ABSTRACT
ABSTRACT: Keratomycosis is a serious corneal infection associated with high ocular morbidity that can lead to severe vision loss. It is estimated to affect more than 1 million patients annually, most commonly occurring in tropical climates, and represents a growing threat to patients worldwide. Despite aggressive medical management, fungal infections have a higher rate of perforation requiring surgical intervention compared with other infectious etiologies. Early diagnosis and appropriate treatment are keys to preserving vision and saving patients' eyes.Timely diagnosis of fungal keratitis helps minimize corneal damage and scarring and increases the likelihood of a favorable outcome. Studies have shown that correct identification of fungal infections is often delayed up to 2 to 3 weeks after initial presentation. This leads to incorrect or ineffective treatment for many patients. Diagnostic techniques explored in this study include corneal scrapings with staining and culture, visualization with in vivo confocal microscopy, molecular diagnostic techniques including polymerase chain reaction, and recently developed omics-based technologies.Treatment of fungal keratitis begins with topical antifungals. Medical management has been proven to be effective, but with limitations including poor drug penetration and low bioavailability. Cases that do not respond to topical therapy require more invasive and novel treatments to control the infection. We review the clinical trials that have shaped current practice patterns, with focus on the efficacy of topical natamycin as the primary therapy for filamentous fungal keratitis. We explore additional management strategies such as localized intrastromal and intracameral injections of antifungal medications, photodynamic therapy, and surgical intervention.
Subject(s)
Antifungal Agents , Eye Infections, Fungal , Keratitis , Humans , Eye Infections, Fungal/diagnosis , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/therapy , Antifungal Agents/therapeutic use , Keratitis/diagnosis , Keratitis/microbiology , Keratitis/drug therapy , Microscopy, ConfocalABSTRACT
BACKGROUND: Mycotic keratitis (MK) represents a corneal infection, with Fusarium species identified as the leading cause. Fusarium is a genus of filamentous fungi commonly found in soil and plants. While many Fusarium species are harmless, some can cause serious infections in humans and animals, particularly Fusarium keratitis, that can lead to severe ocular infections, prevalent cause of monocular blindness in tropical and subtropical regions of the world. Due to its incidence and importance in ophthalmology, we conducted a systematic analysis of clinical cases to increase our understanding of Fusarium keratitis by gathering clinical and demographic data. METHODS: To conduct an analysis of Fusarium keratitis, we looked through the literature from the databases PubMed, Embase, Lilacs, and Google Scholar and found 99 papers that, between March 1969 and September 2023, corresponded to 163 cases of Fusarium keratitis. RESULTS: Our analysis revealed the Fusarium solani species complex as the predominant isolate, with females disproportionately affected by Fusarium keratitis. Notably, contact lens usage emerged as a significant risk factor, implicated in nearly half of cases. Diagnosis primarily relied on culture, while treatment predominantly involved topical natamycin, amphotericin B, and/or voriconazole. Surprisingly, our findings demonstrated a prevalence of cases originating from the United States, suggesting potential underreporting and underestimation of this mycosis in tropical regions. This shows the imperative for heightened vigilance, particularly in underdeveloped regions with substantial agricultural activity, where Fusarium infections may be more prevalent than currently reported. CONCLUSION: Our study sheds light on the clinical complexities of Fusarium keratitis and emphasizes the need for further research and surveillance to effectively tackle this vision-threatening condition. Furthermore, a timely identification and early initiation of antifungal treatment appear to be as important as the choice of initial treatment itself.
Subject(s)
Antifungal Agents , Fusariosis , Fusarium , Keratitis , Humans , Keratitis/microbiology , Keratitis/epidemiology , Keratitis/drug therapy , Fusarium/isolation & purification , Fusarium/classification , Fusarium/genetics , Fusariosis/microbiology , Fusariosis/drug therapy , Fusariosis/epidemiology , Fusariosis/diagnosis , Antifungal Agents/therapeutic use , Antifungal Agents/pharmacology , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/epidemiology , Eye Infections, Fungal/drug therapy , Female , Voriconazole/therapeutic use , Prevalence , Risk Factors , Male , Adult , Middle Aged , Contact Lenses/microbiology , Contact Lenses/adverse effects , Amphotericin B/therapeutic use , Natamycin/therapeutic use , Aged , Young Adult , AdolescentABSTRACT
BACKROUD: Keratitis caused by Lasiodiplodia theobromae is rare and typically associated with a poor prognosis. Current literature lacks sufficient evidence on effective management of patients with this condition. CASE PRESENTATION: A 74-year-old former agricultural worker presented with a red right eye, discomfort, and decreased visual acuity, progressing over three days without treatment. Examination revealed type 2 diabetes and a non-perforating, spiculated corneal abscess with a hypopyon in the right eye. Initial treatment included a triple antibiotic therapy and supportive care. Direct mycological examination identified numerous septate mycelial filaments. Antifungal treatment with natamycin and voriconazole, both topically and orally, was initiated. Cultures confirmed Lasiodiplodia theobromae. The patient showed significant improvement. Treatment continued for eight weeks, with a final visual acuity of 20/50 due to a stromal scar. CONCLUSION: An extensive literature review conducted in November 2023, using databases such as PubMed and Google Scholar with the keywords "lasiodiplodia" and "keratitis" yielded no previous cases of this specific condition being managed solely with the combined use of natamycin and voriconazole. This antifungal combination is commonly included in most management protocols for fungal keratitis. Factors such as the use of corticosteroids and delayed diagnosis were noted to adversely affect the prognosis. This case and this systematic review underscores the potential for non-surgical management options in severe fungal keratitis.
Subject(s)
Antifungal Agents , Ascomycota , Eye Infections, Fungal , Humans , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/diagnosis , Aged , Antifungal Agents/therapeutic use , Ascomycota/isolation & purification , Male , Keratitis/microbiology , Keratitis/drug therapy , Keratitis/diagnosis , Voriconazole/therapeutic use , Visual Acuity/physiology , Natamycin/therapeutic use , Drug Therapy, CombinationABSTRACT
PURPOSE: To study the risk factors, clinical features, and treatment outcomes of patients with culture-negative keratitis (CNK). METHODS: A retrospective data review of 933 patients with CNK was performed from January 2018 to December 2020. The variables such as the history of injury, visual acuity, slit-lamp findings with measurements of size and depth of ulcer, microbiological evaluation, duct patency, blood glucose levels, and treatment were considered, and clinical outcome was analyzed. RESULTS: Of the 933 patients with CNK, 763 (81.8%) were medically managed, with a mean treatment duration of 2.08 ± 1.7 weeks. Among them, 622 (66.7%) were both smear and culture-negative, and 311 (33.3%) showed only smear positivity. Smear-positive patients showed a positive correlation with the history of injury. A higher incidence of fungal growth on repeat culture was observed. Surgical interventions were done only in 18.2% of the patients; the rest were treated with topical medications alone. CONCLUSION: High clinical suspicion, differentiation of causative organisms based on clinical findings, and initiating empirical therapy with broad-spectrum antibiotics and antifungals improve the ultimate prognosis in patients with CNK, even though a standard protocol for empirical medical treatment may differ among institutions and surgeons based on their clinical experience and geographical variations.
Subject(s)
Anti-Bacterial Agents , Eye Infections, Bacterial , Eye Infections, Fungal , Visual Acuity , Humans , Retrospective Studies , Female , Male , Eye Infections, Bacterial/microbiology , Eye Infections, Bacterial/diagnosis , Eye Infections, Bacterial/drug therapy , Middle Aged , Visual Acuity/physiology , Adult , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/diagnosis , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/therapy , Anti-Bacterial Agents/therapeutic use , Bacteria/isolation & purification , Antifungal Agents/therapeutic use , Keratitis/microbiology , Keratitis/diagnosis , Keratitis/drug therapy , Risk Factors , Follow-Up Studies , Fungi/isolation & purification , Cornea/microbiology , Cornea/pathology , AgedABSTRACT
INTRODUCTION: This research aims to describe clinical findings, epidemiology and treatment outcomes in patients with filamentous fungi keratitis of a tertiary centre in Germany over a 7-year period and to compare the efficacy of different antifungal treatments and the effect of additive topical steroids. METHODS: This retrospective study included 25 eyes of 23 patients from October 2013 to December 2020 with cultural isolates of filamentous fungi and corresponding keratitis. Best-corrected visual acuity (BCVA), clinical signs, symptoms, risk factors and outcome were extracted from medical records. RESULTS: Improvement of BVCA was noted in 68% of eyes. Mean BCVA of the study population increased from 0.75 logMAR [median 0.40, standard deviation (SD) 0.82, range 0-2.3] to 0.48 logMAR (median 0.10, SD 0.88, range - 0.1 to 3). The most commonly used antifungal topical treatment was a combination of natamycin 5% and voriconazole 2% (44% of eyes), followed by voriconazole 2% in 36% of cases. An antiinflammatory topical steroid was applied in 52%. In 16% of the eyes, penetrating keratoplasty (pKP) was performed. CONCLUSION: Diagnosis of filamentous fungi keratitis is often difficult or delayed. Outcomes can be poor even with intensive treatment because of high resistance to common antifungals. Access to natamycin 5% seems to lead to favourable outcomes in filamentous fungi keratitis.
Subject(s)
Antifungal Agents , Eye Infections, Fungal , Keratitis , Humans , Retrospective Studies , Female , Male , Antifungal Agents/therapeutic use , Middle Aged , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/microbiology , Keratitis/microbiology , Keratitis/drug therapy , Aged , Adult , Voriconazole/therapeutic use , Aged, 80 and over , Visual Acuity , Treatment Outcome , Natamycin/therapeutic use , Keratoplasty, PenetratingABSTRACT
BACKGROUND: Infectious keratitis, a significant contributor to blindness, with fungal keratitis accounting for nearly half of cases, poses a formidable diagnostic and therapeutic challenge due to its delayed clinical presentation, prolonged culture times, and the limited availability of effective antifungal medications. Furthermore, infections caused by rare fungal strains warrant equal attention in the management of this condition. CASE PRESENTATION: A case of fungal keratitis was presented, where corneal scraping material culture yielded pink colonies. Lactophenol cotton blue staining revealed distinctive spore formation consistent with the Fusarium species. Further analysis using Matrix-Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry (MALDI-TOF MS) identified the causative agent as Fusarium proliferatum. However, definitive diagnosis of Pseudonectria foliicola infection was confirmed through ITS sequencing. The patient's recovery was achieved with a combination therapy of voriconazole eye drops and itraconazole systemic treatment. CONCLUSION: Pseudonectria foliicola is a plant pathogenic bacterium that has never been reported in human infections before. Therefore, ophthalmologists should consider Pseudonectria foliicola as a possible cause of fungal keratitis, as early identification and timely treatment can help improve vision in most eyes.
Subject(s)
Antifungal Agents , Eye Infections, Fungal , Fusarium , Keratitis , Voriconazole , Humans , Keratitis/microbiology , Keratitis/drug therapy , Keratitis/diagnosis , Antifungal Agents/therapeutic use , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/diagnosis , Voriconazole/therapeutic use , Fusarium/isolation & purification , Fusarium/drug effects , Fusarium/pathogenicity , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Itraconazole/therapeutic use , Fusariosis/drug therapy , Fusariosis/microbiology , Fusariosis/diagnosis , Male , Cornea/microbiology , Cornea/pathology , Female , Middle AgedABSTRACT
Purpose: to explore the anti-inflammatory effects of a nanobody (Nb) specific to ß-glucan on fungal keratitis (FK). Methods: in order to verify the therapeutic and anti-inflammatory efficacy of Nb in FK, the severity of inflammation was assessed with inflammatory scores, hematoxylin-eosin (HE) staining, and myeloperoxidase (MPO) assays. In corneas of mice of FK model and human corneal epithelial cells stimulated by fungal hyphae, real-time reverse transcriptase polymerase chain reaction, Western blot, and enzyme-linked immunosorbent assay were used to detect the expression levels of inflammatory cytokines and pattern recognition receptors (PRRs). In vivo, macrophages and neutrophils infiltration in the cornea stroma was detected by immunofluorescence (IFS) staining. Results: In murine models infected with Aspergillus fumigatus (A. fumigatus), Nb treatment could reduce the inflammatory scores. HE staining and MPO results showed Nb significantly alleviated corneal edema and reduced inflammatory cell infiltration 3 days post-infection. In addition, the expression levels of LOX-1 and Dectin-1 were significantly decreased in the Nb group in vivo. The expression of chemokines CCL2 and CXCL2 also decreased in the Nb group. Compared with the PBS group, the number of macrophages and neutrophils in the Nb group was significantly decreased, which was shown in IFS results. Moreover, Nb attenuated the expression of Dectin-1, LOX-1, and inflammatory mediators, including IL-6 and IL-8 in vitro. Conclusion: our study showed that Nb could alleviate FK by downregulating the expression of PRRs and inflammatory factors as well as reducing the infiltration of macrophages and neutrophils.
Subject(s)
Anti-Inflammatory Agents , Aspergillus fumigatus , Disease Models, Animal , Keratitis , Single-Domain Antibodies , beta-Glucans , Animals , Keratitis/drug therapy , Keratitis/microbiology , Mice , beta-Glucans/pharmacology , Anti-Inflammatory Agents/pharmacology , Humans , Single-Domain Antibodies/pharmacology , Cell Wall/chemistry , Aspergillosis/drug therapy , Aspergillosis/microbiology , Aspergillosis/immunology , Cornea/drug effects , Cytokines/metabolism , Macrophages/drug effects , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/microbiology , Neutrophils/drug effects , Neutrophils/immunologyABSTRACT
Fungal keratitis (FK) is a leading cause of preventable blindness and eye loss. The poor antifungal activity, increased drug resistance, limited corneal permeability, and unsatisfactory biosafety of conventional antifungal eye drops are among the majority of the challenges that need to be addressed for currently available antifungal drugs. Herein, this study proposes an effective strategy that employs chitosan-poly(ethylene glycol)-LK13 peptide conjugate (CPL) in the treatment of FK. Nanoassembly CPL can permeate the lipophilic corneal epithelium in the transcellular route, and its hydrophilicity surface is a feature to drive its permeability through hydrophilic stroma. When encountering fungal cell membrane, CPL dissembles and exposes the antimicrobial peptide (LK13) to destroy fungal cell membranes, the minimum inhibitory concentration values of CPL against Fusarium solani (F. solani) are always not to exceed 8 µg peptide/mL before and after drug resistance induction. In a rat model of Fusarium keratitis, CPL demonstrates superior therapeutic efficacy than commercially available natamycin ophthalmic suspension. This study provides more theoretical and experimental supports for the application of CPL in the treatment of FK.
Subject(s)
Antifungal Agents , Chitosan , Cornea , Drug Resistance, Fungal , Fusarium , Keratitis , Microbial Sensitivity Tests , Polyethylene Glycols , Chitosan/chemistry , Chitosan/pharmacology , Keratitis/drug therapy , Keratitis/microbiology , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Fusarium/drug effects , Animals , Rats , Drug Resistance, Fungal/drug effects , Polyethylene Glycols/chemistry , Cornea/drug effects , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/microbiology , Permeability/drug effects , Fusariosis/drug therapy , Antimicrobial Peptides/pharmacology , Antimicrobial Peptides/chemistry , Natamycin/pharmacology , Natamycin/administration & dosage , Male , Disease Models, Animal , Rats, Sprague-DawleyABSTRACT
OBJECTIVES: To investigate the epidemiological characteristics and clinical outcomes of culture-proven bacterial and fungal keratitis at a single tertiary referral centre on Jeju Island, South Korea. DESIGN: A retrospective study design. SETTING: Data from a solitary referral centre on Jeju Island spanning January 2011 to December 2022. PARTICIPANTS: Among the 245 patients clinically diagnosed with infectious microbial keratitis, 110 individuals had culture-positive results. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the identification of causative microbial profiles and epidemiological characteristics, while the secondary outcome was the correlation of these factors with treatment outcomes. RESULTS: Of 245 patients, 110 (44.9%) had culture-positive infectious keratitis, showing 69 bacterial, 32 fungal, 4 superimposed bacterial and 5 cases with coinfection by bacteria and fungus. The most common pathogen was Pseudomonas species in 14.4% of the bacterial keratitis cases, followed by Staphylococcus epidermidis (9%), Staphylococcus aureus (8%) and Moraxella species (7%). The total treatment success rate for bacterial keratitis was 67.5%. The frequency of methicillin-resistant Staphylococcus on Jeju Island did increase during the study period. Fusarium species had the highest incidence at 22.2%, followed by Candida (16.7%) and Colletotrichum species (11.1%). 56.7% of fungal keratitis patients were successfully treated. An initial large corneal lesion (>3 mm) showed a statistically significant association with treatment failure. CONCLUSION: The incidence of Moraxella and Colletotrichum species in our study was higher than that reported in other districts with different climates and environments. The results reported here reflect the unique environmental features of Jeju Island, characterised by high humidity and temperatures.
Subject(s)
Eye Infections, Fungal , Keratitis , Humans , Retrospective Studies , Republic of Korea/epidemiology , Female , Male , Middle Aged , Keratitis/epidemiology , Keratitis/microbiology , Adult , Aged , Eye Infections, Fungal/epidemiology , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/drug therapy , Eye Infections, Bacterial/epidemiology , Eye Infections, Bacterial/microbiology , Anti-Bacterial Agents/therapeutic use , Incidence , Tertiary Care Centers/statistics & numerical dataABSTRACT
This case report discusses a diagnosis of rhino-orbital-cerebral mucormycosis in a man aged 61 years who presented with vision loss, ophthalmoplegia, and ptosis.
Subject(s)
Eye Infections, Fungal , Mucormycosis , Orbital Diseases , Humans , Mucormycosis/diagnosis , Mucormycosis/microbiology , Mucormycosis/drug therapy , Orbital Diseases/microbiology , Orbital Diseases/diagnosis , Orbital Diseases/drug therapy , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/diagnosis , Eye Infections, Fungal/drug therapy , Male , Antifungal Agents/therapeutic use , Magnetic Resonance Imaging , Paranasal Sinus Diseases/microbiology , Paranasal Sinus Diseases/diagnosis , Paranasal Sinus Diseases/drug therapy , Tomography, X-Ray Computed , Nose Diseases/microbiology , Nose Diseases/diagnosis , Nose Diseases/drug therapy , Female , Middle Aged , Amphotericin B/therapeutic useABSTRACT
Fungal keratitis is a severe corneal infection characterized by suppurative and ulcerative lesions. Aspergillus fumigatus is a common cause of fungal keratitis. Antifungal drugs, such as natamycin, are currently the first-line treatment for fungal keratitis, but their ineffectiveness leads to blindness and perforation. Additionally, the development of fungal resistance makes treating fungal keratitis significantly more challenging. The present study used platelet-derived biomaterial (PDB) to manage A. fumigatus keratitis in the animal model. Freezing and thawing processes were used to prepare PDB, and then A. fumigatus keratitis was induced in the mice. Topical administration of PDB, natamycin, and plasma was performed; quantitative real-time PCR (qPCR) and histopathologic examination (HE) were used to assess the inhibitory effect of the mentioned compounds against fungal keratitis. The qPCR results showed that PDB significantly decreased the count of A. fumigatus compared to the control group (P-value ≤ 5). Natamycin also remarkably reduced the count of fungi in comparison to the untreated animal, but its inhibitory effect was not better than PDB (P-value > 5). The findings of HE also demonstrated that treatment with PDB and natamycin decreased the fungal loads in the corneal tissue. However, plasma did not show a significant inhibitory effect against A. fumigatus. PDB is intrinsically safe and free of any infections or allergic responses; additionally, this compound has a potential role in decreasing the burden of A. fumigatus and treating fungal keratitis. Therefore, scientists should consider PDB an applicable approach to managing fungal keratitis and an alternative to conventional antifungal agents.
Subject(s)
Antifungal Agents , Aspergillosis , Aspergillus fumigatus , Keratitis , Aspergillus fumigatus/drug effects , Animals , Keratitis/microbiology , Keratitis/drug therapy , Mice , Aspergillosis/drug therapy , Aspergillosis/microbiology , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Disease Models, Animal , Biocompatible Materials , Blood Platelets/drug effects , Natamycin/pharmacology , Natamycin/administration & dosage , Natamycin/therapeutic use , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/microbiology , Cornea/microbiology , Cornea/pathology , Cornea/drug effectsABSTRACT
A 32-year-old contact lens-wearing man with recent travel history to the Caribbean was referred for a corneal infiltrate in the left eye that worsened following 1-week of steroid-antibiotic therapy. Corneal cultures were obtained and sent to our facility's clinical microbiology laboratory for analysis. Same-day in vivo confocal microscopy revealed fungal elements. Nucleic acid sequencing performed on the isolated determined it to be a member of the entomopathogenic genus Metarhizium. Over the course of 3 months, the patient's corneal infiltrate ultimately resolved following topical natamycin 5 % therapy. This is the first reported case to have originated in the Caribbean and to utilize in vivo confocal microscopy to aid diagnosis. Our case also supports previous reports of success with natamycin therapy in treatment of Metarhizium sp. keratitis.
Subject(s)
Antifungal Agents , Keratitis , Metarhizium , Microscopy, Confocal , Natamycin , Humans , Natamycin/therapeutic use , Natamycin/administration & dosage , Male , Metarhizium/genetics , Metarhizium/isolation & purification , Adult , Keratitis/microbiology , Keratitis/drug therapy , Keratitis/diagnosis , Antifungal Agents/therapeutic use , Caribbean Region , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/diagnosis , Treatment Outcome , Administration, Topical , Cornea/microbiology , Cornea/pathologySubject(s)
Eye Infections, Fungal , Keratitis , Pythiosis , Pythium , Humans , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/diagnosis , Eye Infections, Fungal/drug therapy , Pythium/isolation & purification , Keratitis/microbiology , Keratitis/diagnosis , Keratitis/drug therapy , Pythiosis/diagnosis , Pythiosis/drug therapy , Pythiosis/microbiology , Male , Female , Middle Aged , Antifungal Agents/therapeutic useABSTRACT
Fungal keratitis (FK) is a severe ocular condition resulting from corneal infection that is prevalent in tropical countries, particularly in developing regions of Asia and Africa. Factors like corneal lens misuse, inappropriate steroid use, and diagnostic challenges have provoked the epidemic. FK causes significant vision impairment, scarring, and ocular deformities. Accurate pathological diagnosis is crucial for effective therapeutic intervention. Topical antifungal therapy with surface healing medications proves effective in preventing fungal-borne ulcers. Managing FK requires a comprehensive understanding of fungal pathogenesis, guiding formulation strategies and preventive measures to curb global ocular blindness. This review provides in-depth insights into FK, covering etiology, epidemiology, pathogenesis, therapeutic interventions, antifungal resistance, limitations, prevention, and future perspectives on ocular surface disease management.
Subject(s)
Antifungal Agents , Eye Infections, Fungal , Keratitis , Humans , Keratitis/diagnosis , Keratitis/epidemiology , Keratitis/microbiology , Eye Infections, Fungal/diagnosis , Eye Infections, Fungal/epidemiology , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/drug therapy , Antifungal Agents/therapeutic use , Drug Resistance, FungalABSTRACT
BACKGROUND: Fusarium and allied genera (fusarioid) species are common colonizers of roots and aerial plant parts, or act as phytopathogens in forestry and horticultural or grain crops. However, they can also cause a wide range of infections in humans, including onychomycosis, cutaneous and invasive infections. Fusarioid keratitis is characterized by an infection of the cornea with a suppurative and ulcerative appearance, which may cause damage to vision and permanent blindness. The aim of the present study was to investigate the prevalence of fusarioid species, biofilm formation and antifungal susceptibility profiling of clinical isolates recovered from patients with keratitis and dermatomycoses. METHODOLOGY/PRINCIPAL FINDINGS: The study was performed between March, 2012-December, 2022. Demographic, clinical and epidemiological data of patients were also collected. In the present study, most of the patients with keratitis were male (74%), had a median age of 42 years old, worked with plant material or debris and 26% of them reported eye trauma. Regarding dermatomycosis, most of patients were female and exhibited toenail lesions. Forty-seven isolates belonged to the genus Neocosmospora (78.33%), nine to the Fusarium fujikuroi (15%) and four to the Fusarium oxysporum (6.66%) species complexes. Several strains were moderate biofilm producers, specifically among Fusarium annulatum. Most strains showed increased MICs to amphotericin B and ketoconazole and low MICs to itraconazole. MICs ranged from 0.25 to 16 µg/mL for amphotericin B, 0.0625 to >16 µg/mL for ketoconazole and 0.125 to 8 for itraconazole. CONCLUSIONS/SIGNIFICANCE: It is possible to conclude that fusarioid keratitis in Northeastern Brazil is an important and neglected disease, given the high number of cases, increased need for keratoplasty and poor outcome of the disease.
Subject(s)
Antifungal Agents , Fusarium , Keratitis , Microbial Sensitivity Tests , Humans , Female , Male , Adult , Brazil/epidemiology , Keratitis/microbiology , Keratitis/epidemiology , Prospective Studies , Middle Aged , Antifungal Agents/pharmacology , Fusarium/drug effects , Fusarium/isolation & purification , Fusarium/classification , Fusariosis/microbiology , Fusariosis/epidemiology , Fusariosis/drug therapy , Young Adult , Dermatomycoses/epidemiology , Dermatomycoses/microbiology , Dermatomycoses/drug therapy , Aged , Biofilms/drug effects , Biofilms/growth & development , Prevalence , Adolescent , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/epidemiology , Eye Infections, Fungal/drug therapyABSTRACT
Fungal keratitis (FK) is an infectious keratopathy can cause serious damage to vision. Its severity is related to the virulence of fungus and response of inflammatory. Rosmarinic acid (RA) extracted from Rosmarinus officinalis exhibits antioxidant, anti-inflammatory and anti-viral properties. The aim of this study was to investigate the effect of RA on macrophage autophagy and its therapeutic effect on FK. In this study, we demonstrated that RA reduced expression of proinflammatory cytokine, lessened the recruitment of inflammatory cells in FK. The relative contents of autophagy markers, such as LC3 and Beclin-1, were significantly up-regulated in RAW 264.7 cells and FK. In addition, RA restored mitochondrial membrane potential (MMP) of macrophage to normal level. RA not only reduced the production of intracellular reactive oxygen species (ROS) but also mitochondria ROS (mtROS) in macrophage. At the same time, RA induced macrophage to M2 phenotype and down-regulated the mRNA expression of IL-6, IL-1ß, TNF-α. All the above effects could be offset by the autophagy inhibitor 3-Methyladenine (3-MA). Besides, RA promote phagocytosis of RAW 264.7 cells and inhibits spore germination, biofilm formation and conidial adherence, suggesting a potential therapeutic role for RA in FK.
Subject(s)
Aspergillosis , Aspergillus fumigatus , Autophagy , Cinnamates , Depsides , Eye Infections, Fungal , Macrophages , Reactive Oxygen Species , Rosmarinic Acid , Depsides/pharmacology , Animals , Autophagy/drug effects , Mice , Aspergillosis/drug therapy , Aspergillosis/microbiology , Aspergillosis/metabolism , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/drug therapy , Macrophages/drug effects , Macrophages/metabolism , Macrophages/microbiology , Cinnamates/pharmacology , Reactive Oxygen Species/metabolism , Membrane Potential, Mitochondrial/drug effects , Keratitis/microbiology , Keratitis/drug therapy , Keratitis/metabolism , Disease Models, Animal , RAW 264.7 Cells , Cytokines/metabolism , Phagocytosis/drug effectsABSTRACT
Fungal keratitis is a severely vision-threatening corneal infection, where the prognosis depends on both fungal virulence and host immune defense. Inappropriate host responses can induce substantial inflammatory damage to the cornea. Therefore, in the treatment of fungal keratitis, it is important to concurrently regulate the immune response while efforts are made to eliminate the pathogen. Ebselen is a widely studied organo-selenium compound and has been demonstrated to have antifungal, antibacterial, anti-inflammatory, and oxidative stress-regulatory properties. The effectiveness of ebselen for the treatment of fungal keratitis remains unknown. In this study, ebselen was demonstrated to produce a marked inhibitory effect on Aspergillus fumigatus (A. fumigatus), including spore germination inhibition, mycelial growth reduction, and fungal biofilm disruption. The antifungal activity of ebselen was related to the cell membrane damage caused by thioredoxin (Trx) system inhibition-mediated oxidative stress. On the contrary, ebselen enhanced the antioxidation of Trx system in mammalian cells. Further, ebselen was proven to suppress the expressions of inflammatory mediators (IL-1ß, IL-6, TNF-α, COX-2, iNOS, and CCL2) and reduce the production of oxidative stress-associated indicators (ROS, NO, and MDA) in fungi-stimulated RAW264.7 cells. In addition, ebselen regulated PI3K/Akt/Nrf2 and p38 MAPK signaling pathways, which contributed to the improvement of inflammation and oxidative stress. Finally, we verified the therapeutic effect of ebselen on mouse fungal keratitis. Ebselen improved the prognosis and reduced the fungal burden in mouse corneas. Expressions of inflammatory mediators, as well as the infiltration of macrophages and neutrophils in the cornea were also obviously decreased by ebselen. In summary, ebselen exerted therapeutic effects by reducing fungal load and protecting host tissues in fungal keratitis, making it a promising treatment for fungal infections.
Subject(s)
Anti-Inflammatory Agents , Antifungal Agents , Azoles , Isoindoles , Keratitis , Organoselenium Compounds , Oxidative Stress , Organoselenium Compounds/pharmacology , Organoselenium Compounds/therapeutic use , Animals , Keratitis/drug therapy , Keratitis/microbiology , Mice , Oxidative Stress/drug effects , Azoles/pharmacology , Azoles/therapeutic use , Antifungal Agents/pharmacology , Antifungal Agents/therapeutic use , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , RAW 264.7 Cells , Antioxidants/pharmacology , Aspergillus fumigatus/drug effects , Aspergillosis/drug therapy , Aspergillosis/microbiology , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/metabolism , Disease Models, AnimalABSTRACT
During outdoor work in April 2022, a 48-year-old man was stabbed by a tree branch and underwent intraocular foreign body extraction and repair of the scleral wound with sutures and amniotic membrane graft at a local hospital. Steroid therapy with prednisone was prescribed after a diagnosis of uveitis. Vitrectomy was performed in June 2023; a fungal culture was positive, and ITS sequencing identified the organism as Paradictyoarthrinium diffractum. Empiric antifungal therapy did not have an effect, and, because of deterioration of the condition, the left eye was enucleated in October 2023. P. diffractum is a mangrove host-specific saprophytic fungus that has not been reported in humans.
Subject(s)
Endophthalmitis , Eye Enucleation , Vitrectomy , Humans , Male , Middle Aged , Endophthalmitis/microbiology , Endophthalmitis/drug therapy , Endophthalmitis/diagnosis , Endophthalmitis/surgery , Eye Foreign Bodies/surgery , Eye Foreign Bodies/complications , Eye Foreign Bodies/diagnosis , Eye Foreign Bodies/microbiology , Eye Infections, Fungal/microbiology , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/diagnosis , Eye Infections, Fungal/surgery , Antifungal Agents/therapeutic useABSTRACT
Fluconazole (FNL) is one of the first-line treatments for fungal keratitis as it is an effective broad-spectrum antimicrobial commonly administered orally or topically. However, FNL has a very low water solubility, limiting its drug formulation, therapeutic application, and bioavailability through tissues. To overcome these limitations, this study aimed to develop FNL inclusion complexes (FNL-IC) with cyclodextrin (α-cyclodextrin, sulfobutylether-ß-cyclodextrin, and hydroxypropyl-γ cyclodextrin) and incorporate it into a dissolvable microneedle (DMN) system to improve solubility and drug penetration. FNL-IC was evaluated for saturation solubility, Fourier transform infrared spectroscopy, differential scanning calorimetry, in vitro release, minimum inhibitory concentration, minimum fungicidal concentration, and time-killing assay. DMN-FNL-IC was evaluated for mechanical and insertion properties, surface pH, moisture absorption ability, water vapor transmission, and drug content recovery. Moreover, ocular kinetic, ex vivo antimicrobial, in vivo antifungal, and chorioallantoic membrane (HET-CAM) assays were conducted to assess the overall performance of the formulation. Mechanical strength and insertion properties revealed that DMN-FNL-IC has great mechanical and insertion properties. The in vitro release of FNL-IC was significantly improved, exhibiting a 9-fold increase compared to pure FNL. The ex vivo antifungal activity showed significant inhibition of Candida albicans from 6.54 to 0.73 log cfu/mL or 100-0.94%. In vivo numbers of colonies of 0.87 ± 0.13 log cfu/mL (F2), 4.76 ± 0.26 log cfu/mL (FNL eye drops), 3.89 ± 0.24 log cfu/mL (FNL ointments), and 8.04 ± 0.58 log cfu/mL (control) showed the effectiveness of DMN preparations against other standard commercial preparations. The HET-CAM assay showed that DMN-FNL-IC (F2) did not show any vascular damage. Finally, a combination of FNL-IC and DMN was developed appropriately for ocular delivery of FNL, which was safe and increased the effectiveness of treatments for fungal keratitis.
Subject(s)
Antifungal Agents , Candida albicans , Fluconazole , Keratitis , Fluconazole/pharmacology , Fluconazole/chemistry , Fluconazole/pharmacokinetics , Animals , Antifungal Agents/pharmacology , Antifungal Agents/chemistry , Antifungal Agents/pharmacokinetics , Keratitis/drug therapy , Keratitis/microbiology , Candida albicans/drug effects , Microbial Sensitivity Tests , Rabbits , Needles , Solubility , Eye Infections, Fungal/drug therapy , Eye Infections, Fungal/microbiologyABSTRACT
BACKGROUND: Fungal keratitis is a severe eye infection that can result in blindness and visual impairment, particularly in developing countries. Fusarium spp. are the primary causative agents of this condition. Diagnosis of Fusarium keratitis (FK) is challenging, and delayed treatment can lead to serious complications. However, there is limited epidemiological data on FK, especially in tropical areas. OBJECTIVES: This study aimed to describe the clinical, laboratorial and epidemiological characteristics of FK in a tropical semi-arid region of Brazil. PATIENTS/METHODS: Adult patients with laboratory-confirmed FK diagnosed between October 2019 and March 2022 were evaluated. Fusarium isolates were characterized at molecular level and evaluated regarding antifungal susceptibility. RESULTS: A total of 226 clinical samples from patients suspected of keratitis were evaluated; fungal growth was detected in 50 samples (22.12%); out of which 42 were suggestive of Fusarium spp. (84%). Molecular analysis of a randomly selected set of 27 isolates identified F. solani species complex (n = 14); F. fujikuroi sensu lato (n = 6) and F. dimerum sensu lato (n = 7); a total of 10 haplotypes were identified among the strains. All but one Fusarium strains were inhibited by amphotericin B, natamycin and fluconazole. Most patients were male (71.42%; 30 out of 42), aged from 27 to 73 years old. Trauma was the most important risk factor for FK (40.47%; 17 out of 42). Patients were treated with antifungals, corticoids and antibiotics; keratoplasty and eye enucleation were also performed. CONCLUSIONS: The study provided insights into the characteristics of FK in tropical regions and emphasized the importance of enhanced surveillance and management strategies.