Fungal Eye Infections Research Articles

Non-meningeal, non-pulmonary cryptococcosis with limited posterior uveitis in a kidney organ transplant recipient with antibody-mediated rejection: a case report

BackgroundCryptococcosis is one of the most frequent fungal eye infections in patients with immunosuppression. Currently, treatment approaches for non-meningeal, non-pulmonary cryptococcosis are based on those used for cryptococcal meningitis or pneumonia.Case presentationWe present a rare case of non-meningeal, non-pulmonary cryptococcosis with clinical manifestations limited to one eye of a cadaveric kidney transplant recipient with chronic-active antibody-mediated rejection. Typical manifestations, diagnosis, and treatments, including antifungal therapies, adjunctive therapies, and immunosuppression reduction, are discussed. After timely diagnosis and treatment, her visual acuity recovered to baseline without recurrence or sequelae of cryptococcosis.ConclusionsClinicians should be aware of rare presentations of fungal infections, especially when a kidney transplant recipient with rejection has been treated with intensive immunosuppressants. Early diagnosis with individualized therapies may have a favorable prognosis.

Eye fungal infections: a mini review.

Ocular fungal infections annually affect more than one million individuals worldwide. The management of these infections is problematic, mainly due to the limited availability of effective antifungal agents. Thus, ocular infections are increasingly recognized as important causes of morbidity and blindness, especially keratitis and endophthalmitis. Thus, this review aims to demonstrate the importance of fungal eye infections through the description of the main related aspects, with emphasis on the treatment of these infections. For this purpose, a search for scientific articles was conducted in databases, such as Medline, published from 2000 onwards, addressing important aspects involving fungal eye infections. In addition, this work highlighted the limited therapeutic arsenal available and the severity associated with these infections. Thus, highlighting the importance of constantly updating knowledge about these pathologies, as it contributes to agility in choosing the available and most appropriate therapeutic alternatives, aiming at positive and minimally harmful results for that particular patient.

RETRACTED: Development of thermosensitive hydrogel of Amphotericin-B and Lactoferrin combination-loaded PLGA-PEG-PEI nanoparticles for potential eradication of ocular fungal infections: In-vitro, ex-vivo and in-vivo studies

The most prevalent conditions among ocular surgery and COVID−19 patients are fungal eye infections, which may cause inflammation and dry eye, and may cause ocular morbidity. Amphotericin-B eye drops are commonly used in the treatment of ocular fungal infections. Lactoferrin is an iron-binding glycoprotein with broad-spectrum antimicrobial activity and is used for the treatment of dry eye, conjunctivitis, and ocular inflammation. However, poor aqueous stability and excessive nasolacrimal duct draining impede these agens' efficiency. The aim of this study was to examine the effect of Amphotericin-B, as an antifungal against Candida albicans, Fusarium, and Aspergillus flavus, and Lactoferrin, as an anti-inflammatory and anti-dry eye, when co-loaded in triblock polymers PLGA-PEG-PEI nanoparticles embedded in P188-P407 ophthalmic thermosensitive gel. The nanoparticles were prepared by a double emulsion solvent evaporation method. The optimized formula showed particle size (177.0 ± 0.3 nm), poly-dispersity index (0.011 ± 0.01), zeta-potential (31.9 ± 0.3 mV), and entrapment% (90.9 ± 0.5) with improved ex-vivo pharmacokinetic parameters and ex-vivo trans-corneal penetrability, compared with drug solution. Confocal laser scanning revealed valuable penetration of fluoro-labeled nanoparticles. Irritation tests (Draize Test), Atomic force microscopy, cell culture and animal tests including histopathological analysis revealed superiority of the nanoparticles in reducing signs of inflammation and eradication of fungal infection in rabbits, without causing any damage to rabbit eyeballs. The nanoparticles exhibited favorable pharmacodynamic features with sustained release profile, and is neither cytotoxic nor irritating in-vitro or in-vivo. The developed formulation might provide a new and safe nanotechnology for treating eye problems, like inflammation and fungal infections.

Enhancing the Antifungal Activity and Ophthalmic Transport of Fluconazole from PEGylated Polycaprolactone Loaded Nanoparticles

Fungal eye infections are caused mainly by an eye injury and can result in serious eye damage. Fluconazole (FLZ), a broad-spectrum antifungal agent, is a poorly soluble drug with a risk of hepatotoxicity. This work aimed to investigate the antifungal activity, ocular irritation, and transport of FLZ-loaded poly (ε-caprolactone) nanoparticles using a rabbit eye model. Three formulation factors affecting the nanoparticle's size, zeta potential, and entrapment efficiency were optimized utilizing the Box-Behnken design. Morphological characteristics and antifungal activity of the optimized nanoparticles were studied. The optimized nanoparticles were loaded into thermosensitive in situ hydrogel and hydroxypropylmethylcellulose (HPMC) hydrogel ophthalmic formulations. The rheological behavior, in vitro release and in vivo corneal transport were investigated. Results revealed that the percentage of poly (ε-caprolactone) in the nanoparticle matrix, polymer addition rate, and mixing speed significantly affected the particle size, zeta potential, and entrapment efficiency. The optimized nanoparticles were spherical in shape and show an average size of 145 nm, a zeta potential of -28.23 mV, and a FLZ entrapment efficiency of 98.2%. The antifungal activity of FLZ-loaded nanoparticles was significantly higher than the pure drug. The developed ophthalmic formulations exhibited a pseudoplastic flow, prolonged the drug release and were found to be non-irritating to the cornea. The prepared FLZ pegylated nanoparticles were able to reach the posterior eye segment without eye irritation. As a result, the developed thermosensitive in situ hydrogel formulation loaded with FLZ polymeric nanoparticles is a promising drug delivery strategy for treating deep fungal eye infections.

Development and Optimization of Hyaluronic Acid-Poloxamer In-Situ Gel Loaded with Voriconazole Cubosomes for Enhancement of Activity against Ocular Fungal Infection.

Fungal eye infections are largely disseminated, especially in developing countries where they may leave over half a million people blind per year. The current study aims to boost the voriconazole antifungal efficiency via loading it as cubosomes (VZ-Cub) into hyaluronic acid and poloxamer-based ocular in situ gel. VZ-Cub were fabricated applying Box-Behnken design and employing phytantriol, poloxamer F127, and VZ amounts as independent variables. The produced nano vesicles were evaluated for the dependent variables of particle size (PS), entrapment efficiency (EE%), and transcorneal steady-state flux (Jss) of the VZ, and, the obtained optimal VZ-Cub was loaded into an in situ gel base to enhance its ocular residence time. The in situ gel formulation was tested for its gelation temperature, drug release behavior, transcorneal permeation effects, and antifungal activity. The optimized VZ-Cub consisted of 100 mg of phytantriol, 60 mg of poloxamer F127, and 21 mg of VZ. This formulation led to a minimum PS of 71 nm, an EE% of 66%, Jss value of 6.5 µg/(cm2·min), and stability index of 94 ± 2%. The optimized VZ-Cub-loaded in situ gel released 84% VZ after 12 h and yielded a 4.5-fold increase in drug permeation compared with the VZ aqueous dispersion. The antifungal activity, which was obtained by measuring the fungal growth inhibition zones, revealed that the VZ-Cub-loaded in situ gel formulation had a 3.89-fold increase in antifungal activity compared with the VZ dispersion. In summary, an ocular in situ gel loaded with VZ-Cub could be an effective novel nano-paradigm with enhanced transcorneal permeation and antifungal properties.

New Antimycotics in the Pipeline - For Ophthalmology Too?

Seven new antimycotics are presented that are at different points of development or approval. These substances are mainly first-in-class drugs. They are primarily developed for systemic administration. However, with the support of a pharmacist, the intravenous formulation may be used as eyedrops. In this short review, the activities of the substances against various fungal infections are described. After unsuccessful conventional therapy of fungal eye infections, one of these new substances might be suitable to cure the mycosis.

Eye Infections Caused by Filamentous Fungi: Spectrum and Antifungal Susceptibility of the Prevailing Agents in Germany.

Fungal eye infections can lead to loss of vision and blindness. The disease is most prevalent in the tropics, although case numbers in moderate climates are increasing as well. This study aimed to determine the dominating filamentous fungi causing eye infections in Germany and their antifungal susceptibility profiles in order to improve treatment, including cases with unidentified pathogenic fungi. As such, we studied all filamentous fungi isolated from the eye or associated materials that were sent to the NRZMyk between 2014 and 2020. All strains were molecularly identified and antifungal susceptibility testing according to the EUCAST protocol was performed for common species. In total, 242 strains of 66 species were received. Fusarium was the dominating genus, followed by Aspergillus, Purpureocillium, Alternaria, and Scedosporium. The most prevalent species in eye samples were Fusarium petroliphilum, F. keratoplasticum, and F. solani of the Fusarium solani species complex. The spectrum of species comprises less susceptible taxa for amphotericin B, natamycin, and azoles, including voriconazole. Natamycin is effective for most species but not for Aspergillus flavus or Purpureocillium spp. Some strains of F. solani show MICs higher than 16 mg/L. Our data underline the importance of species identification for correct treatment.

The Antifungal and Ocular Permeation of Ketoconazole from Ophthalmic Formulations Containing Trans-Ethosomes Nanoparticles.

Ketoconazole (KET), a synthetic imidazole broad-spectrum antifungal agent, is characterized by its poor aqueous solubility and high molecular weight, which might hamper its corneal permeation. The aim was to develop an ophthalmic formulation loaded with optimized trans-ethosomal vesicles to enhance KET ocular permeation, antifungal activity, rapid drug drainage, and short elimination half-life. Four formulation factors affecting the vesicles’ size, zeta potential, entrapment efficiency, and flexibility of the trans-ethosomes formulations were optimized. The optimum formulation was characterized, and their morphological and antifungal activity were studied. Different ophthalmic formulations loaded with the optimized vesicles were prepared and characterized. The ocular irritation and in vivo corneal permeation were investigated. Results revealed that the drug-to-phospholipid-molar ratio, the percentage of edge activator, the percentage of ethanol, and the percentage of stearyl amine significantly affect the characteristics of the vesicles. The optimized vesicles were spherical and showed an average size of 151.34 ± 8.73 nm, a zeta potential value of +34.82 ± 2.64 mV, an entrapment efficiency of 94.97 ± 5.41%, and flexibility of 95.44 ± 4.33%. The antifungal activity of KET was significantly improved following treatment with the optimized vesicles. The developed in situ gel formulations were found to be nonirritating to the cornea. The trans-ethosomes vesicles were able to penetrate deeper into the posterior eye segment without any toxic effects. Accordingly, the in situ developed gel formulation loaded with KET trans-ethosomes vesicles represents a promising ocular delivery system for the treatment of deep fungal eye infections.

Cost-Benefit and Cost-Utility Analysis of Amphotericin B Supplementation of Corneal Storage Media With Endothelial Keratoplasty-Prepared Tissue.

To determine the cost-effectiveness of amphotericin B supplementation, we analyzed both current costs to treat postendothelial keratoplasty (EK) fungal infections and potential costs associated with amphotericin B supplementation. We collected 19 US cases of post-EK fungal eye infections from the published literature and assessed the associated costs from the literature. A survey of surgeons was also conducted with questions regarding their experiences in managing these infections. We estimated that the costs to diagnose, manage, and treat post-EK fungal keratitis and post-EK fungal endophthalmitis are USD $21,113 and $34,850, respectively. The largest portion of the costs can be attributed to the need for additional surgical management, which is required in 79% of the cases. We estimated the total cost of amphotericin B supplementation to be $44.39 per graft with use of conventional amphotericin B and conservative assumptions regarding supplementation processes. Cost-effectiveness analysis demonstrated that amphotericin B supplementation is cost-effective at $100,000 per quality-adjusted life-year level only if amphotericin B supplementation can prevent more than 69.62% of post-EK fungal infections, assuming the incidence of post-EK fungal infection remains at the level it was between 2012 and 2017. We found that amphotericin B supplementation can be cost-effective under conservative assumptions if it is moderately effective in preventing post-EK fungal infections.

Fungal Eye Infections: New Hosts, Novel Emerging Pathogens but No New Treatments?

Purpose of Review We sought to explore the current incidence and associated risk factors associated with fungal eye infections. We also reviewed new diagnostic strategies and recent clinical studies exploring the use of topical and oral antifungal agents.

A potential in situ gel formulation loaded with novel fabricated poly(lactide-co-glycolide) nanoparticles for enhancing and sustaining the ophthalmic delivery of ketoconazole.

Oral ketoconazole therapy is commonly associated with serious hepatotoxicity. Improving ocular drug delivery could be sufficient to treat eye fungal infections. The purpose of this study was to develop optimized ketoconazole poly(lactide-co-glycolide) nanoparticles (NPs) with subsequent loading into in situ gel (ISG) formulation for ophthalmic drug delivery. Three formulation factors were optimized for their effect on particle size (Y1) and entrapment efficiency (Y2) utilizing central composite experimental design. Interaction among components was studied using differential scanning calorimetry (DSC) and Fourier transform infrared (FTIR) spectroscopy. Ketoconazole crystalline state was studied using X-ray powder diffraction. Six different polymeric ISG formulations were prepared and loaded with either optimized NPs or a pure drug. The prepared ISG formulations were characterized for in vitro gelation, drug release and antifungal activity. The permeation through human epithelial cell line was also investigated. The results revealed that all the studied formulation parameters significantly affected Y1 and Y2 of the developed NPs. DSC and FTIR studies illustrated compatibility among NP components, while there was a change from the crystalline state to the amorphous state of the NPs. The in vitro release from the ISG formulations loaded with drug NPs showed sustained and enhanced drug release compared to pure drug formulations. In addition, ISG loaded with NPs showed enhanced anti-fungal activity compared to pure drug formulations. Alginate–chitosan ISG formulation loaded with optimized ketoconazole NPs illustrated higher drug permeation through epithelial cell lines and is considered as an effective ophthalmic drug delivery in the treatment of fungal eye infections.

Efficacy of Antibody to PNAG Against Keratitis Caused by Fungal Pathogens.

PurposeDeveloping immunotherapies for fungal eye infections is a high priority. We analyzed fungal pathogens for expression of the surface polysaccharide, poly-N-acetyl glucosamine (PNAG), and used a mouse model of ocular keratitis caused by Aspergillus flavus, A. fumigatus, or Fusarium solani to determine if PNAG was an immunotherapy target and requirements for ancillary cellular and molecular immune effectors.MethodsEnzyme-linked immunosorbent assay (ELISA) or immunofluorescence was used to detect PNAG on fungal cells. Keratitis was induced by scratching corneas of C57BL/6, IL-17R KO, RAG-1 KO, or IL-22 KO mice followed by inoculation with fungal pathogens. Goat antibodies to PNAG, a PNAG-specific human IgG1 monoclonal antibody, or control antibodies were injected either prophylactically plus therapeutically or therapeutically only, and corneal pathology and fungal levels determined in infected eyes at 24 or 48 hours after infection.ResultsAll tested fungal species produced PNAG. Prophylactic or therapeutic treatment by intraperitoneal (IP) injection of antibody to PNAG combined with post-infection topical application of antibody, the latter also used for A. fumigatus, led to reduced fungal levels, corneal pathology, and cytokine expression. Topical administration only of the PNAG monoclonal antibodies (MAb) reduced fungal loads and corneal pathology. There was no antibody protection in IL-17R KO, RAG-1 KO, or IL-22 KO mice.ConclusionsPoly-N-acetyl glucosamine is produced by clinically important fungal ocular pathogens. Antibody to PNAG demonstrated protection against Aspergillus and Fusarium keratitis, requiring T cells producing IL-17 and IL-22. These findings indicate the potential to prevent or treat fungal infections by vaccines and immunotherapeutics to PNAG.

FUNDAMENTAL ASPECTS IN THE DEVELOPMENT OF MICROEMULSION SYSTEMS CONTAINING AMPHOTERICIN B FOR OPHTHALMIC USE

This is an overview of the development of microemulsion systems containing amphotericin B for ophthalmic use. The amphotericin B (AmB) is used to treat a fungal infection of eye and bioavailability of the AmB is the challenge for the research scientist. The poor bioavailability of AmB is due mainly to the corneal barrier, which eventually leads to a precorneal loss and subsequent decrease in the absorption of this drug into the intraocular tissues. Also, AmB has limited permeation across the intact corneal epithelium, which along with the toxicity associated with this molecule, epitomizes a major drawback to its clinical use. Therefore, new effective and safe drug vehicles for ocular delivery of AmB are urgently required. Recently, microemulsions (MEs) have been used in ophthalmic drug delivery system owing to their thermodynamic stability, transparent appearance, and favorable viscosity. Information and proper understanding of the physical chemistry and process of formation of AmB-containing MEs would provide reliable information on the best conditions for the use of these systems as eye drops. The aim of this research was thus to review the main studies on the use of MEs as delivery systems for AmB in topical eye treatment.

Microbiological profile of mycotic eye infections at a tertiary care institution in the Caribbean: A retrospective analysis

Background: This study identifies the aetiologial agents associated with mycotic eye disease in samples sent for fungal investigation, to the Department of Microbiology, University of the West Indies (UWI). Methods & Materials: A retrospective analysis of mycotic eye disease was conducted using microbiology records of all eye related specimens received in the mycology section from January 1998 to December 2014. The study population was comprised mainly of hospitalized patients, those seen in the ophthalmology clinics at the University Hospital of the West Indies (UHWI), as well as those seen by private physicians. The frequency and distribution of the causative agents of fungal eye infections were ascertained. Results: Microbiology records showed that 312 samples were received from 254 patients during the 17 years being examined, with a clinical diagnosis of fungal eye disease. A total of 52 of these samples were positive and the microbiological diagnosis was established in 39 (15.4%) of these patients (26 males, 13 females). Filamentous fungi such as Aspergillus spp n = 17 (32%) and Fusarium spp n = 16 (31%) were the most frequently isolated. They were followed by Penicillium spp n = 5 (9%), Acremonium spp and Aureobasidium spp n = 3 each (6%), Curvalaria spp and Scopularopsis spp n = 2 each (4%), Cladosporium spp, Papulospira and Mucor spp n = 1 each (2%). No yeasts were identified. The ≥ 50 years age group had the most isolates (10/39). Conclusion: Filamentous fungi such as Aspergillus spp and Fusarium spp are the most common causative agents of fungal eye infections in this setting. Consideration should be given to the reviewing of the first line empiric agents used for treatment of clinically diagnosed fungal eye infections locally. Empiric agents to consider should include agents demonstrating high in-vivo activity against moulds. Topical natamycin should be considered as first line for cases of fungal keratitis while voriconazole should be considered in cases of endophthalmitis. Continued surveillance is necessary to identify the introduction of other agents e.g. yeasts such as Candida spp, commonly found in other locations.

Successful Right Orbital Exenteration for Mucormycosis in a Young Woman

Journal of Case Reports in Medicine,2012,1,1,1-2.Published:Jun 2012Type:Case ReportAuthors:Pallavi Ojha, Vincent Lam, Yelena Doych, Myron Yanoff, and Amiram Shapiro Author(s) affiliations:Pallavi Ojha, Vincent Lam, Yelena Doych, Myron Yanoff, and Amiram Shapiro Department of Ophthalmology, Drexel University College of Medicine, Philadelphia, PA 19102, USA. Abstract:Purpose. We report successful treatment of a 32-year-old woman with a history of acute lymphoblastic leukemia who presented with rhino-orbital mucormycosis and successfully underwent right orbital exenteration and treatment of her mucormycosis. Mucormycosis is a severe fungal infection that is often fatal in immunosuppressed patients. The mainstay of therapy is intravenous amphotericin B and surgical debridement of affected tissue. Methods. Treatment included intravenous antifungal agents, debridements with local drug delivery, hyperbaric oxygen, deferasirox, and right orbital exenteration. Results. Integration of numerous therapeutic modalities led to a successful outcome. The patient is alive and well more than 3 years later. Conclusions. Surgical excision is traditionally considered the only treatment for mucormycosis. This case is a reminder of the adjunctive forms of treatment. Keywords:Fungal eye infections; Mucormycosis; Orbital exenterationView:PDF (939.56 KB) PDF Images Figure 1: Magnetic resonance imaging of the brain showed proptosis, inflammation extending to the orbital apex effacing the right optic nerve, and opacification of the right ethmoid and sphenoid air cells.

Colección corneal intraestromal y queratitis por Fusarium Spp: presentación de dos casos y revisión de la literatura

Las infecciones oculares por hongos filamentosos han aumentado su incidencia con el pasar de los años. Los traumas corneales, la terapia inmunosupresora y el uso de lentes de contacto han hecho que éstas aumenten su incidencia, pero existe un pequeño porcentaje de paciente que sin ningún factor de riesgo presentan infecciones por estos mohos. En este artículo reportamos dos casos de infección ocular por Fusarium Spp. en dos pacientes de 21 y 30 años de edad respectivamente, inmunocompetentes,pertenecientes a las Fuerzas Militares y sin factores de riesgo asociados.

Antifúngicos em infecções oculares: drogas e vias de administração

Treatment of fungal eye infections represents a challenge to the ophthalmology practice. For an adequate therapeutic response, besides correct drug choice, it is necessary an effectively administration. This script gathers information about the major antifungal drugs used in eye infections, their concentrations and main administration routes. Antifungals in eye infections: drugs and routes of administration

Voriconazole in the treatment of fungal eye infections: a review of current literature

Background:Voriconazole has an important role to play in the prophylaxis and management of fungal endophthalmitis and keratitis. New-generation triazoles, including voriconazole, posaconazole and ravuconazole, have been shown in laboratory studies...