The results of this study indicate that the prepared solutions of voriconazole, irrespectively of the storage conditions, are in vitro effective against Candida albicans, Aspergillus fumigatus, Alternaria alternata
and Fusarium oxysporum
, as it is shown in Table 1. Only Fusarium solani
presented a full growth at all tested concentrations.
The combination of these results with the existing data from the work of other investigators, leads to the extraction of very useful treatment considerations.
Current literature provides evidence on the penetration of voriconazole into the eye and its effectiveness for the treatment of fungal ocular infections
Dupuis D et al. have reported that voriconazole 1% eye drop
solution remains chemically and visually stable, without any significant variation in the osmolarity and pH for at least 30 days in whatever storage conditions were used. Furthermore, exposure to light did not cause any degradation of the drug [3
]. Amorós-Reboredo P et al. reported that frozen 1% voriconazole ophthalmic solution at -20°C was stable for 90 days, and after thawing remained stable at 5°C for 14 days. The clearness, pH and osmolarity of the solutions remained unchanged, regardless of the solution temperature [11
]. Al-Badriyeh D et al. showed that voriconazole 1% solution, preserved with 0.01% benzalkonium chloride, was stable at 2-8°C for at least 14 weeks, while voriconazole 2% solution was stable for 16 weeks at 2-8°C or at 25°C and for 8 weeks at 40°C [12
The eye drops of voriconazole 1% in our study were unpreserved, and independently of the storage conditions, in the fridge or at room conditions, they retained their efficacy for more than two weeks (18 days) after the reconstitution.
As regards the eye infections, fungal keratitis is a severe condition, which potentially can lead to blindness. The main causes of fungal keratitis are Fusarium, Candida and Aspergillus species as well as Scedosporium or Alternaria and the variety of effective antifungal agents and the clinical outcomes are poor [1
]. Moreover, intraocular infections, such as endophthalmitis, can be treated very difficultly. Topical administration of voriconazole is potentially very useful for the treatment of fungal keratitis and perhaps for prophylaxis against the development of fungal endophthalmitis and in many cases, voriconazole eye drops are used in combination with systemic formulas [13
Vemulakonda GA et al. studied 13 patients and obtained aqueous and vitreous samples after topical administration of 1% voriconazole every 2 hours for 24 hours before surgery. The mean ± SD voriconazole levels in the aqueous humor were 6.49 ± 3.04 μg/ml. Furthermore, the mean ± SD voriconazole levels in the vitreous humor were 0.16 ± 0.08 μg/ml [4
]. In relation to our results, this application with eye drops only, can achieve satisfactory concentrations of the drug in the aqueous humor. However, it is not adequate to give sufficient concentrations in the vitreous cavity.
Hariprasad SM et al. obtained plasma, vitreous, and aqueous samples from 14 patients after oral administration twice of 400 mg of voriconazole, in a period of 12 hours, before surgery. The mean ± SD voriconazole levels were 2.13 ± 0.93 μg/ml, 0.81 ± 0.31 μg/ml and 1.13 ± 0.57) μg/ml, respectively. This study reports that orally administrated voriconazole could achieve therapeutic levels in aqueous and vitreous humors in no inflamed human eyes, for a wide spectrum of microoganisms, including Aspergillus, Candida and other fungal causes of endophthalmitis and thus, oral administration of voriconazole could be very useful and efficacious for the management and prophylaxis of fungal endophthalmitis [16
]. In relation to our results, this application may achieve therapeutic concentrations in the aqueous against Candida albicans
and Aspergilus fumigatus
, questionably against Alternaria alternata
and not against Fusarium oxysporum
and Fusarium solani
. As regards to the vitreous concentrations, they are even lower sand thus are expected to be less effective.
Thiel MA et al. showed that combined oral and topical administration of voriconazole resulted in drug concentration >2.93 μg/ml in aqueous humor, which is efficacious against many fungi. On the other hand, when voriconazole is used topically, the drug concentration in aqueous humor is >0.61 mg/ml, which is above the MIC90 for the majority of Candida species. Thus, the topical application of voriconazole alone is not effective for some less susceptible fungi and it is recommended a combined topical and systemic administration as initial treatment, until the causative microorganism is identified [17
]. Accordingly and in relation to our results, Alternaria alternata
and potentially Fusarium oxysporum
are also sensitive to this combined oral and topical application. The resistance of Fusarium solani
is a problem as has been shown in an interesting work of Oechsler RA et al. Fusarium solani
isolates had significantly higher resistance to voriconazole than the non-solani isolates requiring a concentration of 16 μg/ml [18
Another important issue is the half-life of voriconazole. Shen YC et al. estimated the rapid decline of voriconazole after an intracameral injection. The half-life of the drug in the aqueous humor was 22 minutes [19
] and this rapid decline raises certain considerations about the required frequency of administration. The same authors, after the intravitreal injection of 35 μg/0.1 ml voriconazole, estimated a half-life of 2.5 hours [20
Furthermore, Wei LC et al. in an experimental study found that by increasing the frequency of drops, the drug concentration in the aqueous and in the vitreous increases significantly, especially in eyes with previous mechanical epithelium debridement (scraped corneas). The every 5 minutes application for 30 minutes schedule gave concentrations of 33.44 ± 5.77 μg/ml in the aqueous of the non-scraped and 57.67 ± 6.77 μg/ml in the aqueous of the scraped eyes. With the dosing schedule they followed after this initial installation by installing drops for four additional times every 20 minutes, the aqueous concentration ranged from 19.97 to 23.70 μg/ml 5 min after these doses in the non-scraped eyes and from 44.44 to 49.02 μg/ml in the scraped eyes while the vitreous concentrations remained significantly lower and ranged from 0.38 to 0.49 μg/ml in the non-scraped eyes and from 0.72 to 0.94 μg/ml in the scraped eyes [21
]. These results indicate that the frequent topical application may lead to significantly higher concentrations in the aqueous.
Consequently the therapeutic approach of fungal infections is rather complex. The topical application of voriconazole carries various considerations about the frequency of installation and the duration of the treatment. Combined application increases the drug efficacy. The intravitreal application, for increased concentrations of the drug in the eye, is also an interesting therapeutic approach and more experience has to be gained. The drug monitoring of voriconazole is a useful adjunct.
In conclusion, the solution of voriconazole 1% (reconstituted eye drops in sterile water for injection), proved to be effective in several concentrations, independently of the storage conditions (refrigerator or room storage), for more than two weeks (18 days). In relation to the results of the present study and according to the involved fungus, the topical administration of voriconazole should be adjusted appropriately, so as to achieve the required therapeutic levels of the drug in the eye.