in a Hawaiian population and compare these estimates with those from prior population-based studies. DESIGN Retrospective, population-based cohort study conducted from January 1, 2006, to December 31, 2007. SETTING Kaiser Permanente Hawaii, a multispecialty managed care organization serving approximately 15% of the general Hawaiian population with locations throughout the Hawaiian islands. PARTICIPANTS All patients enrolled in the Kaiser Permanente Hawaii health plan during the study (N = 217,061). MAIN OUTCOMES AND MEASURES Clinical diagnosis of uveitis, either incident or prevalent, during the study determined by an initial search of the electronic medical record database of Kaiser Permanente Hawaii for uveitis-associated International Classification of Diseases, Ninth Revision diagnosis codes and subsequently confirmed through individual record review by a uveitis specialist. RESULTS Of 217,061 eligible patients, 872 were identified using International Classification of Diseases, Ninth Revision codes and 224 cases of uveitis were confirmed. The overall uveitis incidence rate was 24.9 cases per 100,000 person-years. The annual prevalence rates for 2006 and 2007 were 57.5 and 58.0 per 100,000 persons, respectively. No difference in incidence rate was found by sex (P = .63), but female patients had a higher prevalence (P = .008). Incidence and prevalence increased with older age (P < .001 for incidence and prevalence). Pacific Islanders had a lower prevalence rate than non-Pacific Islanders (2006: P = .09, 2007: P = .04), while white individuals had a higher prevalence rate than nonwhite individuals (2006: P = .07, 2007: P = .01). CONCLUSIONS AND RELEVANCE The incidence and prevalence of uveitis in this population were much lower than in the Northern California Epidemiology of Uveitis Study, but similar to the Northwest Veterans Affairs Study. The results of this study highlight incidence and prevalence estimates in a new population and provide novel comparisons by race. These differences by race raise questions regarding the effects of genetic and environmental influences on the pathophysiology of uveitis.

Ranibizumab for Refractory Uveitis-related Macular Edema

PURPOSE To evaluate the effect of intravitreal ranibizumab injections (Lucentis; Genentech Inc, South San Francisco, California, USA) on refractory cystoid macular edema (CME) in patients with controlled uveitis who have failed oral and regional corticosteroid treatment, the mainstays of current medical therapy. DESIGN Prospective, noncomparative, interventional case series. METHODS Seven consecutive patients with controlled uveitis and refractory CME who had failed corticosteroid treatment were studied. One eligible patient chose not to participate and another did not complete follow-up for nonmedical reasons. Intravitreal ranibizumab injections (0.5 mg) were given monthly for 3 months, followed by reinjection as needed. The primary outcome was the mean change in best spectacle-corrected visual acuity (VA) from baseline to 3 months, and the secondary objective was the mean change in central retinal thickness (CRT) on ocular coherence tomography. Six-month outcomes were also assessed. RESULTS At 3 months, the mean increase in acuity for the 6 patients who completed follow-up was 13 letters (2.5 lines), and the mean decrease in CRT was 357 mum. Both VA and CRT improved significantly between baseline and 3 months (P = .03 for each). Although most patients required reinjection, this benefit was maintained at 6 months. There were no significant ocular or systemic adverse effects. CONCLUSIONS Intravitreal ranibizumab led to an increase in VA and regression of uveitis-associated CME in patients refractory to or intolerant of standard corticosteroid therapy. Further studies of this promising treatment are warranted.

Acanthamoeba keratitis: The Persistence of Cases Following a Multistate Outbreak

Purpose: To describe the trend of Acanthamoeba keratitis case reports following an outbreak and the recall of a multipurpose contact lens disinfection solution. Acanthamoeba keratitis is a serious eye infection caused by the free-living amoeba Acanthamoeba that primarily affects contact lens users. Methods: A convenience sample of 13 ophthalmology centers and laboratories in the USA, provided annual numbers of Acanthamoeba keratitis cases diagnosed between 1999–2009 and monthly numbers of cases diagnosed between 2007–2009. Data on ophthalmic preparations of anti-Acanthamoeba therapies were collected from a national compounding pharmacy. Results: Data from sentinel site ophthalmology centers and laboratories revealed that the yearly number of cases gradually increased from 22 in 1999 to 43 in 2003, with a marked increase beginning in 2004 (93 cases) that continued through 2007 (170 cases; p < 0.0001). The outbreak identified from these sentinel sites resulted in the recall of a contact lens disinfecting solution. There was a statistically significant (p ≤ 0.0001) decrease in monthly cases reported from 28 cases in June 2007 (following the recall) to seven cases in June 2008, followed by an increase (p = 0.0004) in reported cases thereafter; cases have remained higher than pre-outbreak levels. A similar trend was seen in prescriptions for Acanthamoeba keratitis chemotherapy. Cases were significantly more likely to be reported during summer than during other seasons. Conclusion: The persistently elevated number of reported cases supports the need to understand the risk factors and environmental exposures associated with Acanthamoeba keratitis. Further prevention efforts are needed to reduce the number of cases occurring among contact lens wearers.

Identifying a Clinically Meaningful Threshold for Change in Uveitic Macular Edema Evaluated by Optical Coherence Tomography

PURPOSE To identify a clinically meaningful threshold for change in retinal thickness measured by optical coherence tomography for patients with uveitic macular edema using correlation with change in visual acuity. DESIGN Cross-sectional and longitudinal study. METHODS One hundred twenty-eight eyes (101 individuals) with macular edema enrolled in the Multicenter Uveitis Steroid Treatment (MUST) trial. At enrollment and after 6 months of follow-up, retinal thickness was measured at the central subfield with time-domain optical coherence tomography and visual acuity was measured with logarithmic (Early Treatment Diabetic Retinopathy Study) visual acuity charts. Participants were classified as having macular edema if the retinal thickness was 260 μm or more. RESULTS A threshold for change in retinal center subfield thickness of 20% balanced the percentage of false positives and false negatives for predicting more than a 10-letter change in visual acuity with a sensitivity of 77% and a specificity of 75%. The results were similar for more than 5-letter changes and for 15-letter or more changes. Those with a 20% or more reduction in retinal thickness had a mean 11.0-letter improvement (95% confidence interval, 7.7 to 14.3) as compared with a -0.4-letter change (95% confidence interval, -4.1 to 3.3) in visual acuity for those without a 20% reduction (P < .01). CONCLUSIONS In addition to being above the level of measurement uncertainty, a 20% change in retinal thickness in patients with macular edema seems to be optimal for clinically important changes in visual acuity and may be considered as an outcome for clinical trials of treatments for uveitic macular edema.

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.).

Practice patterns in the management of fungal corneal ulcers

Purpose: The purpose of this study was to determine the practice patterns of ophthalmologists in the management of fungal corneal ulcers. Methods: In December 2007, a survey of 13 questions addressing the actual and preferred treatment of fungal ulcers was sent to the kera-net e-mail listserv facilitated by the Cornea Society. Results: Ninety-two respondents from North America, South America, Asia, Europe, and Australia participated by completing the electronic questionnaire. Natamycin was the most commonly used topical treatment for ulcers caused by filamentous fungi (96%) followed by amphotericin (75%) and voriconazole (63%). However, voriconazole was most often listed as the preferred topical treatment in an ideal world (79%) compared with 55% for natamycin. Approximately half of the respondents use combination topical therapy (56%) and the remainder monotherapy. The majority of respondents rescrape the epithelium at some time during the course of treatment, but the frequency of rescraping varied among the different topical treatments. The most common reasons cited for not using their preferred treatment were cost and a desire for further evidence to support preferred treatment. Conclusion: There appears to be significant variation in the management of fungal corneal ulcers. Although natamycin was the most commonly used treatment for ulcers caused by filamentous fungi, voriconazole was the most preferred as the ideal treatment. These results highlight the need for more evidence regarding the efficacy of the newer topical antifungals.

Cigarette smoking as a risk factor for uveitis

PURPOSE To determine the association between tobacco smoking history and uveitis. DESIGN Retrospective, case-control study. PARTICIPANTS A total of 564 patients with ocular inflammation seen in the Proctor Foundation uveitis clinic between 2002 and 2009, and 564 randomly selected patients seen in the comprehensive eye clinic within the same time period. METHODS A retrospective medical record review of all cases and controls. MAIN OUTCOME MEASURES A logistic regression analysis was conducted with ocular inflammation as the main outcome variable and smoking as the main predictor variable, while adjusting for age, gender, race, and median income. RESULTS The odds of a smoker having ocular inflammation were 2.2-fold that of a patient who had never smoked (95% confidence interval [CI], 1.7-3.0; P<0.001). All anatomic subtypes of uveitis were associated with a positive smoking history, with odds ratios (ORs) of 1.7 (95% CI, 1.2-2.4; P = 0.002) for anterior uveitis, 2.7 (95% CI, 1.4-5.6; P = 0.005) for intermediate uveitis, 3.2 (95% CI, 1.3-7.9; P = 0.014) for posterior uveitis, and 3.9 (95% CI, 2.4-6.1; P<0.001) for panuveitis. In patients with panuveitis and cystoid macular edema (CME), the OR was 8.0 (95% CI, 3.3-19.5; P<0.001) compared with 3.1 (95% CI, 1.8-5.2; P<0.001) for patients without CME. Patients with intermediate uveitis and CME also had a higher OR (OR 8.4; 95% CI, 2.5-28.8; P = 0.001) compared with patients without CME (OR 1.5; 95% CI, 0.6-3.8; P = 0.342). Patients with a smoking history were at greater odds of having infectious uveitis (OR 4.5; 95% CI, 2.3-9.0; P<0.001) than noninfectious uveitis (OR 2.1; 95% CI, 1.6-2.8; P<0.001), although both were associated with smoking. CONCLUSIONS A history of smoking is significantly associated with all anatomic subtypes of uveitis and infectious uveitis. The association was greater in patients with intermediate uveitis and panuveitis with CME compared with those without CME. In view of the known risks of smoking, these findings, if replicated, would give an additional reason to recommend smoking cessation in patients with uveitis.

A Randomized Clinical Trial Comparing Methotrexate and Mycophenolate Mofetil for Noninfectious Uveitis

OBJECTIVE To compare the relative effectiveness of methotrexate and mycophenolate mofetil for noninfectious intermediate uveitis, posterior uveitis, or panuveitis. DESIGN Multicenter, block-randomized, observer-masked clinical trial. PARTICIPANTS Eighty patients with noninfectious intermediate, posterior, or panuveitis requiring corticosteroid-sparing therapy at Aravind Eye Hospitals in Madurai and Coimbatore, India. INTERVENTION Patients were randomized to receive 25 mg weekly oral methotrexate or 1 g twice daily oral mycophenolate mofetil and were monitored monthly for 6 months. Oral prednisone and topical corticosteroids were tapered. MAIN OUTCOME MEASURES Masked examiners assessed the primary outcome of treatment success, defined by achieving the following at 5 and 6 months: (1) ≤0.5+ anterior chamber cells, ≤0.5+ vitreous cells, ≤0.5+ vitreous haze and no active retinal/choroidal lesions in both eyes, (2) ≤10 mg of prednisone and ≤2 drops of prednisolone acetate 1% a day, and (3) no declaration of treatment failure because of intolerability or safety. Additional outcomes included time to sustained corticosteroid-sparing control of inflammation, change in best spectacle-corrected visual acuity, resolution of macular edema, adverse events, subgroup analysis by anatomic location, and medication adherence. RESULTS Forty-one patients were randomized to methotrexate and 39 to mycophenolate mofetil. A total of 67 patients (35 methotrexate, 32 mycophenolate mofetil) contributed to the primary outcome. Sixty-nine percent of patients achieved treatment success with methotrexate and 47% with mycophenolate mofetil (P = 0.09). Treatment failure from adverse events or tolerability was not different by treatment arm (P = 0.99). There were no differences between treatment groups in time to corticosteroid-sparing control of inflammation (P = 0.44), change in best spectacle-corrected visual acuity (P = 0.68), or resolution of macular edema (P = 0.31). CONCLUSIONS There was no statistically significant difference in corticosteroid-sparing control of inflammation between patients receiving methotrexate or mycophenolate mofetil. However, there was a 22% difference in treatment success favoring methotrexate.