An Update on Voriconazole in Ophthalmology

Ocular mycosis is one of the leading causes of corneal blindness. The range of common antifungal agents available for ocular mycosis remains inadequate and is generally associated with poor clinical outcomes. Voriconazole is a newer generation triazole antifungal agent, only marketed in systemic formulation, with broad-spectrum activity and a high intraocular penetration. Voriconazole has demonstrated effectiveness against ocular mycosis. This review article is aimed at providing comprehensive information about the uses of voriconazole in ophthalmology in different scenarios. Off label preparation and different routes of administration like intrastromal , intracameral and intravitreal etc. been described along with case reports and relevant studies. It has been demonstrated in many case reports that voriconazole has been used as a stand alone therapy, as a second line of drug in unresponsive cases and also as an adjunctive drug along with other antifungals.


Introduction
The 1990s witnessed an expansion of the antifungal armamentarium to include two new azole agents, namely fluconazole and itraconazole . These agents changed our approach in treating many fungal infections. However, neither was an ideal agent. Fluconazole had a limited spectrum of antifungal activity and resistance was soon noted in immunosuppressed hosts who received long term treatment. Itraconazole was plagued by absorption problems. Second-generation triazole agents have been in development for the past decade. The first of these newer agents to receive approval from the US Food and Drug Administration (FDA) is voriconazole. 1 Fungal eye infections, common in temperate climates, have been notoriously difficult to diagnose and treat. Current treatment options are far from optimal. New generation triazoles, including voriconazole, have been shown in laboratory studies and clinical experience to have very good safety profiles with fewer side effects. Voriconazole is a triazole having a structure similar to fluconazole with the addition of a methyl group to the propyl backbone and the replacement of a triazole moiety with a fluoropyrimidine group but with increased activity in vitro, an expanded spectrum, and poor aqueous solubility. 2 (Figure 1).

Mechanism of Action of Voriconazole
The major effect of imidazoles and triazoles on fungi is inhibition of 14-sterol demethylase, a microsomal Cytochrome Peroxidase(CYP). Imidazoles and triazoles thus impair the biosynthesis of ergosterol for the cytoplasmic membrane and lead to the accumulation of 14-methylsterols. These methylsterols may disrupt the close packing of acyl chains of phospholipids, impairing the functions of certain membrane-bound enzyme systems, thus inhibiting the growth of the fungi. 2 ISSN 0972-0200 is given intravenously, SBECD is excreted completely by the kidney. Significant accumulation of SBECD occurs with a creatinine clearance <50 mL/minute. Because toxicity of SBECD at high plasma concentrations is unclear, oral voriconazole is preferred in azotemic patients. 2

Spectrum of Activity
Voriconazole is potent against a wide spectrum of fungi, namely, Candida albicans, Candida parapsilosis, Candida tropicalis, Aspergillus fumigatus, Aspergillus flavus, Fusarium solani, and other less common pathogens from the Paecilomyces, Histoplasma, Scedosporium, Curvularia, and Acremonium species. In a study by Marangon et

Eye drops and Topical formulations Aqueous humor concentration in Non -keratitis and keratitis patients
Three studies have investigated voriconazole penetration through the human cornea (non-keratitis) into the aqueous humor. Two of them investigated 1% voriconazole eye drops and one investigated 2% voriconazole eye drops. 7,8,9 The sixth hourly and hourly dosing, voriconazole concentrations in the aqueous humor were studied which suggested that six-hourly dosing of 1% voriconazole eye drops may be ineffective. Samples taken after hourly dosing were collected approximately one hour after the last dose but the aqueous humor concentrations achieved were not sufficiently high to be effective against all common pathogenic fungi. Although voriconazole concentrations were detected in the aqueous humor after topical administration of voriconazole eye drops, this may not necessarily correlate with efficacy in the clinical setting of fungal keratitis. 10 Well-designed clinical studies of voriconazole eye drops in patients with active fungal keratitis are difficult to perform and therefore such  7,9,10 To date, the penetration of topical voriconazole eye drops in patients with infective keratitis has been reported only twice, in the form of case reports. In these studies good aqueous humor concentrations were achieved following hourly dosing of topical 1% voriconazole and provided enough support for benefit of using voriconazole eye drops. 11,12 Stability of voriconazole eye drops According to the stability study by Al-Badriyeh et al, 1% voriconazole eye drops, prepared in sterile benzalkonium chloride 0.01% solution, were stable for at least 14 weeks when stored at 2-8 0 C, while 2% voriconazole eye drops, also prepared in sterile benzalkonium chloride solution, were stable for 16 weeks at 2-8, 25, and 40 0 C. 13 This was consistent with the stability study by Dupuis et al, where 1% voriconazole eye drops, prepared in sterile water for injection, were stable for at least four weeks when stored at 4 0 C. 14 Such long-term stability data will help minimize wastage and is pivotal to facilitate the use of the eye drops in the outpatient setting.

Drug Interactions
Voriconazole is metabolized by, and inhibits, CYPs. The major metabolite of voriconazole, the voriconazole N-oxide, also inhibits these CYPs. Inhibitors or inducers of these CYPs may increase or decrease voriconazole plasma concentrations, respectively. In addition, there is potential for voriconazole and its major metabolite to increase the plasma concentrations of other drugs metabolized by these enzymes like omeprazole, sirolimus, digoxin, phenytoin and so on. The dose of omeprazole should be reduced by half.
As the sirolimus AUC increases 11-fold when voriconazole is given, co-administration is contraindicated. 2

Side effects
Although voriconazole is generally well tolerated, occasional cases of hepatotoxicity have been reported, and liver function should be monitored. Voriconazole, like some other azoles, causes changes in electrocardiographic wave forms. Patients must be warned about possible visual effects. Transient visual or auditory hallucinations are frequent after the first dose, usually at night and particularly with intravenous administration. Symptoms diminish with time.
Patients receiving their first intravenous infusion have had anaphylactoid reactions, with faintness, nausea, flushing, feverishness and rash.

Formulations and Routes of Administration
Voriconazole is used in different routes and formulations as eye drops, intrastromal, intracameral and intravitreal injection and also systemically by oral route and intravenous routes.  19 In the two case reports by Al-Badriyeh et al, topical 1% voriconazole eye drops were used as a standalone therapy to treat S. apiospermum keratitis and C. albicans keratitis which were unresponsive for empirical treatment. 20,21 In these case reports, voriconazole eye drops were typically administered with a dosing frequency of one drop every 0.5, 1.0, or 2.0 hours for duration of one month. Increasing the concentration of voriconazole eye drops may lead to increased efficacy and/or reduced dosing frequency; however, the benefit of using concentrations greater than 1% has not been evaluated in patients with fungal keratitis . In a comparative study conducted by mycotic ulcer treatment trial group 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 and similar results were also found in another randomized trial conducted by Sharma S et al. 22,23

B.Intrastromal route
After administration of peribulbar anesthesia, under full aseptic conditions, the preloaded drug should be   administered under operating microscope. With the bevel down, the needle is inserted obliquely from the uninvolved clear area to just reach the abscess at mid-stromal level (as the intended level for drug deposit). The drug then is injected and the amount of hydration of the cornea is used as a guide to assess the area covered. Once the desired amount of hydration is achieved, the plunger is withdrawn slightly to ensure discontinuation of the capillary column and thus prevent back-leakage of the drug. Five divided doses are given around the abscess to form a deposit of the drug around the circumference of the lesion. This is done in such a manner that a centripetally directed progressive wave of fluid appeared to encompass the abscess along each meridian. Circumferential injection will ensure the formation of a barrage of intrastromal voriconazole around the entire abscess. The total amount of drug injected intrastromally ranged from 0.05 ml to 0.1 ml. 24

C. Oral
Oral voriconazole 200 mg twice daily for five to 17 weeks (mean, 10 weeks) according to the severity. 24 Bunya VY et al., successfully treated nine patients with oral and topical voriconazole, refractory for standard treatment. 26

D. Intracameral
Intracameral route has been shown to be effective in patients with fungal keratitis associated with fungal endophthalmitis 27 , the usual dose is 50-100ug /0.1ml. 16 Intracameral voriconazole injection should be administered under aseptic conditions using an operating microscope.

Acantahamoeba keratitis
Acanthamoeba keratitis has been recognized with increasing frequency of severe blinding keratitis. Contact lens use or exposure to contaminated water is most commonly associated. The interesting cases reported from India are not associated with contact lens use. Acanthamoeba castelleni is most common pathogen causing keratitis. 28 Voriconazole has been found to be effective in treating acanthamoeba keratitis. Bang S et al., in their case series demonstrated use of topical voriconazole 1% as second-line treatment for acanthamoeba keratitis, unresponsive to chlorhexidine and hexamidine . Topical voriconazole 1% was administered at one hour interval along with oral voriconazole (200 mg twice daily). 29 Tu YE et al., successfully treated recalcitrant, chronic acanthamoeba stromal keratitis with oral 200 mg voriconazole twice daily for 6 week as monotherapy. 30

Fungal endophthalmitis
Fungal endophthalmitis is known to occur by both exogenous and endogenous routes. Endogenous fungal endophthalmitis represents intraocular dissemination of a systemic fungal infection. Among the different fungal species, Candida species is the most common cause of infection, followed by Aspergillus species. Risk factors include immunosuppression, intravenous drug abuse, bacterial sepsis, prolonged hyperalimentation, systemic antibiotics, corticosteroid therapy, recent abdominal surgery, malignancy, alcoholism and diabetes mellitus. 31 Exogenous infections usually are secondary to trauma or surgery caused by variety of fungi, including Paecilomyces, Acremonium, and Sporothrix species. Fungal endophthalmitis is a rare complication after cataract surgery and most common causative fungal pathogens implicated include Candida species and molds such as Aspergillus and Fusarium species. Voriconazole as an intarvitreal route has been shown to be effective in fungal endophthalmitis. 32 Usual dosage is 50-100ug/0.1ml. 16

Major Review
Aspergillus fumigatus is the most common pathogen in human aspergillosis. Aspergillus chorioretinitis is associated with disseminated aspergillosis in immunocompromised individuals or intravenous drug abusers. 36 Vila Arteaga J et al., in their case study had a significant and rapid improvement in patient treated with single dose of injection intravitreal voriconazole (100 μg/0.1 ml) for aspergillus chorioretinitis, obviating the need for vitrectomy. 37 Jang GJ et.al, successfully treated aspergillus chorioretinitis with systemic voriconazole. 38

Fungal tunnel infections
Self-sealing sutureless wounds are almost universal in modern cataract surgery. Data on corneoscleral wound infections suggest both bacteria and fungus as etiological agents. Fungal infections of such incisions are especially difficult to treat because of poor corneal penetration of available antifungal agents and may have poor prognosis even after surgical intervention. 39

Fungal Subretinal abscess
Sub retinal abscesses are a rare occurrence. Whilst most are due to bacteria, reports of fungal subretinal abscess are extremely rare and only a handful of cases have been documented, in the setting of generalised sepsis, immunocompromised states and intravenous drug abuse. 47 Huynh TH et al., demonstrated use of oral voriconazole in a 62-year-old woman who presented with bilateral Candida albicans subretinal abscesses secondary to chronic immunosuppression and the abscess resolved completely within four months of initial presentation. 48 Panigrahi et al in their case report of aspergillus terreus endogenous suretinal abscess, noted successful outcome following treatment with intravitreal and systemic voriconazole. 49

Fungal Scleritis and epibulbar abscess
Fungal scleritis primarily involving sclera is extremely rare ,but have been reported after trauma ,retinal detachment surgery , pterygium surgery and scleral graft and successfully treated with voriconazole. 50-53

Conclusion
Voriconazole is a newer generation antifungal having broad spectrum activity and has less toxicity compared to other antifungals. Voriconazole eye drops appear to be effective when used for the treatment of fungal keratitis caused by a variety of fungi, including F. solani, C. albicans, S. apiospermum and A. niger. However in fusarium keratitis, natamycin seems to be more effective in comparison with voriconazole. It can be used as a first line therapy to treat many fungal infections related to eye both topically and systemically. It has been used as stand alone or as an adjunctive to treat acanthamoeba keratitis. In comparison with Amphoctericin B , voriconazole is safer , can be repeated and is equally efficacious. However more data and long term studies are required to effectively formulate dosage, frequency and duration of the usage of voricanazole.