Novel natamycin therapy shows promising results in recalcitrant fungal keratitis: Study
Fungal keratitis is a visually devastating corneal condition that needs urgent and appropriate management to prevent consequent ocular morbidity. Natamycin (NTM), a tetraene polyene amphoteric macrolide, is the only United States Food and Drug Administration (FDA)‑approved topical antifungal agent. The drug has broad‑spectrum antimycotic activity, is particularly active against Fusarium and Aspergillus species and is presently the most commonly preferred drug for the management of filamentous mycotic keratitis. It has a dose‑related fungicidal effect and blocks fungal growth by binding to ergosterol, an essential component in the fungal cell wall.
However, the topical application has to be repeated frequently for a prolonged time to ensure an adequate drug delivery to the site of infection. This may result in irritation, congestion, epithelial toxicity, tearing, and hypersensitivity reactions. Besides these complications, poor corneal penetration and precipitate formation, attributed to the high molecular weight and suspension form of the presently available commercial ophthalmic preparations, respectively, might decrease the efficacy of NTM for deep mycotic infections and also prevent effective patient monitoring.
The targeted delivery of the antifungal agents at the ulcer site employing intrastromal injections remains an effective alternative method of dealing with deep and recalcitrant fungal infections. Saluja G and team described treatment outcomes with a novel formulation of NTM employed as an intrastromal injection for recalcitrant fungal keratitis.
This was a prospective interventional pilot study in the setting of a tertiary eye‑care center. Twenty eyes of 20 consecutive patients with microbiologically proven recalcitrant fungal keratitis (ulcer size >2 mm, depth >50%, and not responding to topical NTM for 2 weeks) were recruited. The selected patients were injected with a novel composition of IS‑NTM (10 ug/0.1 mL, soluble natamycin) prepared aseptically in the ocular pharmacology department. All the patients continued using topical NTM suspension 5% 4‑hourly until the ulcer healed. Repeat injections were undertaken after 72 h depending on the clinical response and all the patients were followed till 6 months.
The mean age of the patients was 40.42 ± 10.09 years. The mean duration of the presentation was 20.8 ± 5.1 days. The most commonly isolated organisms were Aspergillus sp. (12/20, 60%) and Fusarium sp. (8/20, 40%). No patient had iatrogenic perforation or precipitate formation after IS‑NTM injection. The overall cure rate with IS‑NTM was 95% (19/20 patients). The number of patients who healed with the 1st, 2nd, and 3rd injection was 13, 5, and 1, respectively. One (5%) had no response to treatment and was subjected to penetrating keratoplasty. The average time taken for the resolution of the epithelial defect, stromal infiltrates, and hypopyon was 34 ± 5.2 days, 35.3 ± 6.4 days, and 15 ± 2.5 days. Healing with deep vascularization and cataract was noted in 6/19 eyes (31%) and 13/19 eyes (68.42%), respectively.
Natamycin is the most commonly advocated topical antifungal agent for the management of superficial fungal infections. Poor surgical results despite the high activity of NTM against Fusarium could be attributed to its poor bioavailability and to the variability in in vivo and in vitro drug susceptibilities. However, study experienced an overall cure rate of 95% with three injections and a 65% cure rate with the first IS‑NTM injection along with an improved visual acuity in all the patients. Enhanced success rates in this series could be attributed to our novel water‑soluble NTM (Natasol) injection.
As NTM is insoluble in an aqueous solution, it is always used as a suspension for topical fungal keratitis. Making it soluble by using the inclusion complexation technique enabled it into a soluble form suitable for intrastromal injection. This process probably augmented the delivery of NTM to the site of infection for a prolonged period that ultimately resulted in an enhanced microbiological cure. Moreover, the optically clear and preservative‑free intrastromal formulation further facilitated the healing of the epithelial defect and better patient monitoring. All these factors improved patient compliance by shortening the total duration and frequency of topical NTM. These encouraging preliminary results suggest that the novel NTM formulation could become the antifungal agent of choice for intrastromal injections besides presently being the drug of choice for topical administration
"To conclude, novice NTM inclusion complex‑enabled formulation holds a promising role as a useful adjunct to standard therapy in the management of recalcitrant filamentous fungal keratitis. Regional differences in microbiological profiles should be considered before prescribing them. Also, larger, long‑term randomized comparative trials are required to validate the current results."
Source: Saluja G, Sharma N, Agarwal R, Sharma HP, Maharana P, Satpathy G, et al. Determination of surgical outcomes with a novel formulation of intrastromal natamycin in recalcitrant fungal keratitis: A pilot study. Indian J Ophthalmol 2021;69:2670-4.
