RESUMO
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.
Assuntos
Antifúngicos , Aspergilose , Aspergillus fumigatus , Ceratite , Aspergillus fumigatus/efeitos dos fármacos , Animais , Ceratite/microbiologia , Ceratite/tratamento farmacológico , Camundongos , Aspergilose/tratamento farmacológico , Aspergilose/microbiologia , Antifúngicos/farmacologia , Antifúngicos/uso terapêutico , Modelos Animais de Doenças , Materiais Biocompatíveis , Plaquetas/efeitos dos fármacos , Natamicina/farmacologia , Natamicina/administração & dosagem , Natamicina/uso terapêutico , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Córnea/microbiologia , Córnea/patologia , Córnea/efeitos dos fármacosRESUMO
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.
Assuntos
Antifúngicos , Quitosana , Córnea , Farmacorresistência Fúngica , Fusarium , Ceratite , Testes de Sensibilidade Microbiana , Polietilenoglicóis , Quitosana/química , Quitosana/farmacologia , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Antifúngicos/farmacologia , Antifúngicos/química , Fusarium/efeitos dos fármacos , Animais , Ratos , Farmacorresistência Fúngica/efeitos dos fármacos , Polietilenoglicóis/química , Córnea/efeitos dos fármacos , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Permeabilidade/efeitos dos fármacos , Fusariose/tratamento farmacológico , Peptídeos Antimicrobianos/farmacologia , Peptídeos Antimicrobianos/química , Natamicina/farmacologia , Natamicina/administração & dosagem , Masculino , Modelos Animais de Doenças , Ratos Sprague-DawleyRESUMO
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.
Assuntos
Antifúngicos , Ceratite , Metarhizium , Microscopia Confocal , Natamicina , Humanos , Natamicina/uso terapêutico , Natamicina/administração & dosagem , Masculino , Metarhizium/genética , Metarhizium/isolamento & purificação , Adulto , Ceratite/microbiologia , Ceratite/tratamento farmacológico , Ceratite/diagnóstico , Antifúngicos/uso terapêutico , Região do Caribe , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Infecções Oculares Fúngicas/diagnóstico , Resultado do Tratamento , Administração Tópica , Córnea/microbiologia , Córnea/patologiaRESUMO
Fungal infections of cornea are important causes of blindness especially in developing nations with tropical climate. However, the challenges associated with current treatments are responsible for poor outcome. Natamycin is the only FDA-approved antifungal drug to treat fungal keratitis, but unfortunately due to its poor water solubility, it is available as suspension. The marketed suspension (5% Natamycin) has rapid precorneal clearance, poor corneal permeability, a higher frequency of administration, and corneal irritation due to undissolved suspended drug particles. In our study, we developed clear and stable natamycin-loaded nanomicelles (1% Natcel) to overcome the above challenges. We demonstrated that 1% Natcel could permeate the cornea better than 5% suspension. The developed 1% Natcel was able to provide sustained release for up to 24 h. Further, it was found to be biocompatible and also improved the mean residence time (MRT) than 5% suspension in tears. Therefore, the developed 1% Natcel could be a potential alternative treatment for fungal keratitis.
Assuntos
Antifúngicos , Córnea , Liberação Controlada de Fármacos , Infecções Oculares Fúngicas , Ceratite , Micelas , Nanopartículas , Natamicina , Natamicina/administração & dosagem , Antifúngicos/administração & dosagem , Antifúngicos/química , Antifúngicos/farmacologia , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Animais , Córnea/microbiologia , Córnea/metabolismo , Córnea/efeitos dos fármacos , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Coelhos , Solubilidade , Preparações de Ação Retardada , Lágrimas/metabolismoAssuntos
Ascomicetos/isolamento & purificação , Córnea/microbiologia , Infecções Oculares Fúngicas/diagnóstico , Ceratite Dendrítica/diagnóstico , Natamicina/administração & dosagem , Acuidade Visual , Voriconazol/administração & dosagem , Antifúngicos/administração & dosagem , Córnea/patologia , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Humanos , Ceratite Dendrítica/tratamento farmacológico , Ceratite Dendrítica/microbiologia , Masculino , Pessoa de Meia-Idade , Soluções Oftálmicas , Resultado do TratamentoRESUMO
Natamycin (NT) is a synthetic broad-spectrum antifungal used in eye drops. However, it has low solubility and high molecular weight, limiting its permeation, and generally causes eye discomfort or irritation when administered. Therefore, the present study aimed to develop an ophthalmic in situ gel formulation with NT-loaded cubosomes to enhance ocular permeation, improve antifungal activity, and prolong the retention time within the eye. The NT-loaded cubosome (NT-Cub) formula was first optimized using an I-optimal design utilizing phytantriol, PolyMulse, and NT as the independent formulation factors and particle size, entrapment efficiency %, and inhibition zone as responses. Phytantriol was found to increase particle size and entrapment efficiency %. Higher levels of PolyMulse slightly increased the inhibition zone whereas a decrease in particle size and EE% was observed. Increasing the NT level initially increased the entrapment efficiency % and inhibition zone. The optimized NT-Cub formulation was converted into an in situ gel system using 1.5% Carbopol 934. The optimum formula showed a pH-sensitive increase in viscosity, favoring prolonged retention in the eye. The in vitro release of NT was found to be 71 ± 4% in simulated tear fluid. The optimum formulation enhanced the ex vivo permeation of NT by 3.3 times compared to a commercial formulation and 5.2 times compared to the NT suspension. The in vivo ocular irritation test proved that the optimum formulation is less irritating than a commercial formulation of NT. This further implies that the developed formulation produces less ocular irritation and can reduce the required frequency of administration.
Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Géis/química , Natamicina/farmacologia , Acrilatos/química , Administração Oftálmica , Animais , Antifúngicos/administração & dosagem , Antifúngicos/farmacocinética , Química Farmacêutica , Portadores de Fármacos , Liberação Controlada de Fármacos , Testes de Sensibilidade Microbiana , Natamicina/administração & dosagem , Natamicina/farmacocinética , Tamanho da Partícula , CoelhosRESUMO
BACKGROUND: Fungal keratitis can be more difficult to treat than bacterial keratitis with worse outcomes. OBJECTIVE: To evaluate the therapeutic response time of topical voriconazole combined with intrastromal voriconazole, and topical natamycin on Fusarium keratitis. METHODS: The stroma of corneas of twelve New Zealand White rabbits was inoculated with Fusarium sp spores. Seven days after inoculation, they were divided into 2 groups randomly. Group A was treated with topical natamycin 5% for 21 days. Group B was treated with intrastromal voriconazole 0.05% single injection at the beginning of treatment, continued with topical voriconazole 1% for 21 days. Clinical evaluations for epithelial defect size and clinical scores in each group were performed on 1st, 3rd, 7th, 10th, 14th and 21st days after treatment. Mycological examinations were performed before and after the treatment. RESULTS: After treatment, there was no statistically significant difference between natamycin and voriconazole in reducing epithelial defect size at first, second or third week after treatment (P = .15; P = .39; and P = .90). The clinical scores on both groups also showed no statistically significant differences at first, second and third weeks after treatment (P = .24; P = .09; and P = .32). Qualitative mycological evaluation before and after the treatment showed no statistically significant difference in KOH examination (P = 1; P = 1) and culture in Sabouraud dextrose agar (P = 1; P = 1). CONCLUSION: Intrastromal voriconazole injection combined with topical voriconazole seems to give similar response time but not earlier in improving clinical presentation of Fusarium keratitis as topical natamycin.
Assuntos
Antifúngicos , Infecções Oculares Fúngicas , Fusariose/tratamento farmacológico , Ceratite/tratamento farmacológico , Administração Tópica , Animais , Antifúngicos/administração & dosagem , Antifúngicos/uso terapêutico , Córnea/microbiologia , Úlcera da Córnea/tratamento farmacológico , Úlcera da Córnea/microbiologia , Modelos Animais de Doenças , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Fusarium/efeitos dos fármacos , Humanos , Ceratite/microbiologia , Natamicina/administração & dosagem , Natamicina/uso terapêutico , Coelhos , Voriconazol/administração & dosagem , Voriconazol/uso terapêuticoRESUMO
Purpose: Formulation of new drug delivery system as Natamycin (NT)-loaded nanoparticle niosomal formulae mixed in different polymer gel, with the addition of ketorolac tromethamine (KETR). Pharmaceutical and experimental assessments to evaluate their safety and efficacy in treating Aspergillus keratitis. Methods: NT nanoparticle niosomes prepared by reverse-phase evaporation technique were mixed in different polymers, with the addition of KETR. Two formulae are evaluated in this study: F1 [NT-loaded nanoparticle niosomes/0.5% KETR 4% carboxymethyl cellulose (Na.CMC) gel], F2 [NT-loaded nanoparticle niosomes/0.5% KETR 2% hydroxypropylmethyl cellulose (HPMC)-E4 gel], and mixed marketed products (MMP), namely Natamet® and Ketoroline® suspension eye drops. NT-loaded nanoparticle niosomes/0.5% KETR were evaluated through viscosity determination, mucoadhesive attractive force, and in vitro NT release studies. The in vivo antifungal evaluation was performed on 45 albino rabbits, Aspergillus species were inoculated in right corneas of all rabbits, and then rabbits were subdivided into 3 groups, 15 rabbits each: Group A: received F1, Group B: received F2, and Group C: received MMP. Daily examination of rabbits was performed for evaluation of corneal infiltration, and signs of iritis. Two weeks later, rabbits were euthanized; their corneas were dissected at the limbus and sent for histopathological evaluation. Results: F1 had a higher viscosity and more mucoadhesive power than F2, and showed better results on corneal infiltration, and level of hypopyon. These results were consistent with the histopathological examination. Conclusion: The formula of NT-loaded nanoparticle niosomes/0.5% KT 4% Na.CMC gel has the best results from all pharmaceutical in vitro evaluations and a better cure percent in experimental application.
Assuntos
Aspergilose/tratamento farmacológico , Ceratite/tratamento farmacológico , Cetorolaco/farmacologia , Natamicina/farmacologia , Administração Oftálmica , Animais , Anti-Infecciosos Locais/administração & dosagem , Anti-Infecciosos Locais/farmacologia , Antifúngicos/administração & dosagem , Antifúngicos/farmacologia , Aspergilose/microbiologia , Modelos Animais de Doenças , Combinação de Medicamentos , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Ceratite/microbiologia , Cetorolaco/administração & dosagem , Lipossomos , Nanopartículas , Natamicina/administração & dosagem , Polímeros , CoelhosRESUMO
Purpose: Natamycin (NTM) ophthalmic suspension is the only FDA-approved formulation commercially available for treating ocular fungal infections. However, precorneal residence times and losses/drainage remain the foremost challenges associated with current ocular antifungal pharmacotherapy. In our previous investigations, NTM loaded polyethylene glycol nanolipid carriers (NTM-PNLCs) showed enhanced corneal permeation, both in vitro and in vivo. To further improve the corneal retention of NTM-PNLCs, this study aimed to develop a gelling system composed of carboxyvinyl polymer, guar gum, and boric acid in which the NTM-PNLCs were loaded. Methods: A 23 factorial design was employed in formulating and optimizing the gelling system for NTM-PNLCs, where the independent factors were the gelling excipients (guar gum, boric acid, and Carbopol® 940) and dependent variables were gelling time, gel depot collapse time, rheology, firmness, and work of adhesion. Optimized gel was evaluated for transcorneal permeation using rabbit cornea, in vitro; and tear pharmacokinetics and ocular biodistribution in male New Zealand White rabbits, in vivo. Results: Optimized NTM-PNLC-GEL was found to exhibit shear thinning rheology, adequate firmness, and spreadability, and formed a depot that did not collapse immediately. In addition, the in vitro transcorneal evaluation studies indicated that the NTM-PNLC-GEL exhibited a lower/slower flux and rate in comparison to Natacyn® suspension. NTM-PNLC-GEL (0.3%), at a 16-fold lower dose, exhibited mean residence time and elimination half-life comparable to Natacyn (5%), and provided similar in vivo concentrations in the innermost tissues of the eye. Conclusion: The data indicate that the NTM-PNLC-GEL formulation could serve as an alternative during ophthalmic antifungal therapy.
Assuntos
Antifúngicos/farmacocinética , Composição de Medicamentos/métodos , Infecções Oculares Fúngicas/tratamento farmacológico , Géis/administração & dosagem , Nanopartículas/administração & dosagem , Natamicina/farmacocinética , Animais , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antifúngicos/uso terapêutico , Boratos/administração & dosagem , Boratos/química , Córnea/fisiologia , Cyamopsis/química , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Géis/química , Masculino , Nanopartículas/química , Natamicina/administração & dosagem , Natamicina/efeitos adversos , Natamicina/uso terapêutico , Soluções Oftálmicas/administração & dosagem , Permeabilidade/efeitos dos fármacos , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Polímeros/administração & dosagem , Polímeros/química , Coelhos , Distribuição Tecidual/efeitos dos fármacosRESUMO
Background: Natamycin is the only topical ophthalmic antifungal drug approved by the Food and Drug Administration (FDA) of the United States, but has unsatisfactory factors such as high dosing frequency.Methods: We report the synthesis and preparation of self-assembled poly(ethylene glycol)-block-poly(glycidyl methacrylate) (PEG-b-PGMA) micelles. These nanoparticles exhibit sustained delivery of a hydrophobic natamycin by topical administration on eye due to the hydrolysable properties of PGMA segments of micelle. Hydrolysis of glycidyl groups within a physiologically relevant environment provides an additional driving force for drug release by generation of hydrophilic hydroxyl groups to 'push' the encapsulated hydrophobic drug away from the resultant hydrophilic domains and into surrounding environment.Results: In vitro and in vivo results revealed that the self-assembled micelles and the encapsulated natamycin were not cytotoxic and the released drug have strong antifungal ability to Candida albicans. Importantly, sustained natamycin release from micelles leads to the reduced administration frequency of natamycin from 8 times per day to 3 times per day in rabbits suffering from fungal keratitis (FK).Conclusion: This study demonstrates a facile method that can greatly reduce dosing frequency of natamycin administration and thus improve long-term patient compliance.
Assuntos
Antifúngicos/administração & dosagem , Infecções Oculares Fúngicas/tratamento farmacológico , Ceratite/tratamento farmacológico , Natamicina/administração & dosagem , Administração Tópica , Animais , Liberação Controlada de Fármacos , Humanos , Micelas , Nanopartículas/química , CoelhosRESUMO
BACKGROUND: Fungal keratitis (FK) is a serious pathogenic condition usually associated with significant ocular morbidity. Natamycin (NAT) is the first-line and only medication approved by the Food and Drug Administration for the treatment of FK. However, NAT suffers from poor corneal penetration, which limits its efficacy for treating deep keratitis. PURPOSE: The objective of this work was to prepare NAT solid lipid nanoparticles (NAT-SLNs) to achieve sustained drug release and increased corneal penetration. METHODS: NAT-SLNs were prepared using the emulsification-ultrasonication technique. Box- Behnken experimental design was applied to optimize the effects of independent processing variables (lipid concentration [X1], surfactant concentration [X2], and sonication frequency [X3]) on particle size (R1), zeta potential (ZP; R2), and drug entrapment efficiency (EE%) (R3) as responses. Drug release profile, ex vivo corneal permeation, antifungal susceptibility, and cytotoxicity of the optimized formula were evaluated. RESULTS: The optimized formula had a mean particle size of 42 r.nm (radius in nanometers), ZP of 26 mV, and EE% reached ~85%. NAT-SLNs showed an extended drug release profile of 10 hours, with enhanced corneal permeation in which the apparent permeability coefficient (Papp) and steady-state flux (Jss) reached 11.59×10-2 cm h-1 and 3.94 mol h-1, respectively, in comparison with 7.28×10-2 cm h-1 and 2.48 mol h-1 for the unformulated drug, respectively. Antifungal activity was significantly improved, as indicated by increases in the inhibition zone of 8 and 6 mm against Aspergillus fumigatus ATCC 1022 and a Candida albicans clinical isolate, respectively, and minimum inhibitory concentration values that were decreased 2.5-times against both of these pathogenic strains. NAT-SLNs were found to be non-irritating to corneal tissue. NAT-SLNs had a prolonged drug release rate, that improved corneal penetration, and increased antifungal activity without cytotoxic effects on corneal tissues. CONCLUSION: Thus, NAT-SLNs represent a promising ocular delivery system for treatment of deep corneal keratitis.
Assuntos
Córnea/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Infecções Oculares Fúngicas/tratamento farmacológico , Ceratite/tratamento farmacológico , Lipídeos/química , Nanopartículas/química , Natamicina/administração & dosagem , Natamicina/uso terapêutico , Administração Oftálmica , Análise de Variância , Animais , Antifúngicos/farmacologia , Preparações de Ação Retardada/uso terapêutico , Portadores de Fármacos/uso terapêutico , Liberação Controlada de Fármacos , Fungos/efeitos dos fármacos , Cabras , Humanos , Ceratite/microbiologia , Testes de Sensibilidade Microbiana , Natamicina/farmacologia , Tamanho da Partícula , Permeabilidade , Eletricidade EstáticaRESUMO
Short precorneal residence time and poor transocular membrane permeability are the major challenges associated with topical ocular drug delivery. In the present research, the efficiency of the electrolyte-triggered sol-to-gel-forming system of natamycin (NT) transfersomes was investigated for enhanced and prolonged ophthalmic delivery. Transfersomes were optimized by varying the molar ratios of phospholipid, sorbitan monostearate (Span) and tocopheryl polyethylene glycol succinate (TPGS). NT transfersome formulations (FNs) prepared with a 1:1 molar ratio of phospholipid-to-Span and low levels of TPGS showed optimal morphometric properties, and were thus selected to fabricate the in situ gelling system. Gellan gum-based (0.3% w/v) FN-loaded formulations (FNGs) immediately formed an in situ gel in the simulated tear fluid, with considerable viscoelastic characteristics. In vitro cytotoxicity in corneal epithelial cells and corneal histology studies demonstrated the ocular safety and cytocompatibility of these optimized formulations. Transcorneal permeability of NT from these formulations was significantly higher than in the control suspension. Moreover, the ocular disposition studies of NT, from the FNs and FNGs, in New Zealand male albino rabbits demonstrated the superiority of the electrolyte-sensitive FNGs in terms of NT delivery to the ocular tissues.
Assuntos
Antibacterianos/administração & dosagem , Géis/química , Lipossomos/química , Natamicina/administração & dosagem , Polissacarídeos Bacterianos/química , Administração Oftálmica , Administração Tópica , Animais , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Linhagem Celular , Córnea/efeitos dos fármacos , Córnea/metabolismo , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Elasticidade , Humanos , Masculino , Natamicina/efeitos adversos , Natamicina/farmacocinética , Permeabilidade , Coelhos , ViscosidadeRESUMO
PURPOSE: To determine if there is a benefit to adjuvant intrastromal voriconazole (ISV) injections for primary treatment of filamentous fungal keratitis. DESIGN: Outcome-masked, randomized controlled clinical trial. PARTICIPANTS: Patients with moderate vision loss resulting from a smear-positive fungal ulcer. METHODS: Study eyes were randomized to topical natamycin plus ISV injection versus topical natamycin alone. MAIN OUTCOME MEASURES: The primary outcome of the trial was microbiological cure on 3-day repeat culture analysis. Secondary outcomes included microbiological cure on 7-day repeat culture analysis; 3-week and 3-month best spectacle-corrected visual acuity; infiltrate or scar size or both; rate of perforation; therapeutic penetrating keratoplasty (TPK); and other adverse events. RESULTS: A total of 151 patients with smear-positive ulcers were screened and 70 were enrolled at Aravind Eye Hospital, Pondicherry, India. Baseline cultures grew Fusarium in 19 samples (27%), Aspergillus in 17 samples (24%), and other filamentous fungi in 19 samples (27%) and showed negative results in 13 samples (19%). Those randomized to ISV injection had 1.82 times the odds of 3-day culture positivity after controlling for baseline culture status (95% confidence interval [CI], 0.65-5.23; P = 0.26, bias-corrected logistic regression) and 1.98 times the odds of positive 7-day culture results, after controlling for baseline culture status (95% CI, 0.69-5.91; P = 0.20, bias-corrected logistic regression). Those randomized to ISV injection showed 0.5 logMAR lines (approximately 0.5 Snellen lines) of decreased visual acuity (95% CI, -2.6 to 3.6 lines; P = 0.75) and 0.55 mm worse infiltrate or scar size or both at 3 months after controlling for baseline values (95% CI, -0.13 to 1.25; P = 0.11). Intrastromal voriconazole injections showed a 2.85-fold increased hazard of perforation after controlling for baseline infiltrate depth (95% CI, 0.76-10.75; P = 0.12) but no difference in the rate of TPK (hazard ratio, 0.95; 95% CI, 0.44-2.04; P = 0.90). CONCLUSIONS: There seems to be no benefit to adding ISV injections to topical natamycin in the primary treatment of moderate to severe filamentous fungal ulcers. Studies consistently suggest that voriconazole has a limited role in the treatment of filamentous fungal ulcers.
Assuntos
Antifúngicos/administração & dosagem , Infecções Oculares Fúngicas/tratamento farmacológico , Fungos/isolamento & purificação , Ceratite/tratamento farmacológico , Voriconazol/administração & dosagem , Adulto , Infecções Oculares Fúngicas/microbiologia , Feminino , Humanos , Injeções Intraoculares , Masculino , Pessoa de Meia-Idade , Natamicina/administração & dosagemRESUMO
PURPOSE: To evaluate the efficacy of the topical, systemic and targeted therapy (TST) protocol in management of fungal keratitis. METHOD: All cases of treatment-naive smear- or culture-proven fungal keratitis presenting between June 2013 and May 2017 were recruited. The TST protocol included initial treatment with topical natamycin 5% with addition of oral ketoconazole or voriconazole in ulcers with size >5 mm, depth >50%, or impending perforation. Topical voriconazole 1% was included in case of poor response at 7 to 10 days. Intrastromal or intracameral antifungal injections were administered in case of poor response to combination therapy. Penetrating keratoplasty was performed in case of poor response to any of the regimen. RESULTS: The study included 223 cases of fungal keratitis with a mean age of 43.6 ± 15.3 years and a male-to-female ratio of 1.8:1. The mean area of the ulcer and infiltrate at presentation was 25.52 ± 19 and 25.7 ± 14.4 mm, respectively. Corrected distance visual acuity at presentation was 2.05 ± 0.43 logMAR that improved to 1.6 ± 0.4 logMAR at 3 months. Fusarium (42.2%) was the most common microorganism isolated, followed by Aspergillus (32.8%). The mean healing time was 41.5 ± 22.2 days, with a final scar size of 14.6 ± 8.2 mm. The treatment success rate with the TST protocol was 79.8%. Corneal perforation developed in 7% of cases (n = 15), and keratoplasty was performed for 20.2% of cases (n = 45). CONCLUSIONS: The TST protocol provides a stepwise treatment algorithm for management of cases of fungal keratitis with varying severity.
Assuntos
Antifúngicos/administração & dosagem , Infecções Oculares Fúngicas/tratamento farmacológico , Ceratite/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Injeções Intraoculares , Ceratite/microbiologia , Cetoconazol/administração & dosagem , Masculino , Pessoa de Meia-Idade , Natamicina/administração & dosagem , Soluções Oftálmicas/uso terapêutico , Estudos Prospectivos , Acuidade Visual , Voriconazol/administração & dosagem , Adulto JovemRESUMO
INTRODUCTION: Infectious keratitis of fungal origin mainly affects people in tropical and subtropical countries, and is an important cause of preventable blindness. Topical antifungals, particularly natamycin and voriconazole, are considered effective, but it is not clear which one is the best treatment alternative. METHODS: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified three systematic reviews including three studies overall,all of which were randomized trials. We concluded natamycin probably is associated with better visual acuity after infection, and it prevents corneal perforation and/or need to perform therapeutic keratoplasty compared to voriconazole in fungal keratitis.
INTRODUCCIÓN: La queratitis infecciosa de origen fúngico afecta principalmente a personas de países tropicales y subtropicales, y constituye una importante causa de ceguera prevenible. Los antifúngicos tópicos, en particular la natamicina y el voriconazol, se consideran efectivos, pero no está claro cuál de ellos constituye la mejor alternativa de tratamiento. MÉTODOS: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos tres revisiones sistemáticas que en conjunto incluyeron tres estudios primarios, todos correspondientes a ensayos aleatorizados. Concluimos que natamicina probablemente se asocia a mejor agudeza visual tras la infección, y que previene la perforación corneal y/o la necesidad de realizar queratoplastia terapéutica en comparación a voriconazol en queratitis fúngica.
Assuntos
Infecções Oculares Fúngicas/tratamento farmacológico , Ceratite/tratamento farmacológico , Natamicina/administração & dosagem , Voriconazol/administração & dosagem , Antifúngicos/administração & dosagem , Bases de Dados Factuais , Infecções Oculares Fúngicas/microbiologia , Humanos , Ceratite/microbiologia , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Mycotic keratitis or keratomycosis is a fungal infection with global distribution. The dominant aetiology of this disease varies based on geographical origin, socioeconomic status, and climatic condition. Generally, Aspergillus spp. and Fusarium spp. are common in tropical and subtropical regions and Candida spp. are dominant in temperate areas. Demonstration of fungal elements in microscopic examination besides the isolation of fungi in culture is the gold standard of laboratory diagnosis. As the culture is a time-consuming procedure, other approaches such as in vivo confocal microscopy which produces real-time imaging of corneal tissue and molecular techniques have been developed to facilitate rapid diagnosis of fungal keratitis. The first choice of treatment is topical natamycin, although topical amphotericin B is the best choice for Aspergillus and Candida keratitis. Regarding the diversity of fungal aetiology and the emergence of drug resistance in some genera and species, proper identification using molecular methods and antifungal susceptibility testing could provide useful data. Furthermore, as the better efficacy of combination therapy in comparison to monotherapy is reported, in vitro determination of interactions between various drugs seem informative. This review aims to provide a general and updated view on the aetiology, risk factors, epidemiology, clinical and laboratory diagnosis, and management of fungal keratitis.
Assuntos
Infecções Oculares Fúngicas/diagnóstico , Infecções Oculares Fúngicas/epidemiologia , Fungos/isolamento & purificação , Ceratite/diagnóstico , Ceratite/epidemiologia , Técnicas Microbiológicas/métodos , Microscopia/métodos , Administração Tópica , Anfotericina B/administração & dosagem , Antifúngicos/administração & dosagem , Clima , Quimioterapia Combinada/métodos , Infecções Oculares Fúngicas/tratamento farmacológico , Infecções Oculares Fúngicas/microbiologia , Fungos/classificação , Saúde Global , Humanos , Ceratite/tratamento farmacológico , Ceratite/microbiologia , Técnicas de Diagnóstico Molecular/métodos , Natamicina/administração & dosagem , Fatores de RiscoRESUMO
PURPOSE: To investigate the ocular penetration of natamycin (NAT) and voriconazole (VRC) after topical instillation in New Zealand white rabbits using simplified liquid chromatography-tandem mass spectrometry (LC-MS/MS) and high-performance liquid chromatography. METHODS: Seventy-eight healthy rabbits were randomly divided into 3 groups. In the first 2 groups, 72 rabbits were used for single-dose testing (36 for NAT, 36 for VRC), in which 50 µL of 5.0% NAT or 1.0% VRC was instilled into the rabbits' left eyes. In the 3rd group, 6 rabbits were used for repeated-dose testing in which 50 µL of 5.0% NAT was instilled into their left eyes 12 times (once per hour) during the daytime. These animals were sacrificed immediately to collect their aqueous humors and corneas. RESULTS: After a single topical instillation, the highest concentrations in the cornea and aqueous humor for VRC were 34.1 µg/g and 14.7 µg/mL, respectively. The permeability ratios of aqueous/cornea were from 0.1 to 1.26. The highest concentrations in cornea and aqueous humor for NAT were 299.3 ng/g and 27.1 ng/mL, respectively. The permeability ratios of aqueous/cornea were from 0.02 to 0.23. In the repeated-dose group, the NAT concentrations in the cornea and aqueous humor were 10,569 ng/g and 54.4 ng/mL, respectively. The permeability ratio was as low as 0.0051. CONCLUSION: The better corneal penetration of VRC suggests that it is more suitable for deep corneal fungal infections than NAT via topical ocular administration.
Assuntos
Humor Aquoso/química , Córnea/química , Natamicina/farmacocinética , Soluções Oftálmicas/farmacocinética , Voriconazol/farmacocinética , Administração Tópica , Animais , Cromatografia Líquida , Feminino , Masculino , Natamicina/administração & dosagem , Natamicina/análise , Soluções Oftálmicas/administração & dosagem , Soluções Oftálmicas/análise , Coelhos , Espectrometria de Massas em Tandem , Voriconazol/administração & dosagem , Voriconazol/análiseRESUMO
The present study aimed at formulating and optimizing natamycin (NT)-loaded polyethylene glycosylated nano-lipid carriers (NT-PEG-NLCs) using Box-Behnken design and investigating their potential in ocular applications. Response surface methodology computations and plots for optimization were performed using Design-Expert® software to obtain optimum values for response variables based on the criteria of desirability. Optimized NT-PEG-NLCs had predicted values for the dependent variables which are not significantly different from the experimental values. NT-PEG-NLCs were characterized for their physicochemical parameters; NT's rate of permeation and flux across rabbit cornea was evaluated, in vitro, and ocular tissue distribution was assessed in rabbits, in vivo. NT-PEG-NLCs were found to have optimum particle size (<300 nm), narrow polydispersity index, and high NT entrapment and NT content. In vitro transcorneal permeability and flux of NT from NT-PEG-NLCs was significantly higher than that of Natacyn®. NT-PEG-NLC (0.3%) showed improved delivery of NT across the intact cornea and provided concentrations statistically similar to the marketed suspension (5%) in inner ocular tissues, in vivo, indicating that it could be a potential alternative to the conventional suspension during the course of fungal keratitis therapy.
Assuntos
Anti-Infecciosos Locais/administração & dosagem , Córnea/metabolismo , Portadores de Fármacos/química , Lipídeos/química , Natamicina/administração & dosagem , Polietilenoglicóis/química , Administração Oftálmica , Animais , Anti-Infecciosos Locais/farmacocinética , Composição de Medicamentos , Liberação Controlada de Fármacos , Masculino , Nanoestruturas/química , Natamicina/farmacocinética , Tamanho da Partícula , Permeabilidade , CoelhosRESUMO
Delivery of therapeutic molecules into the deeper ocular compartments is mainly hampered by short precorneal residence and limited transmembrane permeability of topically administered drugs. Hence, the current study was undertaken to fabricate the ion-sensitive in situ gels of natamycin (NT) bilosomes (NB) for efficient ocular delivery. The effect of cholesterol and sodium taurocholate proportion on the properties of the bilosomes were studied and the formulation with better physicochemical properties was optimized and utilized to derive the in situ gelling system (IG). The impact of type/composition of gelling agent on the formation and characteristics of the hydrogel was investigated. The hydrogel formed from IG with 0.3% w/v gellan gum showed optimal viscoelastic and adhesive characteristics. The ocular safety and cytocompatibility of NB and its IG was confirmed by corneal histology and in vitro cytotoxicity evaluation. A 6- to 9-fold enhancement in the transcorneal flux of NB demonstrated efficient ocular penetration of bilosomes. Moreover, the superior mean dose normalized NT levels in the ocular tissues of rabbits treated with optimized NB and IG illustrated the effectiveness of bilosomes loaded ion-sensitive in situ hydrogels as a potential platform for the improved and prolonged ocular pharmacotherapy.
Assuntos
Ácidos e Sais Biliares/química , Hidrogéis/química , Hidrogéis/metabolismo , Lipossomos/química , Natamicina/administração & dosagem , Natamicina/química , Administração Oftálmica , Linhagem Celular , Córnea/metabolismo , Hidrogéis/toxicidade , Tamanho da Partícula , Permeabilidade , ReologiaRESUMO
We report a case of keratitis caused by a rare fungus Podospora austroamericana. Clinical and microbiological evaluation of the corneal ulcer was done and the treatment outcome was studied. The fungus was grown from the corneal scraping, and it was identified as P. austroamericana based on DNA sequence and analysis of the internal transcribed spacer region. The patient was treated with topical azithromycin, natamycin and voriconazole. Despite maximum medical therapy, the ulcer progressed very rapidly and the patient developed panophthalmitis and evisceration of the eye had to be done. This is the first reported case of keratitis caused by P. austroamericana.