Topical Chlorhexidine 0.2% versus Topical Natamycin 5% for the Treatment of Fungal Keratitis in Nepal: A Randomized Controlled Noninferiority Trial.

PURPOSE: To investigate if topical chlorhexidine 0.2%, which is low cost and easy to formulate, is noninferior to topical natamycin 5% for the treatment of filamentous fungal keratitis. DESIGN: Randomized controlled, single-masked, noninferiority clinical trial. PARTICIPANTS: Adults attending a tertiary-level ophthalmic hospital in Nepal with filamentous fungal infection confirmed on smear or confocal microscopy. METHODS: Participants were randomly allocated to receive topical chlorhexidine 0.2% or topical natamycin 5%. Primary analysis (intention-to-treat) was by linear regression, using baseline logarithm of the minimum angle of resolution (logMAR) best spectacle-corrected visual acuity (BSCVA) and treatment arm as prespecified covariates. Mixed fungal-bacterial infections were excluded from the primary analysis but included in secondary analyses and secondary safety-related outcomes. The noninferiority margin was 0.15 logMAR. This trial was registered with ISRCTN, number ISRCTN14332621. MAIN OUTCOME MEASURES: The primary outcome measure was BSCVA at 3 months. Secondary outcome measures included perforation or therapeutic penetrating keratoplasty by 90 days. RESULTS: Between June 3, 2019, and November 9, 2020, 354 eligible participants were enrolled and randomly assigned: 178 to chlorhexidine and 176 to natamycin. Primary outcome data were available for 153 and 151 of the chlorhexidine and natamycin groups, respectively. Of these, mixed bacterial-fungal infections were found in 20 cases (12/153 chlorhexidine, 8/151 natamycin) and excluded from the primary analysis. Therefore, 284 patients were assessed for the primary outcome (141 chlorhexidine, 143 natamycin). We did not find evidence to suggest chlorhexidine was noninferior to natamycin and in fact found strong evidence to suggest that natamycin-treated participants had significantly better 3-month BSCVA than chlorhexidine-treated participants, after adjusting for baseline BSCVA (regression coefficient, -0.30; 95% confidence interval [CI], -0.42 to -0.18; P < 0.001). There were more perforations and emergency corneal grafts in the chlorhexidine arm (24/175, 13.7%) than in the natamycin arm (10/173, 5.8%; P = 0.018, mixed infections included), whereas natamycin-treated cases were less likely to perforate or require an emergency corneal graft, after adjusting for baseline ulcer depth (odds ratio, 0.34; 95% CI, 0.15-0.79; P = 0.013). CONCLUSIONS: Treatment with natamycin is associated with significantly better visual acuity, with fewer adverse events, compared with treatment with chlorhexidine. Natamycin remains the preferred first-line monotherapy treatment for filamentous fungal keratitis.

Epidemiology and clinical outcomes of microbial keratitis in South East Nepal: a mixed-methods study.

OBJECTIVE: To describe the epidemiology of microbial keratitis in patients presenting to a tertiary eye hospital in South East Nepal alongside qualitative interviews exploring patient perspectives on barriers to accessing eye care services. METHODS AND ANALYSIS: All patients with microbial keratitis (>16 years) presenting to Sagarmatha Choudhary Eye Hospital, Nepal between 1 May 2017 and 31 July 2017 were recruited. Data were collected on patient demographics, precipitating factors and pathway to care. Clinical examination was performed and microbiological samples collected. Visual acuity was measured at final follow-up. Semistructured interviews and focus group discussions explored the patient journey and barriers to accessing care. RESULTS: We recruited 174 participants; 88 (51%) were male (mean age of 47 years) and 126 (72%) were farmers. Ocular trauma with vegetative matter was reported by 79 (45%) and 84 (48%) had fungal infections. Visual acuity was <3/60 in 107 (61%) of affected eyes at presentation, reducing to 73 (42%) at last follow-up. Factors associated with poor visual outcome were trauma with vegetative matter, delayed presentation and poor visual acuity at presentation. Qualitative interviews with 40 patients identified lack of awareness of the disease and available services, poor knowledge and practice of community health workers and lack of affordability and accessibility of treatment as important barriers. CONCLUSION: The epidemiology of microbial keratitis in this region was similar to other tropical regions. Patient interviews highlighted need for public health awareness campaigns on microbial keratitis, training of community health staff on the urgency of this condition and improvements in accessibility and affordability of ocular treatments.

Development and Validation of a Digital (Peek) Near Visual Acuity Test for Clinical Practice, Community-Based Survey, and Research.

Purpose: Unaddressed near vision impairment (NVI) affects more than 500 million people. Testing near vision is necessary to identify those in need of services. To make such testing readily accessible, we have developed and validated a new smartphone-based near visual acuity (NVA) test: Peek Near Vision (PeekNV). Methods: Two forms of the PeekNV test were developed: (1) quantitative measurement of NVA, and (2) binary screening test for presence or absence of NVI. The validity study was carried out with 483 participants in Sagarmatha Choudhary Eye Hospital, Lahan, Nepal, using a conventional Tumbling "E" Near Point Vision Chart as the reference standard. Bland-Altman limits of agreement (LoA) were used to evaluate test agreement and test-retest repeatability. NVI screening was assessed using Cohen's kappa coefficient, sensitivity, and specificity. Results: The mean difference between PeekNV and chart NVA results was 0.008 logMAR units (95% confidence interval [CI], -0.005 to 0.021) in right eye data, and the 95% LoA between PeekNV and chart testing were within 0.235 and -0.218 logMAR. As a NVI screening tool, the overall agreement between tests was 92.9% (κ = 0.85). The positive predictive value of PeekNV was 93.2% (95% CI, 89.6% to 96.9%), and the negative predictive value 92.7% (95% CI, 88.9% to 96.4%). PeekNV had a faster NVI screening time (11.6 seconds; 95% CI, 10.5 to 12.6) than the chart (14.9 seconds; 95% CI, 13.5 to 16.2; P < 0.001). Conclusions: The PeekNV smartphone-based test produces rapid NVA test results, comparable to those of an accepted NV test. Translational Relevance: PeekNV is a validated, reliable option for NV testing for use with smartphones or digital devices.

Microbial Keratitis in Nepal: Predicting the Microbial Aetiology from Clinical Features.

Fungal corneal infection (keratitis) is a common clinical problem in South Asia. However, it is often challenging to distinguish this from other aetiologies, such as bacteria or acanthamoeba. In this prospective study, we investigated clinical and epidemiological features that can predict the microbial aetiology of microbial keratitis in Nepal. We recruited patients presenting with keratitis to a tertiary eye hospital in lowland eastern Nepal between June 2019 and November 2020. A structured assessment, including demographics, history, and clinical signs, was carried out. The aetiology was investigated with in vivo confocal microscopy and corneal scrape for microscopy and culture. A predictor score was developed using odds ratios calculated to predict aetiology from features. A fungal cause was identified in 482/642 (75.1%) of cases, which increased to 532/642 (82.9%) when including mixed infections. Unusually, dematiaceous fungi accounted for half of the culture-positive cases (50.6%). Serrated infiltrate margins, patent nasolacrimal duct, raised corneal slough, and organic trauma were independently associated with fungal keratitis (p < 0.01). These four features were combined in a predictor score. The probability of fungal keratitis was 30.1% if one feature was present, increasing to 96.3% if all four were present. Whilst microbiological diagnosis is the "gold standard" to determine the aetiology of an infection, certain clinical signs can help direct the clinician to find a presumptive infectious cause, allowing appropriate treatment to be started without delay. Additionally, this study identified dematiaceous fungi, specifically Curvularia spp., as the main causative agent for fungal keratitis in this region. This novel finding warrants further research to understand potential implications and any trends over time.

Delay in accessing definitive care for patients with microbial keratitis in Nepal.

Background: The aim of this study was to describe the health-seeking journey for patients with microbial keratitis (MK) in Nepal and identify factors associated with delay. Methods: Prospective cohort study where MK patients attending a large, tertiary-referral eye hospital in south-eastern Nepal between June 2019 and November 2020 were recruited. We collected demographic details, clinical history, and examination findings. Care-seeking journey details were captured including places attended, number of journeys, time from symptom onset, and costs. We compared "direct" with "indirect" presenters, analyzing for predictors of delay. Results: We enrolled 643 patients with MK. The majority (96%) self-referred. "Direct" attenders accounted for only 23.6% (152/643) of patients, the majority of "indirect" patients initially presented to a pharmacy (255/491). Over half (328/643) of all cases presented after at least 7 days. The total cost of care increased with increasing numbers of facilities visited (p < 0.001). Those living furthest away were least likely to present directly (p < 0.001). Factors independently associated with delayed presentation included distance >50 km from the eye hospital [aOR 5.760 (95% CI 1.829-18.14, p = 0.003)], previous antifungal use [aOR 4.706 (95% CI 3.139-5.360)], and two or more previous journeys [aOR 1.442 (95% CI 1.111-3.255)]. Conclusions: Most patients visited at least one facility prior to our institution, with time to presentation and costs increasing with the number of prior journeys. Distance to the eye hospital is a significant barrier to prompt, direct presentation. Based on these findings, improving access to eye care services, strengthening referral networks and encouraging early appropriate treatment are recommended to reduce delay, ultimately improving clinical outcomes.

Diagnosis of Fungal Keratitis in Low-Income Countries: Evaluation of Smear Microscopy, Culture, and In Vivo Confocal Microscopy in Nepal.

Clinically diagnosing fungal keratitis (FK) is challenging; diagnosis can be assisted by investigations including in vivo confocal microscopy (IVCM), smear microscopy, and culture. The aim of this study was to estimate the sensitivity in detecting fungal keratitis (FK) using IVCM, smear microscopy, and culture in a setting with a high prevalence of FK. In this cross-sectional study nested within a prospective cohort study, consecutive microbial keratitis (MK) patients attending a tertiary-referral eye hospital in south-eastern Nepal between June 2019 and November 2020 were recruited. IVCM and corneal scrapes for smear microscopy and culture were performed using a standardised protocol. Smear microscopy was performed using potassium hydroxide (KOH), Gram stain, and calcofluor white. The primary outcomes were sensitivities with 95% confidence intervals [95% CI] for IVCM, smear microscopy and culture, and for each different microscopy stain independently, to detect FK compared to a composite referent. We enrolled 642 patients with MK; 468/642 (72.9%) were filamentous FK, 32/642 (5.0%) were bacterial keratitis and 64/642 (10.0%) were mixed bacterial-filamentous FK, with one yeast infection (0.16%). No organism was identified in 77/642 (12.0%). Smear microscopy had the highest sensitivity (90.7% [87.9-93.1%]), followed by IVCM (89.8% [86.9-92.3%]) and culture (75.7% [71.8-79.3%]). Of the three smear microscopy stains, KOH had the highest sensitivity (85.3% [81.9-88.4%]), followed by Gram stain (83.2% [79.7-86.4%]) and calcofluor white (79.1% [75.4-82.5%]). Smear microscopy and IVCM were the most sensitive tools for identifying FK in our cohort. In low-resource settings we recommend clinicians perform corneal scrapes for microscopy using KOH and Gram staining. Culture remains an important tool to diagnose bacterial infection, identify causative fungi and enable antimicrobial susceptibility testing.

Primary Eye Care in Eastern Nepal.

Purpose: Vision 2020 and the Global Action Plan 2013-2019 prioritise primary eye care (PEC) as an important component of reducing avoidable blindness. Studies in sub-Saharan Africa have demonstrated that current PEC provision is poor. There has been no evaluation of the current practice of PEC among primary health care workers (PHCWs) in Nepal.Methods: A mixed methods descriptive cross-sectional study with semi-structured interviews and focus group discussions (FGDs) was carried out in Eastern Nepal. Government employed PHCWs working at health posts in three districts were invited to take part in a PEC knowledge and skills assessment. Each health post was assessed for ophthalmic equipment and medications. Three focus group discussions and eight semi-structured interviews were carried out with community ophthalmic assistants, PHCWs and a district health manager.Results: 107 PHCWs in 35 health posts took part in the quantitative study. Only 8.4% had received eye care training. 27.1% PHCWs could diagnose a corneal ulcer, 83.2% conjunctivitis, 75.7% cataract and 54.2% ophthalmia neonatorum. Only 14.0% could measure visual acuity, and 5.7% of HPs had a vision chart. Ophthalmic assistants described their concern for the low level of PEC at health posts. PHCWs were keen to receive training and highlighted the need for greater government support in the provision of eye care services.Conclusion: PEC knowledge and skills among PHCWs in eastern Nepal is inadequate to provide quality PEC services. There is a pressing need for PEC training in the region, provision of ophthalmic equipment and greater government support for eye care.

Topical chlorhexidine 0.2% versus topical natamycin 5% for fungal keratitis in Nepal: rationale and design of a randomised controlled non-inferiority trial.

INTRODUCTION: Fungal infections of the cornea, fungal keratitis (FK), are challenging to treat. Current topical antifungals are not always effective and are often unavailable, particularly in low-income and middle-income countries where most cases occur. Topical natamycin 5% is usually first-line treatment, however, even when treated intensively, infections may progress to perforation of the eye in around a quarter of cases. Alternative antifungal medications are needed to treat this blinding disease.Chlorhexidine is an antiseptic agent with antibacterial and antifungal properties. Previous pilot studies suggest that topical chlorhexidine 0.2% compares favourably with topical natamycin. Full-scale randomised controlled trials (RCTs) of topical chlorhexidine 0.2% are warranted to answer this question definitively. METHODS AND ANALYSIS: We will test the hypothesis that topical chlorhexidine 0.2% is non-inferior to topical natamycin 5% in a two-arm, single-masked RCT. Participants are adults with FK presenting to a tertiary ophthalmic hospital in Nepal. Baseline assessment includes history, examination, photography, in vivo confocal microscopy and cornea scrapes for microbiology. Participants will be randomised to alternative topical antifungal treatments (topical chlorhexidine 0.2% and topical natamycin 5%; 1:1 ratio, 2-6 random block size). Patients are reviewed at day 2, day 7 (with reculture), day 14, day 21, month 2 and month 3. The primary outcome is the best spectacle corrected visual acuity (BSCVA) at 3 months. Primary analysis (intention to treat) will be by linear regression, with treatment arm and baseline BSCVA prespecified covariates. Secondary outcomes include epithelial healing time, scar/infiltrate size, ulcer depth, hypopyon size, perforation and/or therapeutic penetrating keratoplasty (corneal transplant), positive reculture rate (day 7) and quality of life (EuroQol-5 dimensions, WHO/PBD-VF20, WHOQOL-BREF). ETHICS AND DISSEMINATION: The Nepal Health Research Council, the Nepal Department of Drug Administration and the London School of Hygiene and Tropical Medicine ethics committee have approved the trial. The results will be presented at local and international meetings and submitted to peer-reviewed journals for publication. TRIAL REGISTRATION NUMBER: ISRCTN14332621; pre-results.