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Background: Cataract surgery is one of the most common surgical procedures performed in older adults in the United States and is generally considered to be extremely low-risk. As of 2019, routine preoperative evaluation within 30 days of surgery is no longer mandated by the United States of America (USA) Centers for Medicare & Medicaid Services (CMS) for ambulatory surgery centers, but it is unclear how primary care providers perceive this change., Methods: We performed a qualitative analysis of semi-structured interviews with six primary care providers to explore primary care providers' perspectives on routine preoperative assessment for cataract surgery., Results: Primary care providers commented on the large number of referrals they receive for preoperative assessment before cataract procedures. The analysis revealed an overarching sentiment of resentment over the time, effort, and resources expended on these assessments. Themes included the lack of awareness of the updated regulations that no longer require a history and physical to be completed within 30 days and the perception of a universal lack of medical necessity to perform preoperative assessment for cataract surgery. Providers also commented on the strain on limited resources and the burden on patients. The relationship between specialties and professional roles emerged as another important theme., Conclusions: Referrals for preoperative clearance for cataract surgery continue to burden providers, patients, and the health system, and represent an opportunity to streamline care in this patient population., (© 2024. The Author(s).)

Purpose: The Zoster Eye Disease Study (ZEDS) is a multicenter randomized clinical trial (RCT) funded by the National Eye Institute aiming to determine the efficacy of suppressive valacyclovir treatment in herpes zoster ophthalmicus (HZO) that enrolled fewer participants than planned (527/780, 67.6%). Understanding reasons for nonparticipation of likely eligible prescreened patients provides insights into patient populations that are not represented by ZEDS and barriers in clinical trials., Methods: In this retrospective cohort study, HZO adults likely eligible for ZEDS with a history of a typical rash and a medical record within the past year of an episode of epithelial or stromal keratitis or iritis were prescreened at activated Participating Clinical Centers from 2017 to 2022 using a standard prescreening log. De-identified data including demographic information, reasons for exclusion because of ineligibility, and patient refusal were retrospectively entered into REDCap and analyzed., Results: Prescreening logs with reasons for nonconsent (1244/1706, 72.9%) were included in the data set. Patients were excluded from the study (915/1244, 73.6%) because they did not meet all inclusion criteria (619/915, 67.7%) or met an exclusion criterion (296/915, 32.3%). Among the 12 exclusion criteria for the ZEDS study, immunocompromise (76/296, 25.7%) and renal insufficiency (50/296, 16.9%) were most frequently reported. Patient refusal to participate (327/1,244, 26.3%) was common., Conclusion: The most common reasons for ineligibility were immunocompromise and renal insufficiency. There may be benefits to long-term antiviral use in these populations not captured in ZEDS. A quarter (26.3%) of prescreened patients refused participation, showing the substantial impact of patient preferences on trial participation., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2024 Contact Lens Association of Ophthalmologists.)

Purpose: To test cefiderocol, a siderophore-cephalosporin antibiotic for topical monotherapy treatment of experimental extensively drug-resistant (XDR) Pseudomonas aeruginosa keratitis., Design: Preclinical study., Subjects and Controls: Deidentified P. aeruginosa keratitis isolates, XDR P. aeruginosa from eye drop outbreak, rabbits, saline, cefiderocol 50 mg/ml, ciprofloxacin 0.3%, and tobramycin 14 mg/ml., Methods Intervention or Testing: Cefiderocol antibacterial activity against P. aeruginosa keratitis isolates (n = 135) was evaluated by minimum inhibitory concentration (MIC) testing. Ocular toxicity/tolerability and antibacterial efficacy were tested in vivo with experimental rabbit models. Corneal concentrations and stability were assessed using a bioassay., Main Outcome Measures: Minimum inhibitory concentration analysis for susceptibility, graded tests for ocular toxicity/tolerability, colony-forming unit (CFU) analysis for bacterial burden, corneal cefiderocol concentrations., Results: One hundred percent of P. aeruginosa keratitis isolates were susceptible to cefiderocol (n = 135), the MIC 90 was 0.125 μg/ml including the XDR isolate (MIC = 0.125 μg/ml). Topical cefiderocol 50 mg/ml was minimally toxic to the ocular surface and was well tolerated. For the XDR P. aeruginosa isolate, topical cefiderocol 50 mg/ml, significantly decreased corneal CFU compared with ciprofloxacin 0.3%, tobramycin 14 mg/ml, and saline. In addition, tobramycin 14 mg/ml was more effective than the saline control. Mean cefiderocol corneal concentrations were 191× greater than the MIC 90 of the P. aeruginosa keratitis isolates. Refrigerated cefiderocol maintained antimicrobial activity over a 1-month period., Conclusions: These results demonstrate that cefiderocol is well tolerated on rabbit corneas and is effective against P. aeruginosa keratitis isolates in vitro and was effective in vivo against an XDR isolate in a rabbit keratitis model. Given the recent outbreak of keratitis caused by this XDR P. aeruginosa , cefiderocol is a promising additional antibiotic that should be further evaluated for topical treatment of keratitis caused by antibiotic resistant P. aeruginosa ., Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article., (© 2023 by the American Academy of Ophthalmology.)

Introduction: Pseudomonas aeruginosa causes vision threatening keratitis. The LasR transcription factor regulates virulence factors in response to the quorum sensing molecule N-3-oxo-dodecanoyl-L-homoserine lactone. P. aeruginosa isolates with lasR mutations are characterized by an iridescent high sheen phenotype caused by a build-up of 2-heptyl-4-quinolone. A previous study demonstrated 22% (n=101) of P. aeruginosa keratitis isolates from India between 2010 and 2016 were sheen positive lasR mutants, and the sheen phenotype correlated with worse clinical outcomes for patients. In this study, a longitudinal collection of P. aeruginosa keratitis isolates from Eastern North America were screened for lasR mutations by the sheen phenotype and sequencing of the lasR gene., Methods: Keratitis isolates (n=399) were classified by sheen phenotype. The lasR gene was cloned from a subset of isolates, sequenced, and tested for loss of function or dominant-negative status based on an azocasein protease assay. A retrospective chart review compared outcomes of keratitis patients infected by sheen positive and negative isolates., Results: A significant increase in sheen positive isolates was observed between 1993 and 2021. Extracellular protease activity was reduced among the sheen positive isolates and a defined lasR mutant. Cloned lasR alleles from the sheen positive isolates were loss of function or dominant negative and differed in sequence from previously reported ocular lasR mutant alleles. Retrospective analysis of patient information suggested significantly better visual outcomes for patients infected by sheen positive isolates., Discussion: These results indicate an increase in lasR mutations among keratitis isolates in the United States and suggest that endemic lasR mutants can cause keratitis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Shanks, Atta, Stella, Sundar-Raj, Romanowski, Grewal, Shanks, Mumper, Dhaliwal, Mammen, Callaghan, Calvario, Romanowski, Kowalski, Zegans and Jhanji.)

Introduction: Entry into weightlessness results in a fluid shift and a loss of hydrostatic gradients. These factors are believed to affect the eye and contribute to the ocular changes that occur in space. We measured eye parameters during fluid shifts produced by lower body negative pressure (LBNP) and lower body positive pressure (LBPP) and changes in hydrostatic gradient direction (supine-prone) in normal subjects to assess the relative effects of fluid shifts and hydrostatic gradient changes on the eye. Methods: Ocular parameters (intraocular pressure (IOP), ocular geometry, and optical coherence tomography measures) were measured in the seated, supine, and prone positions. To create a fluid shift in the supine and prone positions, the lower body chamber pressure ranged from -40 mmHg to +40 mmHg. Subjects maintained each posture and LBNP/LBPP combination for 15 min prior to data collection. A linear mixed-effects model was used to determine the effects of fluid shifts (as reflected by LBNP/LBPP) and hydrostatic gradient changes (as reflected by the change from seated to supine and from seated to prone) on eye parameters. Results: Chamber pressure was positively correlated with both increased choroidal thickness ( β = 0.11 , p = 0.01) and IOP ( β = 0.06 p < 0.001). The change in posture increased IOP compared to seated IOP (supine β = 2.1, p = 0.01, prone β = 9.5, p < 0.001 prone) but not choroidal thickness. IOP changes correlated with axial length (R = 0.72, p < 0.001). Discussion: The effects of hydrostatic gradients and fluids shifts on the eye were investigated by inducing a fluid shift in both the supine and prone postures. Both hydrostatic gradients (posture) and fluid shifts (chamber pressure) affected IOP, but only hydrostatic gradients affected axial length and aqueous depth. Changes in choroidal thickness were only significant for the fluid shifts. Changes in hydrostatic gradients can produce significant changes in both IOP and axial length. Fluid shifts are often cited as important factors in the pathophysiology of SANS, but the local loss of hydrostatic gradients in the head may also play an important role in these ocular findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Van Akin, Lantz, Fellows, Toutain-Kidd, Zegans, Buckey and Anderson.)

Bacterial keratitis continues to be one of the leading causes of corneal blindness in the developed as well as the developing world, despite swift progress since the dawn of the "anti-biotic era". Although, we have expeditiously developed our understanding about the different causative organisms and associated pathology leading to keratitis, extensive gaps in knowledge continue to dampen the efforts required for early and accurate diagnosis, and management in these patients, resulting in poor clinical outcomes. The ability of the causative bacteria to subdue the therapeutic challenge stems from their large genome encoding complex regulatory networks, variety of unique virulence factors, and rapid secretion of tissue damaging proteases and toxins. In this review article, we provide an overview of the established diagnostic techniques and therapeutics for keratitis caused by various bacteria. We extensively report the recent in-roads through novel tools for accurately diagnosing mono- and poly-bacterial corneal infections. Furthermore, we outline the recent progress by our groups and others in understanding the sub-cellular genomic changes that lead to antibiotic resistance in these organisms. Finally, we discuss in detail, the novel therapies and drug delivery systems in development for the efficacious management of bacterial keratitis., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Importance: Antifungal resistance has been shown to impact treatment success, but research analyzing antifungal resistance is scarce., Objective: To evaluate changes in antifungal resistance over time., Design, Setting, and Participants: Ad hoc analysis of 3 randomized clinical trials including consecutive patients 18 years and older presenting with smear-positive fungal ulcers to Aravind Eye Hospitals in Madurai, Coimbatore, Pondicherry, and Tirunelveli in South India who participated in 1 of 3 clinical trials: the Mycotic Ulcer Treatment Trials (MUTT) I (2010 to 2011) or II (2010 to 2015) or the Cross-Linking Assisted Infection Reduction (CLAIR) trial (2016 to 2018). This post hoc analysis was designed in March 2021 and data were analyzed in May and November 2021., Interventions: Minimum inhibitory concentration (MIC) of natamycin and voriconazole was determined from corneal cultures obtained using standardized methods outlined in the Clinical and Laboratory Standards Institute., Main Outcomes and Measures: The primary outcome of this post hoc analysis was MIC of natamycin and voriconazole., Results: A total of 890 fungal isolates were obtained from 651 patients (mean [SD] age, 49.6 [13.0]; 191 [43.3%] female) from 2010 to 2018. MICs were available for 522 samples in 446 patients. Fungal isolates overall demonstrated a 1.02-fold increase per year in voriconazole resistance as measured by MICs (95% CI, 1.00-1.04; P = .06). In subgroup analyses, Fusarium species demonstrated a 1.04-fold increase in voriconazole resistance per year (95% CI, 1.00-1.06; P = .01). Fungal isolates showed a 1.06-fold increase in natamycin resistance per year overall (95% CI, 1.03-1.09; P < .001). Fusarium species had a 1.06-fold increase in natamycin resistance (95% CI, 1.05-1.08; P < .001), Aspergillus had a 1.09-fold increase in resistance (95% CI, 1.05-1.15; P < .001), and other filamentous fungi had a 1.07-fold increase in resistance to natamycin per year (95% CI, 1.04-1.10; P < .001)., Conclusions and Relevance: This post hoc analysis suggests that susceptibility to both natamycin and voriconazole may be decreasing over the last decade in South India. While a trend of increasing resistance could impact treatment of mycoses in general and infectious fungal keratitis in particular, further study is needed to confirm these findings and determine their generalizability to other regions of the world., Trial Registration: ClinicalTrials.gov Identifiers: NCT00996736 and NCT02570321.

Background: Many dermatopathologists find conjunctival melanocytic proliferations challenging because they are rare relative to their cutaneous counterparts and have nuanced morphology and nomenclature. PRAME immunohistochemistry has been widely adopted for distinguishing cutaneous nevi from melanoma, but limited data exist assessing its utility in evaluating conjunctival specimens. In particular, it is uncertain whether it can predict the risk of melanoma progression in primary acquired melanosis (PAM)., Methods: Thirty clinically annotated cases (two melanomas, three PAM with atypia, seven PAM without atypia, 15 nevi, two combined nevi, and a diagnostically challenging nevus with atypical features) were retrospectively evaluated with PRAME., Results: Strong, diffuse PRAME expression was present in melanomas and PAM with high-grade atypia, but not in PAM with low-grade atypia, PAM without atypia, or nevi. Scattered, faintly PRAME-positive intraepithelial melanocyte nuclei were identified in six nevi. A clonal nevus and nests of heavily pigmented type-A melanocytes in two additional nevi had cytoplasmic staining., Conclusions: PRAME was useful for distinguishing melanoma and its probable precursors from benign conjunctival melanocytic proliferations in our cohort. The data alert us to two diagnostic pitfalls in nevi: scattered, PRAME-positive intraepithelial melanocytes and cytoplasmic PRAME staining in type-A melanocytes and melanophages. Larger scale investigations are warranted to further substantiate these promising findings., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: To report a case series of patients with treatment-resistant Acanthamoeba keratitis (AK) using oral miltefosine, often as salvage therapy., Design: Descriptive, retrospective multicenter case series., Methods: We reviewed 15 patients with AK unresponsive to therapy who were subsequently given adjuvant systemic miltefosine between 2011 and 2017. The main outcome measures were resolution of infection, final visual acuity, tolerance of miltefosine, and clinical course of disease., Results: All patients were treated with biguanides and/or diamidines or azoles without resolution of disease before starting miltefosine. Eleven of 15 patients retained count fingers or better vision, and all were considered disease free at last follow-up. Eleven of 15 patients had worsening inflammation with miltefosine, with 10 of them improving with steroids. Six patients received multiple courses of miltefosine. Most tolerated oral miltefosine well, with mild gastrointestinal symptoms as the most common systemic side effect., Conclusions: Oral miltefosine is a generally well-tolerated treatment adjuvant in patients with refractory AK. The clinician should be prepared for a steroid-responsive inflammatory response frequently encountered during the treatment course., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A worrisome trend in the study and treatment of infectious disease noted in recent years is the increase in multidrug resistant strains of bacteria concurrent with a scarcity of new antimicrobial agents to counteract this rise. This is particularly true amongst bacteria within the Enterococcus faecium , Staphylococcus aureus , Klebsiella pneumoniae , Acinetobacter baumannii , Pseudomonas aeruginosa , and Enterobacter species (ESKAPE) designation. P. aeruginosa is one of the most common causes of bacterial keratitis. Therefore, it is of vital importance to characterize new antimicrobial agents with anti-Pseudomonal activity for use with the ocular surface. MEDI3902 is a multifunctional antibody that targets the P. aeruginosa persistence factor Psl exopolysaccharide, and the type 3 secretion protein PcrV. We initially assessed this antibody for ocular surface toxicity. The antimicrobial activity of the antibody was then tested by treating mice with established P. aeruginosa keratitis with both topical and intravenous treatment modalities. MEDI3902, was shown to be non-toxic to the ocular surface of mice when given topically. It was also effective compared to the control antibody at preventing P. aeruginosa keratitis with a one-time treatment at the time of infection. Both topical and intravenous administration of MEDI3902 has been proved significant in treating established keratitis infections as well, speeding the resolution of infection significantly more than that of the control IgG. We report the first use of a topical immunotherapeutic multifunctional agent targeting Psl and type 3 secretion on the ocular surface as an antimicrobial agent. While MEDI3902 has been shown to prevent Pseudomonas biofilm formation in keratitis models when given prophylactically intravitally, we show that MEDI3902 has the capability to also treat an active infection when given intravenously to mice with Pseudomonas keratitis. Our data indicate antibodies are well tolerated and nontoxic on the ocular surface. They reduce infection in mice treated concurrently at inoculation and reduced the signs of cornea pathology in mice with established infection. Taken together, these data indicate treatment with monoclonal antibodies directed against Psl and PcrV may be clinically effective in the treatment of P. aeruginosa keratitis and suggest that the design of further antibodies to be an additional tool in the treatment of bacterial keratitis.

Purpose of Review: The United States has experienced a dramatic rise in opioid and injection drug use over the past 2 decades. A public health emergency was declared in 2017 and subsequently, there have been several new reports on the rise of endogenous endophthalmitis specifically associated with injection drug use. The purpose of this review is to provide a current perspective of the ocular harms posed by injection drug use., Recent Findings: The opioid epidemic has prompted several new studies from New England, one of the US regions most heavily affected, that examine the trends and characteristics of injection drug use-associated endogenous endophthalmitis. Patients may delay seeking care and may be infected with a variety of rare and atypical microbes, and as a result clinical appearance may vary widely. Injection drug use also leads to embolic phenomena such as talc retinopathy and septic emboli from endocarditis. HIV is highly associated with injection drug use and although HAART has drastically reduced the morbidity and mortality of HIV-associated infections, a variety of ocular disease may accompany an immunocompromised patient., Summary: Healthcare providers must remain vigilant in the recognition of injection drug use patients with vision loss and ocular inflammation to ensure prompt medical and/or surgical treatment.

The in vitro activities of two antifungal drugs in combination with four nonantifungal ophthalmic agents were evaluated using a broth microdilution method and a collection of eight Fusarium ocular isolates that exhibited resistance to both natamycin (MICs, 14 to 32 μg/ml) and voriconazole (MICs, 4 to >128 μg/ml). Synergistic and indifferent interactions were observed for natamycin and 5-fluorouracil and natamycin with timolol dependent on the Fusarium isolate tested. Isolate-dependent synergistic and indifferent interactions were also observed for natamycin with EDTA and natamycin with dorzolamide. Synergistic or indifferent interactions were observed for voriconazole with timolol and voriconazole with 5-fluorouracil depending on Fusarium isolate. Taken together, these data suggest that commonly used ophthalmic agents enhance the in vitro activity of antifungal drugs against drug-recalcitrant ocular fungal pathogens., (Copyright © 2019 American Society for Microbiology.)

Purpose : We aim to investigate bacterial and fungal cultures of hypothermic donor corneal storage media (Optisol-GS) and donor rims. Methods : All corneal transplants performed from January 1, 2015 to June 30, 2016 by a single surgeon at a single facility were retrospectively reviewed. Aerobic, anaerobic, and fungal cultures were routinely obtained from all donor rims and cornea storage media. Culture results and clinical courses were recorded. Results : Eighty-four corneal transplants were performed. Five of 84 grafts (5.95%) had positive bacteria donor rim cultures. Fungal donor rim cultures were positive in 5/84 grafts (5.95%) of which two grew Candida spp. Storage media bacterial cultures were positive in 2/84 (2.4%) cultures. Storage media fungal cultures were positive in 1/84 (1.2%) cultures. No patients developed any evidence of clinical infection. Conclusions : Given the increasing rates of postkeratoplasty fungal infections, the identification of positive fungal cultures from donor rims and storage media warrants further evaluation of adding antifungals to storage media.

Introduction: We evaluated the reproducibility of two portable, self-administered autorefractors (Netra and SVOne Pro) to assess the time course of visual changes on the ISS., Methods: We measured cycloplegic refractive error at 5 visits at least a week apart in 13 subjects (6 women, 7 men, 30 ± 9 yr) using both devices seated and also prone with lower body positive pressure (LBPP) applied. Axial length was measured with an optical biometer. Subjects completed a questionnaire on device preferences., Results: The SVOne seated intrasession reproducibility coefficient (RPC) was 0.37 diopters (D), while the Netra's was 0.41 D. Intersession seated results were: RPC = 0.67 D for the SVOne and RPC = 0.54 D for the Netra. The average seated to prone LBPP differences were significantly different from zero for both the SVOne and Netra. The SVOne was preferred in four out of five categories on the questionnaire and took half the time to complete a measurement set compared to the Netra., Discussion: Users preferred the SVOne and it took less time. An SVOne refraction change of 0.67 D from baseline would happen by chance less than 5% of the time. If multiple separate measurements were taken, the detection limit could be reduced (e.g., three repeated measurements could reduce it to 0.38 D). Since astronauts with visual changes show spherical equivalent changes of 0.5 to 1.0 D, in-flight autorefractors could help determine the time course of refractive changes in space from which changes in axial length could be inferred.Masterova KS, Anderson AP, Cowan DR, Fellows AM, Zegans ME, Buckey JC. Portable autorefractors for detecting axial length changes in space. Aerosp Med Hum Perform. 2018; 89(8):724-730.

Purpose: To identify fungal keratitis patients who are at risk of a poor outcome and may benefit from closer follow-up or more aggressive treatment., Design: Secondary analysis of randomized clinical trial data., Methods: We compared the clinical outcomes of patients who had positive 6-day fungal cultures with those who did not, using backward stepwise regression with covariates for all baseline clinical characteristics., Subjects: Patients presenting with a smear-positive filamentous fungal ulcer and visual acuity of 20/400 or worse, and who subsequently had a 6-day fungal culture performed at the Aravind Eye Care system (India), Lumbini Eye Hospital (Nepal), or Bharatpur Eye Hospital (Nepal)., Main Outcome Measures: The primary outcome is rate of corneal perforation and/or the need for therapeutic penetrating keratoplasty. Secondary outcomes include 3-month best spectacle-corrected visual acuity (BSCVA), 3-month infiltrate and/or scar size, and rate of re-epithelialization., Results: Patients who tested positive at their 6-day culture had twice the hazard of experiencing a corneal perforation or the need for therapeutic penetrating keratoplasty (P = .002) than those who tested negative, even after controlling for baseline ulcer characteristics. These patients also had on average 0.26 logMAR lines worse BSCVA at 3 months (P = .001). Culture positivity at day 6 was not a statistically significant predictor of 3-month infiltrate/scar-size (-0.24 mm 1 ; P = .45) or time to re-epithelialization (hazard ratio = .81; P = .31)., Conclusions: Here we identify a uniquely valuable clinical tool, day 6 culture results, for the treatment of severe fungal keratitis. Risk stratification based on repeat culture positivity is an objective way to assess response to medical therapy and identify patients who are at high risk of a poor clinical outcome. This establishes a new standard of care for severe fungal keratitis management., (Published by Elsevier Inc.)

Acute lung injury is characterized by excessive extracellular matrix proteolysis and neutrophilic inflammation. A major risk factor for lung injury is bacterial pneumonia. However, host factors that protect against pathogen-induced and host-sustained proteolytic injury following infection are poorly understood. Pseudomonas aeruginosa (PA) is a major cause of nosocomial pneumonia and secretes proteases to amplify tissue injury. We show that thrombospondin-1 (TSP-1), a matricellular glycoprotein released during inflammation, dose-dependently inhibits PA metalloendoprotease LasB, a virulence factor. TSP-1-deficient (Thbs1-/-) mice show reduced survival, impaired host defense, and increased lung permeability with exaggerated neutrophil activation following acute intrapulmonary PA infection. Administration of TSP-1 from platelets corrects the impaired host defense and aberrant injury in Thbs1-/- mice. Although TSP-1 is cleaved into 2 fragments by PA, TSP-1 substantially inhibits Pseudomonas elastolytic activity. Administration of LasB inhibitor, genetic disabling of the PA type II secretion system, or functional deletion of LasB improves host defense and neutrophilic inflammation in mice. Moreover, TSP-1 provides an additional line of defense by directly subduing host-derived proteolysis, with dose-dependent inhibition of neutrophil elastase from airway neutrophils of mechanically ventilated critically ill patients. Thus, a host matricellular protein provides dual levels of protection against pathogen-initiated and host-sustained proteolytic injury following microbial trigger.

Importance: Identifying patients with infectious keratitis who are at risk of experiencing a poor outcome may be useful to allocate resources toward high-risk patients, particularly in resource-poor settings., Objective: To determine baseline patient and ulcer characteristics that predict a high risk of developing corneal perforation and/or the need to undergo therapeutic penetrating keratoplasty (TPK)., Design, Setting, and Participants: This is a secondary analysis of Mycotic Ulcer Treatment Trial II, a multicenter, double-masked, placebo-controlled randomized clinical trial that enrolled 240 patients with smear-positive filamentous fungal corneal ulcers who enrolled between May 2010 and August 2015. Participants had a baseline visual acuity of 20/400 or worse and were randomized to receive oral voriconazole or a placebo (all participants received topical voriconazole, 1%). After 39 participants (16.3%) were enrolled, topical natamycin, 5%, was also added., Main Outcomes and Measures: The primary outcome of this secondary analysis was the rate of corneal perforation or the need to undergo TPK., Results: The mean (SD) age at enrollment was 49 (13) years, 104 participants (43.3%) were women, and all were of Southeast Asian descent. The presence of hypopyon at baseline indicated 2.28 times the odds of the patient developing corneal perforation and/or needing TPK (95% CI, 1.18-4.40; P = .01). Study participants whose infiltrate involved the posterior one-third had a 71.4% risk of developing corneal perforation and/or needing TPK. For each 1-mm increase in the geometric mean of the infiltrate, there was 1.37 (95% CI, 1.12-1.67; P = .002) increased odds of developing perforation and/or needing TPK. Other clinical features such as visual acuity, baseline culture positivity, type of filamentous fungal organism and duration of symptoms, and demographic characteristics, such as sex and occupation, were not significant predictors in the multivariable regression analysis., Conclusions and Relevance: These results suggest that risk stratification from baseline ulcer characteristics can identify those at highest risk for developing corneal perforation and/or needing TPK., Trial Registration: clinicaltrials.gov Identifier: NCT00996736.

Some astronauts are returning from long-duration spaceflight with structural ocular and visual changes. We investigated both the transient and sustained effects of changes in the direction of the gravity vector acting on the eye using changes in body posture. Intraocular pressure (IOP; measured by Perkins tonometer), ocular geometry (axial length, corneal thickness, and aqueous depth-noncontact biometer), and the choroid (volume and subfoveal thickness optical coherence tomography) were measured in 10 subjects (5 males and 5 females). Measures were taken over the course of 60 min and analyzed with repeated-measures analysis of covariance to assess the effects of posture and time. In the supine position, choroidal volume increased significantly with time (average value at <5 min = 8.8 ± 2.3 mm 3 , 60 min = 9.0 ± 2.4 mm 3 , P = 0.03). In the prone position, IOP and axial length increased with time (IOP at <5 min 15 ± 2.7 mmHg, 60 min = 19.8 ± 4.1 mmHg, P < 0.0001; axial length at <5 min = 24.29 ± 0.77 mm, 60 min = 24.31 ± 0.76 mm, P = 0.002). Each increased exponentially, with time constants of 5.3 and 14 min, respectively. Prone corneal thickness also increased with time (<5 min = 528 ± 35 μm, 60 min = 537 ± 35 μm 3 , P < 0.001). Aqueous depth was shortened in the prone position (baseline = 3.22 ± 0.31 mm, 60 min = 3.18 ± 0.32 mm, P < 0.0001) but did not change with time. The data show that changes in the gravity vector have pronounced transient and sustained effects on the geometry and physiology of the eye. NEW & NOTEWORTHY We show that gravity has pronounced transient and sustained effects on the eye by making detailed ocular measurements over 60 min in the supine and prone postures. These data inform our understanding of how gravitational forces can affect ocular structures, which is essential for hypothesizing how ocular changes could occur with microgravity exposure., (Copyright © 2017 the American Physiological Society.)

Importance: Fusarium keratitis is common and often results in poor outcomes. No new treatments since natamycin have become available., Objective: To explore the role of adjuvant oral voriconazole on clinical outcomes in Fusarium keratitis., Design, Setting, and Participants: In this prespecified subgroup analysis of a multicenter, double-masked, placebo-controlled randomized clinical trial, 240 patients from the Aravind Eye Care System in India, the Lumbini Eye Hospital and Bharatpur Eye Hospital in Nepal, and the University of California, San Francisco, who had culture-positive fungal ulcer and baseline visual acuity of 20/400 or worse were randomized to receive oral voriconazole vs placebo. Enrollment started May 24, 2010, and the last patient study visit was November 23, 2015. All patients received topical voriconazole, 1%, and after the results of the Mycotic Ulcer Treatment Trial (MUTT) II became available, topical natamycin, 5%, was added for all patients. Data analysis was performed from September 2 to October 28, 2016., Main Outcomes and Measures: The primary outcome of the trial was the rate of corneal perforation or the need for therapeutic penetrating keratoplasty. Secondary outcomes included rate of reepithelialization, best spectacle-corrected visual acuity, and infiltrate or scar size at 3 months., Results: Of the 240 study participants, 72 (30.4%) were culture positive for Fusarium species (41 [56.9%] male and 31 [43.1%] female; median [interquartile range] age, 50 [45-57] years). Of these, 33 (45.8%) were randomized to oral voriconazole and 39 (54.2%) to placebo. Fusarium ulcers randomized to oral voriconazole had a 0.43-fold decreased hazard of perforation or therapeutic penetrating keratoplasty compared with placebo after controlling for baseline infiltrate depth (95% CI, 0.22-fold to 0.84-fold; P = .01). Multiple linear regression revealed a 1.89-mm decreased infiltrate and/or scar size at 3 weeks (95% CI, -2.69 to -1.09 mm; P < .001) and a 0.83-mm decreased infiltrate and/or scar size at 3 months after correcting for baseline values (95% CI, -1.33 to -0.32 mm; P = .001) in eyes randomized to oral voriconazole vs placebo. Eyes treated with oral voriconazole also had a mean 0.29 decreased logMAR (improved) (Snellen equivalent 20/40) visual acuity at 3 months after controlling for baseline visual acuity, although this finding was not statistically significant (95% CI, -0.57 to 0.002; P = .052)., Conclusions and Relevance: Although MUTT II could not find a benefit for all corneal ulcers, Fusarium keratitis may benefit from the addition of oral voriconazole to topical natamycin, and physicians should consider prescribing oral voriconazole in these cases., Trial Registration: clinicaltrials.gov Identifier: NCT00996736.

Purpose: To determine whether the cif gene is present in pathogenic Pseudomonas aeruginosa isolates from patients with bacterial keratitis at Aravind Eye Hospital, a referral eye care center in southern India, and from corresponding environmental isolates., Methods: Polymerase chain reaction amplification was performed on strains of P. aeruginosa isolated from ocular infections and environmental soil samples were collected from the area surrounding Aravind Eye Hospital. DNA sequencing of 16S ribosomal DNA amplicons was performed to verify strain identity., Results: We determined that 45 of 48 patient isolates carry a genomic copy of cif. Analysis of a catalog of environmental strains previously isolated from the surrounding area revealed that only 4 of 10 P. aeruginosa strains and 1 of 14 strains of related species carry the cif gene., Conclusions: This is the first study to show that P. aeruginosa strains with ocular pathogenicity carry the cif gene and that the presence of this gene may be enriched over its prevalence in the environment. Taken together, these results suggest a potential role for Cif in acute bacterial keratitis.

Objective: To compare oral voriconazole with placebo in addition to topical antifungals in the treatment of filamentous fungal keratitis., Design, Setting, and Participants: The Mycotic Ulcer Treatment Trial II (MUTT II), a multicenter, double-masked, placebo-controlled, randomized clinical trial, was conducted in India and Nepal, with 2133 individuals screened for inclusion. Patients with smear-positive filamentous fungal ulcers and visual acuity of 20/400 (logMAR 1.3) or worse were randomized to receive oral voriconazole vs oral placebo; all participants received topical antifungal eyedrops. The study was conducted from May 24, 2010, to November 23, 2015. All trial end points were analyzed on an intent-to-treat basis., Interventions: Study participants were randomized to receive oral voriconazole vs oral placebo; a voriconazole loading dose of 400 mg was administered twice daily for 24 hours, followed by a maintenance dose of 200 mg twice daily for 20 days, with dosing altered to weight based during the trial. All participants received topical voriconazole, 1%, and natamycin, 5%., Main Outcomes and Measures: The primary outcome of the trial was rate of corneal perforation or the need for therapeutic penetrating keratoplasty (TPK) within 3 months. Secondary outcomes included microbiologic cure at 6 days, rate of re-epithelialization, best-corrected visual acuity and infiltrate and/or scar size at 3 weeks and 3 months, and complication rates associated with voriconazole use., Results: A total of 2133 patients in India and Nepal with smear-positive ulcers were screened; of the 787 who were eligible, 240 (30.5%) were enrolled. Of the 119 patients (49.6%) in the oral voriconazole treatment group, 65 were male (54.6%), and the median age was 54 years (interquartile range, 42-62 years). Overall, no difference in the rate of corneal perforation or the need for TPK was determined for oral voriconazole vs placebo (hazard ratio, 0.82; 95% CI, 0.57-1.18; P = .29). In prespecified subgroup analyses comparing treatment effects among organism subgroups, there was some suggestion that Fusarium species might have a decreased rate of perforation or TPK in the oral voriconazole-treated arm; however, this was not a statistically significant finding after Holms-Šidák correction for multiple comparisons (effect coefficient, 0.49; 95% CI, 0.26-0.92; P = .03). Patients receiving oral voriconazole experienced a total of 58 adverse events (48.7%) compared with 28 adverse events (23.1%) in the placebo group (P < .001 after Holms-Šidák correction for multiple comparisons)., Conclusions and Relevance: There appears to be no benefit to adding oral voriconazole to topical antifungal agents in the treatment of severe filamentous fungal ulcers. All patients in this study were enrolled in India and Nepal; therefore, it is possible that organisms in this region may exhibit characteristics different from those in other regions of the world., Trial Registration: clinicaltrials.gov Identifier: NCT00996736.

Unlabelled: The given strain of Aspergillus fumigatus under study varies across laboratories, ranging from a few widely used "standards," e.g., Af293 or CEA10, to locally acquired isolates that may be unique to one investigator. Since experiments concerning physiology or gene function are seldom replicated by others, i.e., in a different A. fumigatus background, the extent to which behavioral heterogeneity exists within the species is poorly understood. As a proxy for assessing such intraspecies variability, we analyzed the light response of 15 A. fumigatus isolates and observed striking quantitative and qualitative heterogeneity among them. The majority of the isolates fell into one of two seemingly mutually exclusive groups: (i) "photopigmenters" that robustly accumulate hyphal melanin in the light and (ii) "photoconidiators" that induce sporulation in the light. These two distinct responses were both governed by the same upstream blue light receptor, LreA, indicating that a specific protein's contribution can vary in a strain-dependent manner. Indeed, while LreA played no apparent role in regulating cell wall homeostasis in strain Af293, it was essential in that regard in strain CEA10. The manifest heterogeneity in the photoresponses led us to compare the virulence levels of selected isolates in a murine model; remarkably, the virulence did vary greatly, although not in a manner that correlated with their overt light response. Taken together, these data highlight the extent to which isolates of A. fumigatus can vary, with respect to both broad physiological characteristics (e.g., virulence and photoresponse) and specific protein functionality (e.g., LreA-dependent phenotypes)., Importance: The current picture of Aspergillus fumigatus biology is akin to a collage, patched together from data obtained from disparate "wild-type" strains. In a systematic assessment of 15 A. fumigatus isolates, we show that the species is highly heterogeneous with respect to its light response and virulence. Whereas some isolates accumulate pigments in light as previously reported with strain Af293, most induce sporulation which had not been previously observed. Other photoresponsive behaviors are also nonuniform, and phenotypes of identical gene deletants vary in a background-dependent manner. Moreover, the virulence of several selected isolates is highly variable in a mouse model and apparently does not track with any observed light response. Cumulatively, this work illuminates the fact that data obtained with a single A. fumigatus isolate are not necessarily predictive of the species as whole. Accordingly, researchers should be vigilant when making conclusions about their own work or when interpreting data from the literature., (Copyright © 2016 Fuller et al.)

The Steroids for Corneal Ulcers Trial (SCUT) was a multicenter, international study of bacterial keratitis in which 101 Pseudomonas aeruginosa infections were treated. Twenty-two of 101 P. aeruginosa isolates collected had a colony morphology characteristic of a loss-of-function mutation in lasR, the gene encoding a quorum-sensing master regulator. Ulcers caused by these 22 strains were associated with larger areas of corneal opacification, worse vision, and a lower rate of vision recovery in response to treatment than ulcers caused by the other isolates. The lasR sequences from these isolates each contained one of three nonsynonymous substitutions, and these strains were deficient in production of LasR-regulated protease and rhamnolipids. Replacement of lasR with either of the two most common lasR alleles from the SCUT isolates was sufficient to decrease protease and rhamnolipid production in PA14. Loss of LasR function is associated with increased production of CupA fimbriae, and the LasR-defective isolates exhibited higher production of CupA fimbriae than LasR-intact isolates. Strains with the same lasR mutation were of the same multilocus sequence type, suggesting that LasR-deficient, environmental P. aeruginosa strains were endemic to the area, and infections caused by these strains were associated with worse patient outcomes in the SCUT study. (This study has been registered at ClinicalTrials.gov under registration no. NCT00324168.) IMPORTANCE The LasR transcription factor is an important regulator of quorum sensing in P. aeruginosa and positively controls multiple virulence-associated pathways. The emergence of strains with lasR loss-of-function alleles in chronic disease is well described and is thought to represent a specific adaptation to the host environment. However, the prevalence and virulence of these strains in acute infections remain unclear. This report describes observations revealing that lasR mutants were common among isolates from a large, multicenter clinical study of keratitis and were associated with worse clinical outcomes than LasR-intact strains despite reduced production of LasR-regulated factors. Additionally, these lasR mutants were closely related strains or clones, as determined by molecular analysis. Because bacterial keratitis is community acquired, these data indicate infection by endemic, LasR-deficient strains in the environment. These results suggest that the conventional paradigm regarding the role for LasR-mediated regulation of virulence is more complex than previously appreciated.

Importance: The development of multiple triazole resistance in pathogenic filamentous fungi has become an increasing clinical concern and has been shown to increase the risk for treatment failure., Objective: To determine whether antifungal resistance increased during the Mycotic Ulcer Treatment Trial I (MUTT I), as measured by minimum inhibitory concentrations (MICs) in baseline cultures., Design, Setting, and Participants: This secondary analysis of a double-masked, multicenter, randomized clinical trial included patients with culture- or smear-positive filamentous fungal corneal ulcer and a baseline visual acuity of 20/40 to 20/400. Culture-positive samples with susceptibility testing were included in this analysis. The patients were treated at multiple locations of the Aravind Eye Care Hospital system in South India. Data were collected from April 3, 2010, to December 31, 2011, and analyzed from July 15 to September 1, 2015., Interventions: Corneal smears and cultures were obtained from all study participants at baseline. Susceptibility testing was performed for each culture-positive specimen., Main Outcomes and Measures: Minimum inhibitory concentration of voriconazole and natamycin in baseline cultures., Results: Of 323 participants with smear-positive specimens (183 men [56.7%]; 140 women [43.3%]; median [interquartile range] age, 47 [38-56] years), fungal-positive cultures were obtained for 256 (79.3%). The MIC data were available for 221 of 323 participants (68.4%), because 35 samples had no growth during susceptibility testing. A 2.14-fold increase per year (95% CI, 1.13-4.56; P = .02) in voriconazole MICs after controlling for the infectious organism was found. This association was not found when looking at natamycin MICs of baseline cultures after controlling for the infectious organism (1.26; 95% CI, 0.13-12.55; P = .85)., Conclusions and Relevance: Susceptibility to voriconazole appeared to decrease during the relatively short enrollment period of the clinical trial. This decrease may be more related to increased resistance of environmental fungi rather than previous treatment with azoles, because presenting with azole treatment was not a risk factor for resistance., Trial Registration: clinicaltrials.gov Identifier: NCT00996736.

Purpose: To compare treatment strategies for ocular surface squamous neoplasia (OSSN), ranging from surgical excision to empiric topical interferon alpha-2b (IFN-α2b)., Methods: A decision model was constructed to determine which of 4 treatment strategies minimized expected persistence/recurrence of disease in patients with OSSN: excision followed by repeat excision for positive surgical margins, excision followed by IFN-α2b for positive margins, incisional biopsy followed by IFN-α2b for positive biopsies, and empiric treatment with IFN-α2b. Probabilities were estimated from literature published between 1983 and 2015. Expected values for the probability of recurrence could range from 0 (no persistence/recurrence) to 1 (persistence/recurrence). Sensitivity analyses were performed for each variable., Results: Excision followed by IFN-α2b for positive margins was estimated to minimize persistence/recurrence of OSSN (expected value 0.13 versus 0.17 for empiric IFN-α2b, 0.22 for excision-only, and 0.30 for incisional biopsy-directed IFN-α2b). The optimal strategy was sensitive to 3 variables: efficacy of IFN-α2b, recurrence after negative surgical margins, and accuracy of excisional biopsy., Conclusions: In our decision analysis using studies published between 1983 and 2015, surgical excision followed by IFN-α2b for positive margins is the favored strategy for minimizing persistence/recurrence of OSSN. Future prospective studies would add to the certainty of these conclusions.

Intraocular pressure (IOP) initially increases when an individual enters microgravity compared with baseline values when an individual is in a seated position. This has been attributed to a headward fluid shift that increases venous pressures in the head. The change in IOP exceeds changes measured immediately after moving from seated to supine postures on Earth, when a similar fluid shift is produced. Furthermore, central venous and cerebrospinal fluid pressures are at or below supine position levels when measured initially upon entering microgravity, unlike when moving from seated to supine postures on Earth, when these pressures increase. To investigate the effects of altering gravitational forces on the eye, we made ocular measurements on 24 subjects (13 men, 11 women) in the seated, supine, and prone positions in the laboratory, and upon entering microgravity during parabolic flight. IOP in microgravity (16.3 ± 2.7 mmHg) was significantly elevated above values in the seated (11.5 ± 2.0 mmHg) and supine (13.7 ± 3.0 mmHg) positions, and was significantly less than pressure in the prone position (20.3 ± 2.6 mmHg). In all measurements,P< 0.001. Choroidal area was significantly increased in subjects in a microgravity environment (P< 0.007) compared with values from subjects in seated (increase of 0.09 ± 0.1 mm(2)) and supine (increase of 0.06 ± 0.09 mm(2)) positions. IOP results are consistent with the hypothesis that hydrostatic gradients affect IOP, and may explain how IOP can increase beyond supine values in microgravity when central venous and intracranial pressure do not. Understanding gravitational effects on the eye may help develop hypotheses for how microgravity-induced visual changes develop., (Copyright © 2016 the American Physiological Society.)

Purpose: To describe 2 Candida interface keratitis infections occurring in the setting of positive donor rim cultures from precut corneal tissue used for Descemet stripping automated endothelial keratoplasty (DSAEK) and the ensuing public health investigation., Methods: Following 2 clinical Candida interface keratitis infections, patients from 2012 to 2014 in the same surgical center were evaluated for bacterial and fungal rim cultures and subsequent infection. All cases of fungal infections occurring post-DSAEK were analyzed. Data included patient demographics, surgical technique, donor rim cultures, donor mate outcomes, clinical courses, and outcomes. A review of the relevant literature was also undertaken., Results: From 2012 to 2014, among 99 DSAEK procedures performed, 7 (7.1%) donor rim cultures were positive for fungi. Use of this tissue with positive donor rim cultures resulted in 2 (28.6%) episodes of confirmed fungal interface keratitis, both Candida species, and presumptive treatment in an additional 2 patients. An investigation did not identify any breach in sterile technique or procedures by the surgeon or surgery center. Our literature review identified 15 reports of postoperative fungal infection associated with DSAEK, of which 11 involved Candida spp., Conclusions: While postoperative infection remains rare, our 2 additional cases along with those previously reported suggest that DSAEK may be susceptible to infection with Candida spp. Furthermore, this report of correlated rim cultures and clinical infection suggests a need for reevaluation of the utility of obtaining routine corneoscleral donor rim fungal culture.

Importance: Bacterial virulence factors are increasingly recognized as important in the understanding of clinical infections., Objective: To determine whether 2 potential virulence factors, in vitro biofilm formation and Psl exopolysaccharide (EPS) expression, influence clinical presentation or outcomes in Pseudomonas aeruginosa keratitis., Design, Setting, and Participants: Laboratory investigation using P aeruginosa clinical isolates from the double-blind Steroids for Corneal Ulcers Trial (SCUT), which included patients at Aravind Eye Hospital, Proctor Foundation, University of California, San Francisco, and Dartmouth-Hitchcock Medical Center. SCUT was conducted from September 1, 2006, through February 22, 2010. All data used in this study were obtained during this period. Pseudomonas aeruginosa clinical isolates from SCUT were evaluated for in vitro biofilm formation, and Psl EPS expression was assessed using an anti-Psl monoclonal antibody (mAb) enzyme-linked immunosorbent assay. Planktonic growth kinetics and the susceptibility to anti-Psl mAb-mediated opsonophagocytic killing (OPK) were also evaluated in a subset of isolates. Linear regression assessed associations between SCUT patients' visual acuity and their corresponding biofilm formation and Psl EPS expression. Generalized estimating equation regression models were used to assess whether the change in visual acuity among SCUT patients was associated with Psl EPS expression or biofilm formation., Main Outcomes and Measures: Biofilm formation, Psl production, OPK, and visual acuity., Results: The P aeruginosa SCUT strains produced a mean (SD) in vitro biofilm score of 1.06 (0.32) (range 0.17-2.12). A 1-unit increase in biofilm was associated with a worse visual acuity of 2 lines measured in SCUT patients at baseline (0.20 logMAR; 95% CI, -0.03 to 0.44; P = .09) and 3 months (0.21 logMAR; 95% CI, 0.003 to 0.44; P = .047). Of 101 confirmed P aeruginosa SCUT isolates, 100 expressed Psl EPSs. In addition, all Psl-positive strains evaluated in the OPK assay were susceptible to anti-Psl mAb-mediated OPK., Conclusions and Relevance: The ability of P aeruginosa keratitis isolates to form biofilms in vitro was correlated with worse vision at presentation and after 3 months in SCUT. Ninety-nine percent of P aeruginosa keratitis isolates from SCUT produced Psl EPSs, and 100% of these evaluated Psl-positive isolates were susceptible to anti-Psl mAb-mediated OPK. These data indicate that biofilm formation and Psl EPSs may be candidate targets for novel therapeutics against P aeruginosa keratitis.

Streptococcus pneumoniae, an inhabitant of the upper respiratory mucosa, causes respiratory and invasive infections as well as conjunctivitis. Strains that lack the capsule, a main virulence factor and the target of current vaccines, are often isolated from conjunctivitis cases. Here we perform a comparative genomic analysis of 271 strains of conjunctivitis-causing S. pneumoniae from 72 postal codes in the United States. We find that the vast majority of conjunctivitis strains are members of a distinct cluster of closely related unencapsulated strains. These strains possess divergent forms of pneumococcal virulence factors (such as CbpA and neuraminidases) that are not shared with other unencapsulated nasopharyngeal S. pneumoniae. They also possess putative adhesins that have not been described in encapsulated pneumococci. These findings suggest that the unencapsulated strains capable of causing conjunctivitis utilize a pathogenesis strategy substantially different from that described for S. pneumoniae at other infection sites.

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.

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., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose: To validate computer software developed to assess digital corneal photographs of fungal keratitis in clinical research., Methods: A cornea specialist and five medical students (after training) graded on two occasions 100 corneal photographs of patients with fungal keratitis using Optscore software. Variables assessed were lesion area, location, degree of opacity, percentage of the ulcer lying within a central 4 mm circle of the cornea. Intraclass correlation coefficients (ICCs) were used to assess intragrader reliability, agreement of the students with the corneal specialist, and the reliability of the group mean of the student raters. The area determined using Optscore was compared to the area estimated from slit lamp and to visual acuity., Results: As a group, medical students achieved an ICC greater than 0.9 for five out of the seven assessed variables. Similar levels of consistency were found after analyzing the graders' individual results compared to the specialist. The area estimated using slit lamp examination was highly correlated with the mean area determined by Optscore, as was the logarithm of the minimum angle of resolution visual acuity at enrollment., Conclusions: Non-expert graders using Optscore to assess digital photographs of fungal keratitis are self-consistent, agree with an expert grader both as a group and individually, and measurements of ulcer area obtained from Optscore are highly correlated with measurements of the same patients obtained on clinical examination. These observations support the validity of Optscore for assessing corneal pathology associated with fungal keratitis and make it a promising clinical research tool.

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.

Objective: To compare topical natamycin vs voriconazole in the treatment of filamentous fungal keratitis., Methods: This phase 3, double-masked, multicenter trial was designed to randomize 368 patients to voriconazole (1%) or natamycin (5%), applied topically every hour while awake until reepithelialization, then 4 times daily for at least 3 weeks. Eligibility included smear-positive filamentous fungal ulcer and visual acuity of 20/40 to 20/400., Main Outcome Measures: The primary outcome was best spectacle-corrected visual acuity at 3 months; secondary outcomes included corneal perforation and/or therapeutic penetrating keratoplasty., Results: A total of 940 patients were screened and 323 were enrolled. Causative organisms included Fusarium (128 patients [40%]), Aspergillus (54 patients [17%]), and other filamentous fungi (141 patients [43%]). Natamycintreated cases had significantly better 3-month best spectacle-corrected visual acuity than voriconazole-treated cases (regression coefficient=0.18 logMAR; 95% CI, 0.30 to 0.05; P=.006). Natamycin-treated cases were less likely to have perforation or require therapeutic penetrating keratoplasty (odds ratio=0.42; 95% CI, 0.22 to 0.80; P=.009). Fusarium cases fared better with natamycin than with voriconazole (regression coefficient=0.41 logMAR; 95% CI,0.61 to 0.20; P<.001; odds ratio for perforation=0.06; 95% CI, 0.01 to 0.28; P<.001), while non-Fusarium cases fared similarly (regression coefficient=0.02 logMAR; 95% CI, 0.17 to 0.13; P=.81; odds ratio for perforation=1.08; 95% CI, 0.48 to 2.43; P=.86)., Conclusions: Natamycin treatment was associated with significantly better clinical and microbiological outcomes than voriconazole treatment for smear-positive filamentous fungal keratitis, with much of the difference attributable to improved results in Fusarium cases., Application to Clinical Practice: Voriconazole should not be used as monotherapy in filamentous keratitis., Trial Registration: clinicaltrials.gov Identifier: NCT00996736

Objectives: To determine whether cytotoxic and invasive Pseudomonas aeruginosa strains differentially influence clinical presentation, outcomes, or therapeutic response in bacterial keratitis., Methods: Pseudomonas aeruginosa isolates from the National Eye Institute-funded Steroids for Corneal Ulcers Trial were subtyped as cytotoxic or invasive strains. The main outcome measure compared between the 2 subtypes was change in visual acuity at 3 months using Huber robust regression, adjusting for topical corticosteroid treatment., Results: Of 101 confirmed P aeruginosa isolates from the Steroids for Corneal Ulcers Trial, 74 had a classically cytotoxic or invasive genotype. While corneal ulcers caused by genotypically invasive P aeruginosa strains were associated at presentation with significantly better visual acuity than corneal ulcers caused by genotypically cytotoxic P aeruginosa strains when adjusting for the effect of ulcer location (P= .008), invasive ulcers had improved significantly less than cytotoxic ulcers at 3 months (0.35; 95% CI, 0.04-0.66 logMAR; P= .03 [3.5-line difference]). Compared with topical moxifloxacin alone, adjunctive treatment with topical corticosteroids was associated with significantly more improvement in visual acuity in the invasive subgroup (P= .04) but was associated with less improvement in visual acuity in the cytotoxic subgroup (P= .07)., Conclusions: Rational profiling of differentially expressed virulence determinants (eg, cytotoxicity and invasiveness for P aeruginosa) could be used as a tool for decision making in the management of infections to optimize outcomes.

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., (Copyright © 2012 Elsevier Inc. All rights reserved.)