Nonresponding fungal keratitis: Hope with intrastromal injections

Fungal keratitis often presents with deep-stromal abscess and endothelial plaque that needs to be managed timely and appropriately to prevent resultant ocular morbidity. Standard topical therapy with commonly used antifungal agents, namely, natamycin (NTM) 5% and voriconazole (VCZ) 1%, may not be sufficient for treating nonresponding fungal keratitis due to limited efficacy and the low capability of the medications to penetrate the deep layers of the cornea. Various other interventions, such as penetrating keratoplasty (PKP), collagen cross-linking with photoactivated riboflavin (PACK-CXL), excisional keratectomy combined with focal cryotherapy and amniotic membrane inlay, have been proposed to deal with these cases.[1–3] However, these have their own limitations and targeted delivery of antifungal agents at the ulcer site by means of intrastromal injections remains an effective alternative of bypassing these complex options. These injections are known to enhance the drug levels at the desired site of the cornea, thereby allowing successful healing of the corneal ulcer.[4,5] Intrastromal injections are a safe and effective adjunct to conventional therapy in the management of recalcitrant fungal keratitis.[5] Voriconazole is the most commonly used antifungal agent for intrastromal delivery (ISVCZ), and numerous studies have previously proven its efficacy in recalcitrant cases.[5] Similarly, intrastromal amphotericin B (ISAMB) has also been employed successfully for targeted drug delivery.[6] While many studies have individually described the utility of these drugs for intrastromal injections in recalcitrant fungal keratitis, there is a relative paucity of peer-reviewed literature prospectively comparing the safety and efficacy of these drugs. Bagga et al.[7] in the current retrospective study on Comparative Efficacy of Intrastromal Amphotericin B versus Voriconazole in Treating Deep-Stromal Refractory Fungal Keratitis have reported intrastromal amphotericin B to have better outcomes than intrastromal voriconazole in the management of refractory fungal keratitis. 86% of cases in the intrastromal voriconazole and 41% of cases in the intrastromal amphotericin group needed therapeutic keratoplasty. None of the patients with intrastromal injections showed corneal toxicity, except for corneal vascularization in the intrastromal amphotericin B patients which also regressed with time. The superior effect of amphotericin B in comparison with voriconazole can be due to various facts, including longer stay in the corneal stroma, more susceptibility for Aspergillus flavus, and probably more inflammation as evidenced by more stromal vascularization. Limitations of this study include its retrospective design and unequal number of patients in the two groups, with the absence of antifungal susceptibility data. Although the sample size was small, they observed a significant difference in outcomes between the two groups, and based on the observations have plans for a prospective study with a larger sample size. Though Saluja et al.[8] in a prospective study comparing the efficacy of intrastromal amphotericin B, voriconazole and natasol group have recommended ISVCZ to be the best first-line anti-stromal agent and a novel composition of NTM holding promising results and its applicability for treating recalcitrant fungal keratitis. The major limitations of this study include its relatively small sample size, the lack of a standard, clearly defined dose, and pharmacokinetics of intrastromal natamycin, as well as its added cost. Similarly, Narayana et al.[9] found no additional benefit with intrastromal voriconazole and a 2.85-fold increase in corneal perforation. To conclude, intrastromal antifungal agents can be a safe and useful adjunct to standard therapy for management of recalcitrant fungal keratitis, specifically caused by filamentary fungi. However, larger, long-term, randomized comparative trials are needed to determine the most efficacious and safest intrastromal agent. Financial support and sponsorship: Nil. Conflicts of interest: There are no conflicts of interest.About the author Ritu AroraDr Ritu Arora is currently a senior consultant (Cornea &Refractive Surgery) and Academic Director, Shroff Eye Centre, Kailash Colony, New Delhi, India She is a trained in Cornea, Ocular Surface and Refractive Surgery from Dr RP Center of Ophthallmic Sciences, AIIMS, New Delhi, Will’s Eye Hospital(Philadelphia) University of Toronto (Canada) having over 3 decades of experience in managing medical and surgical corneal and refractive disorders. She received her training in lamellar corneal surgeries under Mark Terry at University of Portland, Oregon. She has been training ophthalmology residents and senior residents in cornea, ocular surface and refractive surgery. She has been examiner for FRCO since 2022 and NBE since 2006. She was Director Guru Nanak Eye Center and later Dean MAMC She has 180 peer-reviewed publications, and is a reviewer for AJO, Eye, JCRS, Eye and Contact Lens and IJO. She has also received AAO achievement award. Her special interests are ocular surface disorders, keratoconus, infective keratitis, lamellar corneal surgeries. and KLEX. She is a member of the AAO, Royal college of ophthalmologists, EBAI and AIOS.