Intravitreally Implantable Voriconazole Drug Delivery System For Experimental Fungal Endophthalmitis

Objective To investigate the therapeutic effect and optimal dose of sustained, intravitreally implantable voriconazole drug delivery systems (VCZ-DDS) in experimental endophthalmitis of Aspergillus fumigatus, and the in vivo release regularity of VCZ-DDS.Methods VCZ-DDS was composed of voriconazole and its carrier PLGA. Right eyes of forty-two albino rabbits were infected with an intravitreal inoculation of susceptible Aspergillus fumigatus(\,000 CFU/mL). Forty-eight hours later, the 42 inoculated eyes of 42 rabbits were randomized into six groups. There was no treatment in group A (n=6). The other groups all had vitrectomy performed with PLGA implantation(n=6), voriconazole injection(n=6), and intravitreal VCZ DDS containing 0.5 mg(n=8),0.9 mg(n=8) and 1.2 mg(n=8) of voriconazole in the DDS, respectively. Clinical grading system including aqueous flare, cells and vitreous opacity was used to assess the severity of inflammation, and vitreous humor smear and culture were compared at selected intervals thereafter. Two months after operation, histopathologic examination was performed to observe the effect of fungi and medicines to the structure of the eyes. One VCZ-DDS containing 1.2mg voriconazole was implanted into each right eye of 6 rabbits after vitrectomy. Then vitreous humor was aspirated and the concentration of voriconazole was determined by High performance liquid chromatography-mass spectrometry (HPLC-MS-MS).Results Aspergillus of 103CFU/mL induced endophthalmitis in all untreated and PLGA implanted rabbits, showing no difference in the first 7 days (p≥0.212). The eyes rapidly developed to panophthalmitis, and ocular atrophy at the end of follow-up. The inflammation in the drug-treated eyes was milder in comparison to that in the eyes of the control and blank PLGA groups (p≤0.046). The 0.9 and 1.2mg VCZ-DDS implanted eyes showed milder anterior chamber inflammation and vitreous opacity than VCZ injected eyes (p≤0.044) in the first three weeks, but only the vitreous of 1.2mg VCZ-DDS group was clearer than VCZ injected group (p≤0.037) thereafter. The vitreous of 1.2mg VCZ-DDS group was clearer than those of 0.5mg VCZ-DDS group (p=0.023) on days 10 and 14, but similar to 0.9mg VCZ-DDS group (p≥0.144). Smear and fungal culture results were negative in all VCZ-DDS implanted groups, while most samples in other groups were positive. Histopathological examination showed normal structures in the cured eyes, while most untreated eyes had atrophy and eyeball destroyed. Conclusions The curative effect of intravitreal VCZ-DDS is significantly better than that of traditional intraocular injection of voriconazole. The optimal dose is 1.2mg VCZ-DDS.