We have produced a curved antifungal contact lens with the ability to kill fungi for at least 3 weeks (). The efficacy and duration of the killing was dependent on the drug loading of the contact lens. Econazole, the drug released in this study, is U. S. Food and Drug Administration (FDA)–approved for topical use in the treatment of skin infections, but has not been approved for ophthalmic use. In the United States, there is only one drug (natamycin 5%) that is FDA approved for topical ophthalmic use to treat fungal ocular infections.31,32
From a survey of American ophthalmologists, half would prefer to use more than one medication as a first-line treatment, and most would use a different antifungal than natamycin for monotherapy, if the various antifungals were readily available.32
Econazole is commonly used in the developing world and in the United Kingdom.33
We chose it because of its low cost, wide availability in the developing world, and broad-spectrum antifungal properties.18
It is effective at killing both filamentous fungi and molds. Comparative minimum inhibitory concentration (MIC) and in vivo data suggest that C. albicans
is more difficult to kill than Fusarium
when treating with econazole.34
Therefore, since this device is effective at killing C. albicans
, then it should also kill Fusarium
, which has a lower MIC for econazole. Azole antifungal drugs have been used as adjunctive therapies for amebic keratitis; it is conceivable that they could play the same role via a drug-eluting lens.
PLGA, the polymer used here, has been widely studied and FDA approved for ocular use.19–22
Using a similar contact lens design (drug-polymer film encapsulated in HEMA hydrogel), we have previously demonstrated that the rate of drug release could be altered by either changing the molecular weight of the PLGA or by changing the proportion of PLGA to drug within the film.17
Based on these observations, it is likely that the duration of fungicidal action could have been lengthened by using a PLGA with a higher molecular mass or by increasing the ratio of PLGA to drug within the film.
The curved nature of the lens studied here is an advance over our previously reported proof-of-principle prototype drug-eluting lens.17
Both the curvature (8.05 mm base curve) and the diameter (15.5 mm) are consistent with measurements of commercially available lenses.
Storage of drug-eluting lenses could be problematic if in the wet state, particularly if the drug-containing polymer were biodegradable, as it was here. Lyophilization, or freeze drying, is therefore an attractive potential means of storage.35
Lyophilization did not have an appreciable effect on the ability of the lenses to kill fungi.
An econazole-eluting contact lens would expand ophthalmologists' armamentarium for treating fungal keratitis, which can be difficult to diagnose and to treat. Because fungus may not grow from cultures for up to 14 days, ophthalmologists often initiate treatment based on the clinical scenario and the cornea ulcer's appearance. An inadequate treatment response could be due to several factors that include an inaccurate fungal diagnosis or poor patient compliance. Therefore, poor patient compliance can complicate the ophthalmologist's treatment decision-making process. In the case of fungal keratitis, compliance is particularly difficult because of the taxing nature of the treatment regimen, which initially includes hourly drop administration throughout the night. For the patients who are compliant, the lack of sleep adds to the stress of this potentially blinding condition.
A potential concern is whether sustained elution of econazole or any other antifungal agent would lead to more rapid selection of resistant forms. Although this matter deserves close study, it seems unlikely that the development of resistance would be a greater issue than is the case with the alternative, which is eye drops.
A drug-eluting contact lens may entail considerations relating to lens care. These considerations are minimized if the lens is worn continuously. Similar to a bandage contact lens, a fungicidal contact lens could be inserted by an ophthalmologist and left in place until it is removed and/or replaced by the physician. However, it is important to understand that if the lens is removed by the patient, it will continue to release drug, and any biodegradable components will continue to degrade, albeit at a slower rate if stored at room temperature. The release would continue until some equilibrium was reached with the drug in the storage solution. In the case of an antifungal contact lens, release while in storage could be helpful in preventing fungal keratitis, which has been identified as a problem with lens care.36
Based on this study, an econazole-eluting contact lens could effectively kill Candida for weeks at a time using an HEMA hydrogel. The hydrogel materials used here were model compounds used for proof-of-concept. It may be possible to use other hydrogel materials, such as a silicone-based hydrogel which is more oxygen-permeable and may be a better candidate for a continuous-wear contact lens. However, it is possible that the design or specific elements of the production process would have to be modified to accommodate a change in the hydrogel material, or that some materials would not be amenable to formulation in the manner described here. Therefore, additional testing would be necessary to determine the feasibility of incorporating a silicone hydrogel into this design.
When developing a medical device for clinical use, it is important to consider the regulatory path that the product must travel. In the United States, a drug-releasing contact lens may be regulated by the FDA as a combination drug device, since it contains more than one regulated component.37
The primary mode of action of the lens would be determined by the FDA who would then assign the lead center (drug or device) based on this decision.37
Fungal keratitis would likely be the treatment indication for an econazole-releasing contact lens.
In the industrialized world, an antifungal contact lens could improve the treatment of mycotic eye infections by reducing the treatment burden and by increasing patient compliance. However, warm, humid areas of the developing world may most benefit from this device, since the inhabitants of those regions experience a high prevalence of mycotic eye infections.1,32,38,39
Because of trachoma and other diseases, they also have a high rate of cornea blindness, but ophthalmologists have been reluctant to use a keratoprosthesis in this patient population because of the fear of fungal endophthalmitis. In such areas, econazole-releasing contact lenses may not only improve the treatment of mycotic eye infections, but they may also expand the surgical options to include keratoprosthesis and other forms of ocular reconstruction.