Carboxyvinyl Polymer and Guar-Borate Gelling System Containing Natamycin Loaded PEGylated Nanolipid Carriers Exhibit Improved Ocular Pharmacokinetic Parameters.

Purpose: Natamycin (NTM) ophthalmic suspension is the only FDA-approved formulation commercially available for treating ocular fungal infections. However, precorneal residence times and losses/drainage remain the foremost challenges associated with current ocular antifungal pharmacotherapy. In our previous investigations, NTM loaded polyethylene glycol nanolipid carriers (NTM-PNLCs) showed enhanced corneal permeation, both in vitro and in vivo. To further improve the corneal retention of NTM-PNLCs, this study aimed to develop a gelling system composed of carboxyvinyl polymer, guar gum, and boric acid in which the NTM-PNLCs were loaded. Methods: A 23 factorial design was employed in formulating and optimizing the gelling system for NTM-PNLCs, where the independent factors were the gelling excipients (guar gum, boric acid, and Carbopol® 940) and dependent variables were gelling time, gel depot collapse time, rheology, firmness, and work of adhesion. Optimized gel was evaluated for transcorneal permeation using rabbit cornea, in vitro; and tear pharmacokinetics and ocular biodistribution in male New Zealand White rabbits, in vivo. Results: Optimized NTM-PNLC-GEL was found to exhibit shear thinning rheology, adequate firmness, and spreadability, and formed a depot that did not collapse immediately. In addition, the in vitro transcorneal evaluation studies indicated that the NTM-PNLC-GEL exhibited a lower/slower flux and rate in comparison to Natacyn® suspension. NTM-PNLC-GEL (0.3%), at a 16-fold lower dose, exhibited mean residence time and elimination half-life comparable to Natacyn (5%), and provided similar in vivo concentrations in the innermost tissues of the eye. Conclusion: The data indicate that the NTM-PNLC-GEL formulation could serve as an alternative during ophthalmic antifungal therapy.

Gellan Gum Based Sol-to-Gel Transforming System of Natamycin Transfersomes Improves Topical Ocular Delivery.

Short precorneal residence time and poor transocular membrane permeability are the major challenges associated with topical ocular drug delivery. In the present research, the efficiency of the electrolyte-triggered sol-to-gel-forming system of natamycin (NT) transfersomes was investigated for enhanced and prolonged ophthalmic delivery. Transfersomes were optimized by varying the molar ratios of phospholipid, sorbitan monostearate (Span) and tocopheryl polyethylene glycol succinate (TPGS). NT transfersome formulations (FNs) prepared with a 1:1 molar ratio of phospholipid-to-Span and low levels of TPGS showed optimal morphometric properties, and were thus selected to fabricate the in situ gelling system. Gellan gum-based (0.3% w/v) FN-loaded formulations (FNGs) immediately formed an in situ gel in the simulated tear fluid, with considerable viscoelastic characteristics. In vitro cytotoxicity in corneal epithelial cells and corneal histology studies demonstrated the ocular safety and cytocompatibility of these optimized formulations. Transcorneal permeability of NT from these formulations was significantly higher than in the control suspension. Moreover, the ocular disposition studies of NT, from the FNs and FNGs, in New Zealand male albino rabbits demonstrated the superiority of the electrolyte-sensitive FNGs in terms of NT delivery to the ocular tissues.

The mycotic ulcer treatment trial: a randomized trial comparing natamycin vs voriconazole.

OBJECTIVE: To compare topical natamycin vs voriconazole in the treatment of filamentous fungal keratitis. METHODS: This phase 3, double-masked, multicenter trial was designed to randomize 368 patients to voriconazole (1%) or natamycin (5%), applied topically every hour while awake until reepithelialization, then 4 times daily for at least 3 weeks. Eligibility included smear-positive filamentous fungal ulcer and visual acuity of 20/40 to 20/400. MAIN OUTCOME MEASURES: The primary outcome was best spectacle-corrected visual acuity at 3 months; secondary outcomes included corneal perforation and/or therapeutic penetrating keratoplasty. RESULTS: A total of 940 patients were screened and 323 were enrolled. Causative organisms included Fusarium (128 patients [40%]), Aspergillus (54 patients [17%]), and other filamentous fungi (141 patients [43%]). Natamycintreated cases had significantly better 3-month best spectacle-corrected visual acuity than voriconazole-treated cases (regression coefficient=0.18 logMAR; 95% CI, 0.30 to 0.05; P=.006). Natamycin-treated cases were less likely to have perforation or require therapeutic penetrating keratoplasty (odds ratio=0.42; 95% CI, 0.22 to 0.80; P=.009). Fusarium cases fared better with natamycin than with voriconazole (regression coefficient=0.41 logMAR; 95% CI,0.61 to 0.20; P<.001; odds ratio for perforation=0.06; 95% CI, 0.01 to 0.28; P<.001), while non-Fusarium cases fared similarly (regression coefficient=0.02 logMAR; 95% CI, 0.17 to 0.13; P=.81; odds ratio for perforation=1.08; 95% CI, 0.48 to 2.43; P=.86). CONCLUSIONS: Natamycin treatment was associated with significantly better clinical and microbiological outcomes than voriconazole treatment for smear-positive filamentous fungal keratitis, with much of the difference attributable to improved results in Fusarium cases. APPLICATION TO CLINICAL PRACTICE: Voriconazole should not be used as monotherapy in filamentous keratitis. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00996736

[Fusarium keratitis and endophthalmitis treated by intravenous ambisome].

PURPOSE: This is a case study of Fusarium keratitis progressing to endophthatmitis that was successfully treated with a tiposomal formulation of amphotericin B (AmBisome] and local natamycin 5%. METHODS: A 41-year-old man presented with a clinical picture of endophthalmitis following deep Fusarium solani keratitis. Treatment with natamycin 5% drops and intravenous amphotericin B 150 mg per day caused renal failure and did not alleviate the endophthalmitis. Therefore, intravenous amphotericin B was replaced with intravenous AmBisome, 300 mg per day, to a cumulative dosage of 5.4 g. RESULTS: Both the endophthalmitis and keratitis were alleviated within several weeks after starting AmBisome treatment. No systemic toxicity was noted. The final ophthalmoLogic examination showed a paracentral corneal scar, and a satisfactory best corrected visual acuity of 20/40. CONCLUSIONS: Due to their relatively low systemic toxicity, liposomal formulations of amphotericin B can be administered in higher doses than traditional unencapsulated ntravenous amphotericin B achieving higher concentrations in the target organ.

Intravitreal effects of pimaricin in experimental fungal endophthalmitis.

Evaluation of 25, 50, and 100 mug of pimaricin given intravitreally to albino rabbits with Aspergillus endophthalmitis revealed that 25 mug of pimaricin, while nontoxic to the retina, was ineffective in inhibiting the fungal process. A dose of 50 mug was significantly more effective in inhibiting fungal disease but also caused significant retinal damage with loss of retinal function and iridoplegia. Dosages above this level resulted in vitreous retraction and degeneration, iridoplegia, and retinal detachment. Twenty-five micrograms of pimaricin given in three dosages spaced three days apart may be effective in inhibiting fungal endophthalmitis.