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Fungal keratitis and corneal scarring. (A) Active fungal keratitis with signs of acute inflammation and corneal ulceration. Photograph taken at presentation to SCEH. (B) Corneal scar, the blinding sequela of a resolved episode of fungal keratitis. Photograph taken at 2 months following presentation (same patient as (A)). SCEH, Sagarmatha Choudhary Eye Hospital.
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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,...
Citations
... Antimycotic agents such as voriconazole are already used off label in topical eye drops, but fungal keratitis can also be treated with chlorhexidine and itraconazole, either administered in a systemic or topical formulation [7][8][9], even though concentrationdependent toxicity has been reported for these compounds [10]. Natamycin is a strong antimycotic agent already available in commercial formulations, being the only FDAapproved treatment of ocular fungal infections. ...
Fungal eye infections are responsible for half a million blindness cases each year worldwide, and current treatments require frequent application of the antifungal drug Natamycin, one of the most powerful antimycotic agents known today. Despite its strength, Natamycin has very low water solubility and bioavailability. Encapsulating this drug in lipid-based nanosystems could improve its permeation through the cornea and effectiveness against infections. Our work focuses on the physiochemical and supramolecular characterization of three newly synthesized lipid-based nanosystems, and their comparison in terms of structure, dimensions and encapsulation efficiency.
... Antimycotic agents such as voriconazole are already used off label in topical eye drops, but fungal keratitis can also be treated with chlorhexidine and itraconazole, either administered in a systemic or topical formulation [7][8][9], even though concentrationdependent toxicity has been reported for these compounds [10]. Natamycin is a strong antimycotic agent already available in commercial formulations, being the only FDAapproved treatment of ocular fungal infections. ...
Natamycin is a tetraene polyene that exploits its antifungal properties by irreversibly binding components of fungal cell walls, blocking the growth of infections. However, topical ocular treatments with natamycin require frequent application due to the low ability of this molecule to permeate the ocular membrane. This limitation has limited the use of natamycin as an antimycotic drug, despite it being one of the most powerful known antimycotic agents. In this work, different lipidic nanoformulations consisting of transethosomes or lipid nanoparticles containing natamycin are proposed as carriers for optical topical administration. Size, stability and zeta potential were characterized via dynamic light scattering, the supramolecular structure was investigated via small- and wide-angle X-ray scattering and 1H-NMR, and the encapsulation efficiencies of the four proposed formulations were determined via HPLC-DAD.
... Biodiversity 2024, e202301389 (1 of 15) Figure 2. The image collage featuring various ocular disease and ailments. (A) age related macular degeneration, [22] (B) corneal wound, [23] (C) microbial keratitis, [24] (D) corneal fibrosis, [25] (E) acute angle closure glaucoma, [26] (F) ocular inflammation, [27] (G) proliferative vitreoretinopathy, [28] and (H) strabismus surgery. [29] [The figures were reproduced with appropriate copyright permissions obtained from the respective publishers.] ...
Pirfenidone, initially indicated for lung fibrosis, has gone beyond its original purpose, and shown promise in eye care. This detailed review tracks its evolution from lung treatment to aiding eye healing as evidenced by published literature. Pirfenidone's multifaceted attributes extend to mitigating corneal fibrosis, inflammation, and trauma. Through rigorous investigations, its efficacy emerges in diabetic retinopathy, macular degeneration, and postoperative glaucoma interventions. As an unheralded protagonist, pirfenidone reshapes ocular care paradigms, inviting renewed research opportunities.
... 5% natamycin or 0.1% to 0.2% amphotericin B are the treatment of choice for FK. [6] Deep lamellar keratoplasty or penetrating keratoplasty can be used. [7] Natamycin eye drops have obvious therapeutic effects on FK, but their relative molecular weight is high, their tissue penetration is poor, and they can cause conjunctival edema, punctate keratitis, and other adverse reactions. ...
Rationale:
Currently, the primary treatments for fungal keratitis (FK) are drugs and surgery. However, drug treatment has low efficacy and many side effects, and surgical treatment is costly. Therefore, it is critical to develop a new method of FK treatment. This report describes a 56-year-old male patient with FK who was treated with a combination of traditional Chinese medicine (TCM) and Western medicine with noticeable results and few side effects.
Patient concerns:
The main symptoms were blurred vision in the right eye and pain. On the corneal surface, a large area of ulcer with a turbid margin was visible, along with an oral ulcer. Additionally, the patient was afraid of corneal transplantation due to financial constraints.
Diagnoses:
The case was diagnosed as FK. In vivo confocal microscopy is the first choice for the diagnosis of this condition. Corneal ulcer was infiltrated with numerous inflammatory cells and dendritic fungal hyphae, as determined by in vivo confocal microscopy.
Interventions:
Early in his illness, the patient was treated with only Western medicine, which resulted in poor outcomes and severe adverse reactions. Corneal transplantation was recommended by the first hospital. The patient was later transferred to our hospital for treatment with TCM decoction.
Outcomes:
After 21 days of treatment, the corneal ulcer of the patient became shallower, his vision improved, and his discomfort disappeared. Due to financial concerns, the patient and his family requested early discharge, so no follow-up disease information was obtained. However, when analyzing the disease development process in the hospital, the combination of TCM and Western medicine had obvious effects and a high level of safety.
Lessons:
This case report shows that TCM is safe and effective in the treatment of FK and is worthy of promotion. However, in practice, we found that TCM is better for patients with early FK, so early diagnosis of FK is crucial.
... Chlorhexidine 0.2% has recently been compared to natamycin 5% in a non-inferiority trial conducted in Nepal [55,56]. This trial found strong evidence to suggest that natamycintreated 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). ...
... p = 0.013). Chlorhexidine 0.2% has recently been compared to natamycin 5% in a non-inferiority trial conducted in Nepal [55,56]. This trial found strong evidence to suggest that natamycin-treated participants had significantly better 3-month BSCVA than chlorhexidinetreated participants, after adjusting for baseline BSCVA (regression coefficient, −0.30; 95% confidence interval [CI], −0.42 to −0.18; p < 0.001). ...
... Chlorhexidine 0.2% has been considered as a potential alternative agent that could be readily available [55]. However, in a recent large randomised controlled trial conducted in Nepal, natamycin has been shown to be superior to chlorhexidine for the treatment of filamentous FK and remains the first-line treatment [56]. ...
Filamentous fungal infections of the cornea known as filamentous fungal keratitis (FK) are challenging to treat. Topical natamycin 5% is usually first-line treatment following the results of several landmark clinical trials. However, even when treated intensively, infections may progress to corneal perforation. Current topical antifungals are not always effective and are often unavailable. Alternatives topical therapies to natamycin include voriconazole, chlorhexidine, amphotericin B and econazole. Surgical therapy, typically in the form of therapeutic penetrating keratoplasty, may be required for severe cases or following corneal perforation. Alternative treatment strategies such as intrastromal or intracameral injections of antifungals may be used. However, there is often no clear treatment strategy and the evidence to guide therapy is often lacking. This review describes the different treatment options and their evidence and provides a pragmatic approach to the management of fungal keratitis, particularly for clinicians working in tropical, low-resource settings where fungal keratitis is most prevalent.
... Fungal keratitis usually responds to treatment slowly over several weeks. Less effective alternative therapies include voriconazole 1% eye drops, chlorhexidine 0.2% and systemic therapy with itraconazole or voriconazole [7,[44][45][46]. Randomized controlled trials (RCT) have shown that natamycin was superior in terms of visual improvement and prevention of complications and that voriconazole should not be recommended as a monotherapy for filamentous fungal keratitis [47]. ...
Amongst the treatable cause of blindness among young people, fungal keratitis ranks high. There are an estimated 1,051,787 to 1,480,916 eyes affected annually, with 8–11% of patients having to have the eye removed. Diagnosis requires a corneal scraping, direct microscopy and fungal culture with a large number of airborne fungi implicated. Treatment involves the intensive application of antifungal eye drops, preferably natamycin, often combined with surgery. In low-resource settings, inappropriate corticosteroid eye drops, ineffective antibacterial therapy, diagnostic delay or no diagnosis all contribute to poor ocular outcomes with blindness (unilateral or bilateral) common. Modern detailed guidelines on fungal keratitis diagnosis and management are lacking. Here, we argue that fungal keratitis should be included as a neglected tropical disease, which would facilitate greater awareness of the condition, improved diagnostic capability, and access to affordable antifungal eye medicine.
... This cross-sectional study nested within a prospective cohort study formed part of the triaging assessment used to enrol eligible patients with FK into a randomised controlled trial comparing natamycin 5% to chlorhexidine 0.2%. The full protocol for this study and results have already been published [20,21]. We have previously described the methodology relating to clinical findings, microbiological diagnosis, and in vivo confocal microscopy in our earlier work [22]; we therefore describe these briefly here. ...
... There were several strengths to our study. This was a large, prospective, consecutivecase study, conducted in an area with a high prevalence of FK, that followed a rigid, published protocol and standard operating procedures [20,21]. Most other studies assessing diagnostic accuracy for diagnosing fungal keratitis have used culture as the "gold standard" reference [7,8,10,11,[17][18][19]. ...
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.
... It formed part of the triaging assessment used to enroll eligible patients with fungal keratitis (FK) into a randomized controlled trial comparing natamycin 5% to chlorhexidine 0.2%. The full protocol for this study has been published (16). SCEH is a tertiary ophthalmic referral hospital within Province 2 of south-eastern Nepal that serves a population of ∼5 million people. ...
... The BSCVA protocol followed that used in the Steroids for Corneal Ulcers Trial (SCUT) (17), using a 3 m, proportionally-reduced version of the 4 m Early Treatment Diabetic Retinopathy Study tumbling "E" chart (Good-Lite, Illinois, USA) (18). Slit-lamp examination by a trial-certified ophthalmologist or ophthalmic assistant followed a structured approach: eyelid assessment, corneal ulcer features, anterior chamber characteristics (flare, cells, hypopyon shape, and size), and perforation status (16). Infiltrate and epithelial defect size was calculated as the mean of the maximum diameter of the infiltrate and the widest perpendicular diameter (19). ...
... All the images were reviewed during the procedure in real-time and classified into the various forms of keratitis, by one experienced observer. Corneal specimens were obtained for microbiological testing on site (16). ...
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.
... A current randomised control trial is investigating the use of a cheap and more widely available medication, chlorhexidine 0.2% eye-drop, as a non-inferior alternative to natamycin 5% eye-drop which is currently first line. 23 Although on the WHO Essential Medicines List 2017, natamycin 5% eye-drops are often not available in much of sub-Saharan Africa and some Asian countries, and where it is available it is prohibitively expensive. 10 The main limitation of this study is the potential for selection bias and researcher bias in the qualitative interviews. ...
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.
... This formed part of the triaging assessment used to enrol eligible patients with FK into a randomised controlled trial comparing natamycin 5% to chlorhexidine 0.2%. The full protocol for this study has been published in [12]. SCEH is a tertiary ophthalmic referral hospital in southeastern Nepal that serves a population of approximately 5 million people. ...
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.
