Platelet-derived biomaterial controls aspergillus fumigatus keratitis by decreasing fungal burden: an in vivo study.

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.

Multifunctional Polymer Vesicles for Synergistic Antibiotic-Antioxidant Treatment of Bacterial Keratitis.

As an acute ophthalmic infection, bacterial keratitis (BK) can lead to severe visual morbidity, such as corneal perforation, intraocular infection, and permanent corneal opacity, if rapid and effective treatments are not available. In addition to eradicating pathogenic bacteria, protecting corneal tissue from oxidative damage and promoting wound healing by relieving inflammation are equally critical for the efficient treatment of BK. Besides, it is very necessary to improve the bioavailability of drugs by enhancing the ocular surface adhesion and corneal permeability. In this investigation, therefore, a synergistic antibiotic-antioxidant treatment of BK was achieved based on multifunctional block copolymer vesicles, within which ciprofloxacin (CIP) was simultaneously encapsulated during the self-assembly. Due to the phenylboronic acid residues in the corona layer, these vesicles exhibited enhanced muco-adhesion, deep corneal epithelial penetration, and bacteria-targeting, which facilitated the drug delivery to corneal bacterial infection sites. Additionally, the abundant thioether moieties in the hydrophobic membrane enabled the vesicles to both have ROS-scavenging capacity and accelerated CIP release at the inflammatory corneal tissue. In vivo experiments on a mice model demonstrated that the multifunctional polymer vesicles achieved efficient treatment of BK, owing to the enhanced corneal adhesion and penetration, bacteria targeting, ROS-triggered CIP release, and the combined antioxidant-antibiotic therapy. This synergistic strategy holds great potential in the treatment of BK and other diseases associated with bacterial infections.

Secondary Amine Pendant ß-Peptide Polymers Displaying Potent Antibacterial Activity and Promising Therapeutic Potential in Treating MRSA-Induced Wound Infections and Keratitis.

Interest in developing antibacterial polymers as synthetic mimics of host defense peptides (HPDs) has accelerated in recent years to combat antibiotic-resistant bacterial infections. Positively charged moieties are critical in defining the antibacterial activity and eukaryotic toxicity of HDP mimics. Most examples have utilized primary amines or guanidines as the source of positively charged moieties, inspired by the lysine and arginine residues in HDPs. Here, we explore the impact of amine group variation (primary, secondary, or tertiary amine) on the antibacterial performance of HDP-mimicking ß-peptide polymers. Our studies show that a secondary ammonium is superior to either a primary ammonium or a tertiary ammonium as the cationic moiety in antibacterial ß-peptide polymers. The optimal polymer, a homopolymer bearing secondary amino groups, displays potent antibacterial activity and the highest selectivity (low hemolysis and cytotoxicity). The optimal polymer displays potent activity against antibiotic-resistant bacteria and high therapeutic efficacy in treating MRSA-induced wound infections and keratitis as well as low acute dermal toxicity and low corneal epithelial cytotoxicity. This work suggests that secondary amines may be broadly useful in the design of antibacterial polymers.

Propolis-Based Nanofiber Patches to Repair Corneal Microbial Keratitis.

In this research, polyvinyl-alcohol (PVA)/gelatin (GEL)/propolis (Ps) biocompatible nanofiber patches were fabricated via electrospinning technique. The controlled release of Propolis, surface wettability behaviors, antimicrobial activities against the S. aureus and P. aeruginosa, and biocompatibility properties with the mesenchymal stem cells (MSCs) were investigated in detail. By adding 0.5, 1, and 3 wt.% GEL into the 13 wt.% PVA, the morphological and mechanical results suggested that 13 wt.% PVA/0.5 wt.% GEL patch can be an ideal matrix for 3 and 5 wt.% propolis addition. Morphological results revealed that the diameters of the electrospun nanofiber patches were increased with GEL (from 290 nm to 400 nm) and Ps addition and crosslinking process cause the formation of thicker nanofibers. The tensile strength and elongation at break enhancement were also determined for 13 wt.% PVA/0.5 wt.% GEL/3 wt.% Ps patch. Propolis was released quickly in the first hour and arrived at a plateau. Cell culture and contact angle results confirmed that the 3 wt.% addition of propolis reinforced mesenchymal stem cell proliferation and wettability properties of the patches. The antimicrobial activity demonstrated that propolis loaded patches had antibacterial activity against the S. aureus, but for P. aeruginosa, more studies should be performed.

Phomopsidione nanoparticles coated contact lenses reduce microbial keratitis causing pathogens.

Microbial keratitis is the infection caused by pathogenic microorganisms that commonly occurs among the contact lens users. Various antimicrobial compounds were coated on contact lenses to kill keratitis causing microorganisms, however these compounds caused several adverse side effects. Hence, the aim of this study is to develop a silicone hydrogel contact lens coated with phomopsidione nanoparticle that inhibit keratitis causing clinical isolates. Phomopsidione nanoparticles were synthesized using polyvinyl alcohol as encapsulant. The nanoparticles showed an average size of 77.45 nm, with neutral surface charge. Two drug release patterns were observed in the drug release profile, which are the initial slow release phase with extended drug release (release rate 46.65 µg/h), and the burst release phase observed on Day 2 (release rate 2224.49 µg/h). This well-regulated drug delivery system enables the control of drug release to meet the therapeutic requirements. On agar diffusion assay, 3 out of 5 test microorganisms were inhibited by phomopsidione nanoparticle coated contact lenses, including two Gram negative bacteria. Besides, all test microorganisms showed at least 99% of growth reduction, with the treatment of the contact lens model. The drug loaded onto the nanoparticles is sufficient to prevent the bacterial growth. In conclusion, this study provides an effective alternative to combat keratitis-causing microorganisms among contact wearers.

Natamycin niosomes as a promising ocular nanosized delivery system with ketorolac tromethamine for dual effects for treatment of candida rabbit keratitis; in vitro/in vivo and histopathological studies.

OBJECTIVES: This study was aimed to develop dual-purpose natamycin (NAT)-loaded niosomes in ketorolac tromethamine (KT) gels topical ocular drug delivery system to improve the clinical efficacy of natamycin through enhancing its penetration through corneal tissue and reducing inflammation associated with Fungal keratitis (FK). SIGNIFICANCE: Nanosized carrier systems, as niosomes would provide great potential for improving NAT ocular bioavailability.NAT niosomal dispersion formulae were prepared and then incorporated in 0.5%KT gels using different mucoadhesive viscosifying polymers. METHODS: Niosomes were prepared using the reverse-phase evaporation technique. In vitro experimental, and in vivo clinical evaluations for these formulations were done for assessment of their safety and efficacy for treatment of Candida Keratitis in Rabbits. In vitro release study was carried out by the dialysis method. In vivo and histopathological studies were performed on albino rabbits. RESULTS: NAT niosomes exhibited high entrapment efficiency percentage (E.E%) up to96.43% and particle size diameter ranging from 181.75 ± 0.64 to 498.95 ± 0.64 nm, with negatively charged zeta potential (ZP). NAT niosomal dispersion exhibited prolonged in vitro drug release (40.96-77.49% over 24h). NAT-loaded niosomes/0.5%KT gel formulae revealed retardation in vitro release, compared to marketed-product (NATACYN®) and NAT-loaded niosomes up to57.32% (F8). In vivo experimental studies showed the superiority for F8 in treatment of candida keratitis and better results on corneal infiltration and hypopyon level. These results were consistent with histopathological examination in comparison with F5 and combined marketed products (NATACYN® and Ketoroline®). CONCLUSIONS: This study showed that F8 has the best results from all pharmaceutical in vitro evaluations and a better cure percent in experimental application and enhancing the prolonged delivery of NAT and penetrating the cornea tissues.

Antimicrobial Activity and Cell Selectivity of Synthetic and Biosynthetic Cationic Polymers.

The mammalian and microbial cell selectivity of synthetic and biosynthetic cationic polymers has been investigated. Among the polymers with peptide backbones, polymers containing amino side chains display greater antimicrobial activity than those with guanidine side chains, whereas ethylenimines display superior activity over allylamines. The biosynthetic polymer ε-polylysine (εPL) is noncytotoxic to primary human dermal fibroblasts at concentrations of up to 2,000 µg/ml, suggesting that the presence of an isopeptide backbone has greater cell selectivity than the presence of α-peptide backbones. Both εPL and linear polyethylenimine (LPEI) exhibit bactericidal properties by depolarizing the cytoplasmic membrane and disrupt preformed biofilms. εPL displays broad-spectrum antimicrobial properties against antibiotic-resistant Gram-negative and Gram-positive strains and fungi. εPL elicits rapid bactericidal activity against both Gram-negative and Gram-positive bacteria, and its biocompatibility index is superior to those of cationic antiseptic agents and LPEI. εPL does not interfere with the wound closure of injured rabbit corneas. In a rabbit model of bacterial keratitis, the topical application of εPL (0.3%, wt/vol) decreases the bacterial burden and severity of infections caused by Pseudomonas aeruginosa and Staphylococcus aureus strains. In vivo imaging studies confirm that εPL-treated corneas appeared transparent and nonedematous compared to untreated infected corneas. Taken together, our results highlight the potential of εPL in resolving topical microbial infections.

Broad-Spectrum Antimicrobial/Antifouling Soft Material Coatings Using Poly(ethylenimine) as a Tailorable Scaffold.

Microbial colonization and biofilm formation is the leading cause of contact lens-related keratitis. Treatment of the condition remains a challenge because of the need for prolonged therapeutic course and high doses of antimicrobial agents especially for biofilm eradication. The development of strategies to prepare nonfouling contact lens surfaces is a more practical way to ensure users' safety and relieve the excessive public healthcare burden. In this study, we report a series of polymers that were modified to introduce functionality designed to facilitate coating adhesion, antimicrobial and antifouling properties. Cyclic carbonate monomers having different functional groups including adhesive catechol, antifouling poly(ethylene glycol) (PEG), and hydrophobic urea/ethyl were conjugated onto branched poly(ethylenimine) (bPEI, 25 kDa) at various degrees in a facile and well-controlled manner using a simple one step, atom economical approach. Immersion of contact lenses into an aqueous solution of the catechol-functionalized polymers at room temperature resulted in robust and stable coating on the lens surfaces, which survived the harsh condition of autoclaving and remained on the surface for a typical device application lifetime (7 days). The deposition of the polymer was unambiguously confirmed by static contact angle measurement and X-ray photoelectron spectroscopy (XPS). Polymer coating did not change light transmission significantly. Combinatorial optimization demonstrated that lenses coated with bPEI functionalized with catechol, PEG (5 kDa) and urea groups at 1:12:3:23 molar ratio for 18 h provided the highest antifouling effect against four types of keratitis-causing pathogens: Staphylococcus aureus, Pseudomonas aeruginosa, Candida albicans, and Fusarium solani, after 7 days of incubation. The polymer coating also inhibited protein adsorption onto the contact lens surfaces after exposure to bovine serum albumin solution for up to 24 h, owing to the flexible and large PEG constituent. Notably, all the polymer coatings used in this study were biocompatible, achieving ≥90% cell viability following direct contact with human corneal epithelial cells for 24 h. Hence, these polymer coatings are envisaged to be promising for the prevention of contact lens-related keratitis.

Antifungal activity of a liposomal itraconazole formulation in experimental Aspergillus flavus keratitis with endophthalmitis.

The aim of this study was to assess the efficacy of topical application of a liposomal formulation of itraconazole for the treatment of experimental keratitis with endophthalmitis caused by Aspergillus flavus. The liposomes were obtained by the lipid film hydration method followed by sonication. Adult female Wistar rats (weighing 200-220 g) were immunosuppressed by intraperitoneal injection of 150 mg/kg of cyclophosphamide 3 days before infection by exposure to the fungus A. flavus (10(7) spores/ml). Forty-eight hours later, the animals were treated with the liposomal formulation. For comparison, one group of animals (n = 6) was treated with the same drug not encapsulated. At the end of the experiment, the animals were evaluated for clinical signs and number of colony forming units (CFU/g), along with direct microscopic examination. The results indicated that the liposomal formulation of itraconazole has better antifungal activity than the unencapsulated drug in the treatment of fungal keratitis with endophthalmitis caused experimentally by A. flavus in Wistar rats.

Comparative studies for ciprofloxacin hydrochloride pre-formed gels and thermally triggered (in situ) gels: in vitro and in vivo appraisal using a bacterial keratitis model in rabbits.

This article reports on comparative in vitro characterization and in vivo evaluation of pre-formed cellulose-based gels, methylcellulose (MC) and carboxymethylcellulose sodium (CMC) and in situ gel-forming Pluronic F127 (PL) for ocular delivery of ciprofloxacin hydrochloride (Cipro) by using a bacterial keratitis model and histological corneal examination. Drug-polymer interactions were studied employing thermal analysis. Further, different concentrations (1-3% w/w or 10-30% w/w) of gels depending on the nature of the polymer used were prepared, characterized for clarity, pH, rheology and in vitro release. Selected gel formulations were evaluated for ocular delivery to Staphylococcus aureus-infected rabbit corneas; and ocular toxicity through histological examination of the cornea. The results demonstrated no Cipro-polymers physicochemical interactions and pseudoplastic flow for all gels used at 35 °C. Both polymer concentrations and drug solubility in the gels are dominantly the rate-determining factors for in vitro drug release. The corneal healing rate for all gel-based formulations was significantly faster (p < 0.05) than that for Cipro solution-treated rabbits. PL-based gel induced significant swelling/edema of the corneal stroma, compared with MC- and CMC-based gels. In conclusion, cellulose-based polymers have superior ocular tolerability/dramatically less irritant; and superior efficacy with more convenient administration compared with PL and Cipro solution, respectively.

Rational design of antibiotic-free antimicrobial contact lenses: Trade-offs between antimicrobial performance and biocompatibility.

Microbial keratitis associated with contact lenses (CLs) wear remains a significant clinical concern. Antibiotic therapy is the current standard of care. However, the emergence of multidrug-resistant pathogens necessitates the investigation of alternative strategies. Antibiotic-free antimicrobial contact lenses (AFAMCLs) represent a promising approach in this regard. The effectiveness of CLs constructed with a variety of antibiotic-free antimicrobial strategies against microorganisms has been demonstrated. However, the impact of these antimicrobial strategies on CLs biocompatibility remains unclear. In the design and development of AFAMCLs, striking a balance between robust antimicrobial performance and optimal biocompatibility, including safety and wearing comfort, is a key issue. This review provides a comprehensive overview of recent advancements in AFAMCLs technology. The focus is on the antimicrobial efficacy and safety of various strategies employed in AFAMCLs construction. Furthermore, this review investigates the potential impact of these strategies on CLs parameters related to wearer comfort. This review aims to contribute to the continuous improvement of AFAMCLs and provide a reference for the trade-off between resistance to microorganisms and wearing comfort. In addition, it is hoped that this review can also provide a reference for the antimicrobial design of other medical devices.

A biomimetic human disease model of bacterial keratitis using a cornea-on-a-chip system.

Bacterial keratitis is a common form of inflammation caused by the bacterial invasion of the corneal stroma after trauma. In extreme cases, it can lead to severe visual impairment or even blindness; therefore, timely medical intervention is imperative. Unfortunately, widespread misuse of antibiotics has led to the development of drug resistance. In recent years, organ-on-chips that integrate multiple cell co-cultures have extensive applications in fundamental research and drug screening. In this study, immortalized human corneal epithelial cells and primary human corneal fibroblasts were co-cultured on a porous polydimethylsiloxane membrane to create a cornea-on-a-chip model. The developed multilayer epithelium closely mimicked clinical conditions, demonstrating high structural resemblance and repeatability. By introducing a consistently defective epithelium and bacterial infection using the space-occupying method, we successfully established an in vitro model of bacterial keratitis using S. aureus. We validate this model by evaluating the efficacy of antibiotics, such as levofloxacin, tobramycin, and chloramphenicol, through simultaneously observing the reactions of bacteria and the two cell types to these antibiotics. Our study has revealed the barrier function of epithelium of the model and differentiated efficacy of three drugs in terms of bactericidal activity, reducing cellular apoptosis, and mitigating scar formation. Altogether, the cornea on chip enables the assessment of ocular antibiotics, distinguishing the impact on corneal cells and structural integrity. This study introduced a biomimetic in vitro disease model to evaluate drug efficacy and provided significant insights into the extensive effects of antibiotics on diverse cell populations within the cornea.

Targeted Bacterial Keratitis Treatment with Polyethylene Glycol-Dithiothreitol-Boric Acid Hydrogel and Gatifloxacin.

INTRODUCTION/OBJECTIVE: To prolong the ocular residence time of gatifloxacin and enhance its efficacy against bacterial keratitis, this study developed a velocity-controlled polyethylene glycol-dithiothreitol-boric acid (PDB) hydrogel loaded with gatifloxacin. METHODS: First, the basic properties of the synthesized PDB hydrogel and the gatifloxacin-loaded PDB hydrogel were assessed. Secondly, the in vitro degradation rate of the drug-loaded PDB was measured in a simulated body fluid environment with pH 7.4/5.5. The release behavior of the drug-loaded PDB was studied using a dialysis method with PBS solution of pH 7.4/5.5 as the release medium. Finally, a mouse model of bacterial keratitis was established, and tissue morphology was observed using hematoxylin-eosin staining. Additionally, mouse tear fluid was extracted to observe the antibacterial effect of the gatifloxacin-loaded PDB hydrogel. RESULTS: The results showed that the PDB hydrogel had a particle size of 124.9 nm and a zeta potential of -23.3 mV, with good porosity, thermosensitivity, viscosity distribution, rheological properties, and high cell compatibility. The encapsulation of gatifloxacin did not alter the physical properties of the PDB hydrogel and maintained appropriate swelling and stability, with a high drug release rate in acidic conditions. Furthermore, animal experiments demonstrated that the gatifloxacin- loaded PDB hydrogel exhibited superior therapeutic effects compared to gatifloxacin eye drops and displayed strong antibacterial capabilities against bacterial keratitis. CONCLUSION: This study successfully synthesized PDB hydrogel and developed a gatifloxacin drug release system. The hydrogel exhibited good thermosensitivity, pH responsiveness, stability, and excellent biocompatibility, which can enhance drug retention, utilization, and therapeutic effects on the ocular surface.

Exploring the potential of nanoparticles-based polydopamine for effective treatment of refractory keratitis: Mild photothermal loop therapy.

Keratitis is the leading cause of blindness worldwide. In refractory cases, it can even lead to eyeball enucleation. The critical challenges of refractory keratitis are the drug-resistant bacteria and bacterial biofilms formation. Therefore, we established an innovative therapeutic approach for keratitis based on mild photothermal loop (MPL) therapy. First, we analyzed the bactericidal effect of methicillin-resistant Staphylococcus aureus (MRSA) under various loops and temperature durations to determine the optimal condition. Then, RAN-seq was applied to explore the underlying mechanisms. Additionally, we formulated a dual-purpose polyvinyl alcohol-polydopamine (PDA/PVA) hydrogel system and explored its effects on the reactive oxygen species (ROS) scavenging capability, antibacterial properties, and anti-inflammatory properties in vitro, as well as its effect in vivo. The results indicated substantial bactericidal properties after exposure in four loops, each lasting 10 min at 45 °C. RNA-seq revealed the altered genes related to virulence and biofilm formation. In addition to good photothermal performance, the PDA/PVA system could effectively eliminate MRSA, reduce ROS, inhibit biofilm formation, and decrease inflammatory factors expression. Moreover, the in vivo results demonstrated the potential of MPL for bacterial keratitis. This study serves as the first attempt to use MPL therapy for refractory keratitis, offering a new approach for clinical practice.

Topical Vancomycin is More Efficient than Povidone-Iodine Treatment in Controlling Bacterial Growth in Methicillin-Resistant Staphylococcus Aureus Keratitis Model in Rabbits.

To evaluate the efficacy of topical vancomycin and povidone iodine (PI) application on methicillin-resistant Staphylococcus aureus (MRSA) keratitis model in rabbits.MRSA keratitis was induced by injecting 0.1 mL MRSA containing 1000 colony-forming units (CFU) into central cornea of right eyes of 24 New Zealand White rabbits. Animals were divided into four groups (n = 6): control (treated with balanced salt solution), 50 mg/mL topical vancomycin, 5% topical PI, and combination; examined before and after treatment, and corneal tissues were harvested for analysis at 9th hour of treatment.Bacterial load was determined as: 7.63 ± 0.82 log10 CFU/g in control group, 6.95 ± 1.66 log10 CFU/g in PI group, 4.67 ± 0.77 log10 CFU/g in combination group, and 4.33 ± 0.71 log10 CFU/g in vancomycin group (p = 0.001). Median of total clinical score increased significantly from 7 [range: 5-8] to 11.5 [range: 11-15] (p = 0.001) in control group, did not change (6 [range: 5-8] to 7 [range: 5-7]; p = 0.695) in vancomycin group, increased significantly from 7 [range: 5-8] to 12.5 [range: 10-14] (p < 0.001) in PI group, increased significantly from 6.5 [range: 5-7] to 8 [range: 7-9] in combination group (p = 0.002). Post-treatment clinical scores for chemosis, conjunctival injection, iritis, hypopyon, epithelial erosion, and corneal infiltrate were significantly lower in vancomycin-treated groups compared to others (p < 0.05). In PI-treated groups, especially scores for chemosis, conjunctival injection, epithelial erosion and corneal infiltrate were significantly higher than vancomycin (p < 0.05).Topical vancomycin significantly inhibited bacterial growth in MRSA keratitis. However, PI was ineffective in controlling this growth; additionally, exerted toxic effect on ocular surface. When vancomycin was combined with PI, no additional increase in efficacy of treatment was detected compared to only vancomycin.

Antibiotic-free ocular sterilization while suppressing immune response to protect corneal transparency in infectious keratitis treatment.

Clinical guidelines for infectious keratitis treatment require that anti-inflammatory drugs can only be used after infection elimination, which causes irreversible inflammatory damage to the cornea. In this work, photodynamic metal organic frameworks (PCN-224) were used as drug carrier to load Pt NPs with catalase-like activity and anti-inflammatory drug (Dexamethasone, DXMS) for endogenous oxygen generation and reduced corneal damage, respectively. The photodynamic therapy (PDT) effect was greatly enhanced in bacteria elimination and bacterial biofilms removal through catalysis of overexpressed hydrogen peroxide (H2O2, ∼8.0 and 31.0 µM in bacterial solution and biofilms, respectively) into oxygen by Pt NPs. More importantly, the cationic liposome modified PCN-224@Pt@DXMS@Liposomes (PPDL NPs) greatly enhanced the adhesion to negatively charged ocular surface and penetration into corneal barrier and bacterial biofilms. Both in vitro cell viability test and in vivo eye irritation tests proved good biocompatibility of PPDL NPs under 660 nm laser irradiation. Furthermore, PDT of PPDL NPs in rapid bacteria killing was verified through infectious keratitis animal model. The superior bactericidal effect of antibacterial materials could largely replace the bactericidal effect of the immune system. It is worth mentioning that this simultaneous sterilization and anti-inflammation treatment mode is a new exploration against the clinical treatment guidelines.

Breaking Down the Barriers of Drug Resistance and Corneal Permeability with Chitosan-Poly(ethylene glycol)-LK13 Peptide Conjugate to Combat Fungal Keratitis.

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.

Microbial keratitis: could contact lens material affect disease pathogenesis?

Microbial keratitis is a sight-threatening complication associated with contact lenses. The introduction of silicone hydrogel lens materials with increased oxygen transmission to the ocular surface has not significantly altered the incidence of microbial keratitis. These data suggest that alternate, or additional, predisposing factors involving lens wear must be addressed to reduce or eliminate these infections. The contact lens can provide a surface for microbial growth in situ and can also influence ocular surface homeostasis through effects on the tear fluid and corneal epithelium. Thus, it is intuitive that future contact lens materials could make a significant contribution to preventing microbial keratitis. Design of the "right" material to prevent microbial keratitis requires understanding the effects of current materials on bacterial virulence in the cornea and on ocular surface innate defenses. Current knowledge in each of these areas will be presented with a discussion of future directions needed to understand the influence of lens material on the pathogenesis of microbial keratitis.

The effects of silicone hydrogel lens wear on the corneal epithelium and risk for microbial keratitis.

Previous studies using animal models and human clinical trials have demonstrated that the use of low-oxygen-transmissible contact lens materials produce corneal epithelial surface damage resulting in increased Pseudomonas aeruginosa (PA) adhesion and raft-mediated internalization into surface corneal epithelial cells. These findings led to the testable clinical predictions that (1) microbial keratitis (MK) risk is expected to be the greatest during the first 6 months of wear; (2) there is no difference between 6 and 30 night extended wear; and (3) that wear of hyperoxygen-transmissible lenses would reduce the reported incidence of infection. Subsequent epidemiologic studies have confirmed the first two predictions; however, increased oxygen transmissibility with silicone hydrogel (SiHy) lens wear has not altered the overall incidence of MK. In this review, more recent clinical and basic studies that investigate epithelial alterations and bacterial adhesion to corneal epithelial cells after the wear of SiHy lenses with and without concomitant exposure to chemically preserved multipurpose solutions (MPS) will be examined. The collective results of these studies demonstrate that even in the absence of lens-related hypoxia, MPS induce ocular surface changes during SiHy lens wear that are associated with a pathophysiologic increase in PA adherence and internalization in the corneal epithelium, and therefore, predict a greater risk for PA-MK. In addition, new data supporting an interactive role for inflammation in facilitating PA adherence and internalization in the corneal epithelium will also be discussed.

The epidemiology of microbial keratitis with silicone hydrogel contact lenses.

It was widely anticipated that after the introduction of silicone hydrogel lenses, the risk of microbial keratitis would be lower than with hydrogel lenses because of the reduction in hypoxic effects on the corneal epithelium. Large-scale epidemiological studies have confirmed that the absolute and relative risk of microbial keratitis is unchanged with overnight use of silicone hydrogel materials. The key findings include the following: (1) The risk of infection with 30 nights of silicone hydrogel use is equivalent to 6 nights of hydrogel extended wear; (2) Occasional overnight lens use is associated with a greater risk than daily lens use; (3) The rate of vision loss due to corneal infection with silicone hydrogel contact lenses is similar to that seen in hydrogel lenses; (4) The spectrum of causative organisms is similar to that seen in hydrogel lenses, and the material type does not impact the corneal location of presumed microbial keratitis; and (5) Modifiable risk factors for infection include overnight lens use, the degree of exposure, failing to wash hands before lens handling, and storage case hygiene practice. The lack of change in the absolute risk of disease would suggest that exposure to large number of pathogenic organisms can overcome any advantages obtained from eliminating the hypoxic effects of contact lenses. Epidemiological studies remain important in the assessment of new materials and modalities. Consideration of an early adopter effect with studies involving new materials and modalities and further investigation of the impact of second-generation silicone hydrogel materials is warranted.