Comparison of Safety and Efficacy of Intrastromal Injections of Voriconazole, Amphotericin B and Natamycin in Cases of Recalcitrant Fungal Keratitis: A Randomized Controlled Trial

Abstract

Objective To compare the safety and efficacy of intrastromal voriconazole (IS-VCZ), amphotericin B (IS-AMB) and natamycin (IS-NTM) as an adjunct to topical natamycin (NTM) in cases of recalcitrant fungal keratitis. Design Prospective randomized trial. Setting Tertiary eye centre. Participants Sixty eyes of 60 patients with microbiologically proven recalcitrant fungal keratitis (ulcer size >2 mm, depth >50% of stroma, and not responding to topical NTM therapy for two weeks) were recruited. Methods patients were randomized into three groups of 20 eyes, each receiving ISVCZ 50ug/0.1 mL, ISAMB, 5ug/0.1 mL and ISNTM 10ug/0.1 mL (prepared aseptically in ocular pharmacology). The patients in all three groups continued topical NTM 5% every four hours until the ulcer healed. Primary outcome measure was time taken till complete clinical resolution of infection, and secondary outcome measure was best corrected visual acuity (BCVA) at six months. Results All three groups had comparable baseline parameters. The mean duration of healing was significantly better (p=0.02) in the ISNTM group (34±5.2 days) as compared to the ISVCZ group (36.1±4.8 days) and the ISAMB group (39.2±7.2 days). About 95%, 90% and 95% patients healed successfully in the ISVCZ, ISAMB and ISNTM groups, respectively. In terms of healing, deep vascularization was significantly greater in the ISAMB group (55%, p=0.02) when compared to the ISVCZ and ISNTM groups (31% and 26%, respectively). There were fewer repeat injections in the ISNTM group (7/20 vs 8/20 and 9/20 in the ISVCZ and ISNTM groups, respectively). Conclusion Intrastromal injections are a safe and effective adjunct to conventional therapy in the management of recalcitrant fungal keratitis. ISNTM had a similar visual outcome with faster healing while ISAMB had a higher rate of deep vascularization after healing.

Fusarium Keratitis—Review of Current Treatment Possibilities

“…The mean duration of healing was shorter in the group treated with intrastromal NAT. Higher rates of vascularization were reported in the AMB group [ 81 ].…”

Recent Perspectives in the Management of Fungal Keratitis

“…The intrastromal injection of amphotericin B has been found to be useful in indolent keratitis caused by Candida and other species. A higher rate of deep vascularization on healing was noted with intrastromal amphotericin B in a recent [88] comparison of intrastromal voriconazole, amphotericin B and natamycin. The relatively smaller number of patients and adjunctive use of other topical or systemic antifungal agents preclude a convincing conclusion on intrastromal usage.…”

“…Natamycin solution at a concentration of 1% for topical use and 0.01% for intrastromal injection was evaluated for efficacy and toxicity in rabbit models and was found non-inferior to a 5% commercially available natamycin suspension. A clinical study [88] comparing the intrastromal use of this solution form of natamycin and other commonly used agents like voriconazole and amphotericin B showed this formulation to have significantly better mean healing time than the other two groups. Further studies with larger sample sizes need to be undertaken in this regard for better validation of this novel natamycin solution.…”

“…However, Narayana et al's [87] randomized control study, assessing the efficacy of addition of intrastromal voriconazole 1% to a treatment regimen for moderate to severe filamentous fungal keratitis, found no added advantage in terms of day three and day seven culture positivity, final scar size, 3 month visual acuity or reduced rate of perforation/reduced need for TPK with the addition of intrastromal voriconazole when compared with topical natamycin 5% monotherapy. A recent study [88] comparing the safety and efficacy of the intrastromal injection of voriconazole, amphotericin and natamycin showed all three groups to be comparable in efficacy with the amphotericin group in comparison to the other two, which require more injections and also result in a large scar size with deep vascularization as a complication. The conflicting results between randomized control trials done by Narayana et al [87] and Saluja et al [88] have been attributed to variations in the fungal isolates obtained in each study with Fusarium predominating in the former and Aspergillus in the latter.…”

“…A recent study [88] comparing the safety and efficacy of the intrastromal injection of voriconazole, amphotericin and natamycin showed all three groups to be comparable in efficacy with the amphotericin group in comparison to the other two, which require more injections and also result in a large scar size with deep vascularization as a complication. The conflicting results between randomized control trials done by Narayana et al [87] and Saluja et al [88] have been attributed to variations in the fungal isolates obtained in each study with Fusarium predominating in the former and Aspergillus in the latter. Further randomized control trials in this direction need to be performed to verify the dose, dosing interval, minimum and maximum number of injections, indications, efficacy and safety of this mode of treatment.…”