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Review

Voriconazole in the treatment of fungal eye

infections: a review of current literature
S M Hariprasad,1 W F Mieler,1 T K Lin,1 W E Sponsel,2 J R Graybill2
1
Department of Ophthalmology ABSTRACT identified, Fusarium species were the most frequent
and Visual Science, Vitreoretinal Background: Voriconazole has an important role to play fungal pathogen (49.4%), followed by Curvularia
Service, University of Chicago,
in the prophylaxis and management of fungal (8.1%), Aspergillus (7.1%) and Paecilomyces species
Chicago, IL, USA; 2 Department
of Ophthalmology, The endophthalmitis and keratitis. New-generation triazoles, (5%). Earlier accounts also point to Fusarium
University of Texas Health including voriconazole, posaconazole and ravuconazole, species as the source of many fungal keratitis
Science Center at San Antonio, have been shown in laboratory studies and clinical infections.5 The most common corneal yeast
San Antonio, TX, USA isolates at Bascom Palmer were Candida albicans
experience to have very good safety profiles with few side
Correspondence to: effects. Fungal eye infections, while not common in (9.5%) and C. parapsilosis (6.7%). Of the 122
Dr S M Hariprasad, Department temperate climates, have been notoriously difficult to intraocular pathogens isolated, almost half were
of Ophthalmology and Visual diagnose and treat, and generally result in protracted yeasts, specifically Candida species; Aspergillus was
Science, Vitreoretinal Service, found to be the most common intraocular mould.
University of Chicago, 5841 therapy with poor final outcomes. Current treatment
South Maryland Avenue—MC options are far from optimal.
2114, Chicago, IL 60637 USA; Aims: This paper will review studies and clinical case
[email protected] Current treatment
reports published in the ophthalmic literature that address Current treatment protocols for mycotic infections
the safety of these drugs in the eye, penetration and are far from optimal, due to a combination of the
Accepted 26 April 2008
concentration in ocular tissues and media, and efficacy in growth characteristics of fungi, late diagnosis,
treating common pathogens implicated in fungal keratitis scarcity of effective antifungal agents and poor
and endophthalmitis. tissue penetration of the currently available ther-
Conclusions: Over 40 clinical case reports of treatment apeutic agents.
with voriconazole suggest that it may be used safely and The most common antifungal treatments for
effectively against a broad range of fungal pathogens. fungal endophthalmitis are intravenous and/or
intravitreal amphotericin B. At times, treatment
is combined with a vitrectomy due to limited
Fungal eye infections have potentially devastating intraocular drug penetration. Amphotericin B may
consequences. Fungal keratitis may be caused by also be injected directly into the vitreous to achieve
ocular trauma with involvement of organic matter, higher concentrations; however, toxicity to the
or may be related to contact lens wear or refractive retina has been reported, especially if accidentally
surgery. If not successfully treated, it can progress injected into an air-filled eye. Limitations of
into the eye, causing endophthalmitis. Fungal intravenous amphotericin B include required hos-
endophthalmitis may also be the result of trauma, pitalisation, severe ocular inflammation and
endogenous disease or a complication of intraocu- numerous systemic adverse effects such as nephro-
lar surgery. toxicity, fever, rigors and hypotension. Moreover,
Fungal infections are relatively rare in the United the effectiveness of amphotericin B against the
States and other temperate climates. However, the most commonly implicated fungal isolates is
US Centers for Disease Control (CDC) recently limited. For example, O’Day and colleagues
reported an outbreak of at least 130 confirmed demonstrated that intravitreal concentrations of
cases of Fusarium keratitis among contact lens amphotericin B barely reach the minimum inhibi-
wearers in 26 states.1 The CDC’s case-control tory concentration at which 90% of isolates are
investigation found an association between the inhibited (MIC90) for Candida parapsilosis6 after
infections and use of a particular contact lens systemic administration.
solution (ReNu with MoistureLoc, Bausch & Fluconazole, an older-generation triazole, has
Lomb, Rochester, NY), which was subsequently been used systemically as a supplement or alter-
withdrawn from the US and global markets. native to amphotericin B, but it lacks the broad
In South Asia, Africa and other warmer climates, spectrum of coverage necessary for the most
fungal infections occur more frequently than in commonly encountered fungal species in eye
cooler climates. Relative incidence reports from disease. Furthermore, intraocular penetration is
India indicate that more than 20% of postcataract marginal. Itraconazole is rarely used in the treat-
endophthalmitis cases2 and as much as 44% of all ment of ocular fungal eye infections, as it lacks a
central corneal ulcers3 are caused by fungi. broad spectrum of coverage, specifically against
Candida yeast species and filamentous fungi, Fusarium species4 (fig 1).
especially Fusarium species, are the most frequent Topical natamycin, a polyene, is the only Food
culprits in the United States, according to a and Drug Administration (FDA)-approved and
recently published analysis of fungal isolates commercially available topical antifungal. It has
associated with keratitis or endophthalmitis cases good efficacy against filamentous fungi but does
treated at the Bascom Palmer Eye Institute over the not penetrate well into the cornea. Additionally, it
past two decades.4 Of the 421 corneal isolates forms precipitates upon instillation and degrades

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fluconazole and itraconazole.16 17 Activity against Fusarium

species has been variable.
It has been reported to be fungicidal against most Aspergillus
species and some dematiaceous fungi.11 18 Voriconazole has also
become the new standard of care in the treatment of invasive
aspergillosis which may occur in immunocompromised patients,
including allogeneic BMT, other haematological cancers and
solid organ transplants. This is based on the results of a large,
randomised study in which it proved superior to amphotericin B
with 53% complete or partial response, compared with 32% for
amphotericin B.19 In another large, randomised study comparing
voriconazole to amphotericin B for empiric therapy in patients
with neutropenia and persistent fever, the success rate for
treatment with voriconazole was slightly lower than ampho-
tericin B at 26.0% to 30.6%, respectively, but there were much
fewer side effects in the voriconazole group compared with the
amphotericin group.20
Figure 1 General susceptibilities of fungi isolates (Aspergillus species, Adverse effects, including visual disturbances and skin rashes,
n = 4; Fusarium species, n = 9; Candida species, n = 20) to have been mild and transient. Visual disturbances, including
amphotericin B, fluconazole, ketoconazole, 5-flucytosine, itraconazole abnormal vision, colour vision change and/or photophobia,
and voriconazole. Reprinted from Marangon FB et al. In vitro typically resolve within 1 month, even with continued therapy.
investigation of voriconazole susceptibility for keratitis and Elevations in hepatic enzyme levels can occur.
endophthalmitis fungal pathogens. Am J Ophthalmol 2004;137:820–5, by This paper is intended primarily to review studies and clinical
permission of the authors and Elsevier. case reports published in the ophthalmic literature that address
the safety of these drugs in the eye, penetration and concentra-
easily, requiring storage in a dark container. Topical amphoter- tion in ocular tissues and media, and efficacy in treating
icin B is commonly used in the management of fungal keratitis, common pathogens implicated in fungal keratitis and
but it requires preparation by a compounding pharmacy. endophthalmitis.

New-generation triazoles OCULAR SAFETY

There are promising reports in the literature suggesting that Gao and colleagues were the first to show the safety of
newer-generation triazole agents may overcome the significant voriconazole in the eye.21 They examined retinal toxicity in a
shortcomings of existing therapies. Triazoles inhibit the rodent animal model and found that intravitreal voriconazole in
biosynthesis of ergosterol, an essential component of the fungal high concentrations of up to 25 mg/ml caused no electroretino-
cell wall. The newest triazole agents, including ravuconazole, graphic or histological abnormality in the rat retina.
posaconazole and voriconazole, are synthetic derivatives of In human clinical use, none of the case reports we reviewed
fluconazole but have a significantly broader spectrum of (multiple reports of voriconazole treatment;8 22–34 36 38 39 41–50 two
activity. At present, only voriconazole (Vfend, Pfizer, New reports of posaconazole treatment) identified any adverse
York) is commercially available. It has been approved by the effects other than mild, transient visual disturbances and
FDA for the treatment of invasive aspergillosis, espophageal elevation of liver enzymes. The safety profile of these triazole
candidiasis and other systemic indications, and is available in agents represents a remarkable improvement when contrasted
oral and intravenous formulations. with the extremely negative side effects of amphotericin B.
Ravuconazole (Bristol-Myers Squibb, Wallingford, CT) has
been shown to have in vitro activity against non-ocular isolates
of yeasts, Aspergillus species and other filamentous fungi, black OCULAR PENETRATION AND CONCENTRATION
moulds, and some Mucorales.7 8 Some Fusarium species were In 2004, Hariprasad and colleagues demonstrated that orally
resistant. administered voriconazole showed good tolerability and bioa-
Posaconazole (Noxafil) oral suspension (Schering-Plough, vailability, achieving therapeutic concentrations in the non-
Kenilworth, NJ) was recently FDA approved in the fall of inflamed eye.35 Fourteen patients scheduled for elective pars
2006. In vitro and in vivo studies have shown it to have broad- plana vitrectomy were given two 400 mg doses of voriconazole
spectrum activity against non-ocular isolates of most Candida 12 h apart prior to surgery. Aqueous, vitreous and plasma
species, Cryptococcus neoformans, Aspergillus species, Fusarium samples were obtained during surgery, within 3 h of the second
species, zygomycetes and endemic fungi.9 One study showed it dose of voriconazole.
to be active against a majority of isolates resistant to After two doses, the mean plasma concentration of vorico-
fluconazole and itraconazole, and the most active of any nazole was 2.13 mg/ml, which resulted in voriconazole concen-
antifungal agent tested against Aspergillus.10 Adverse events, trations of 0.81 mg/ml (38.1% of plasma levels) in the vitreous
most commonly gastrointestinal complaints, are generally and 1.13 mg/ml (53.0% of plasma levels) in the aqueous. The
mild.11 concentrations achieved in the vitreous in this study far exceed
Voriconazole has been shown to have a broad spectrum of the MIC90 for a wide spectrum of yeasts and moulds, although
activity against non-ocular isolates of Aspergillus species, not for Fusarium species (table 1).
Candida species, Paecilomyces lilacinus, Cryptococcus neoformans, Separately, they also reported aqueous and vitreous levels
Scedosporium species, Curvularia species and others.12–15 It has from a patient with active fungal inflammation who died
excellent in vitro activity with low MIC values against Candida 1 week after initiating treatment with intravenous vori-
and Aspergillus species known to be resistant to amphotericin B, conazole 200 mg twice daily.36 Postmortem analysis showed

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Table 1 In vitro susceptibilities of voriconazole showing minimum In the one case report involving posaconazole, the drug was
inhibitory concentrations at which 90% of isolates are inhibited (mg/ml) given orally four times daily (200 mg each) and topically, with
Organisms Concentration (mg/ml)* an hourly application of the same 10 mg/0.1 ml oral suspension.
A diagnostic vitrectomy indicated that the concentration of
Yeast and yeast-like species posaconazole in the vitreous was 0.25 mg/ml, compared with
Candida albicans 0.06
1.2 mg/ml in the plasma.41
Candida parapsilosis 0.12 to 0.25
Candida tropicalis{ 0.25 to .16.0
Cryptococcus neoformans 0.06 to 0.25 OCULAR EFFICACY: LABORATORY MODELS
Moniliaceous moulds In 2004, Marangon and colleagues published an investigation of
Aspergillus fumigatus 0.50 antifungal susceptibility, in which voriconazole was the only
Aspergillus flavus 0.50 agent of six tested with 100% activity against a wide variety of
Fusarium species 2.0 to 8.0
Aspergillus, Fusarium and Candida isolates4 (figs 1, 2).
Paecilomyces lilacinus 0.50
They evaluated the in vitro susceptibility of 36 keratitis or
Acremonium alabamensis 0.25
endophthalmitis isolates (21 Candida species, 10 Fusarium
Dimorphic fungi
Blastomyces dermatitidis 0.25
species, four Aspergillus species and one Paecilomyces species) to
Coccidioides immitis 0.25 various antifungals.
Histoplasma capsulatum 0.25 All yeast isolates were sensitive in vitro to most antifungal
Penicillium marneffei 0.03 agents including voriconazole. All moulds were resistant to
Dematiaceous fungi fluconazole. In vitro susceptibility profiles are shown in fig 2.
Curvularia species 0.06 to 0.25 Voriconazole had a very low MIC90 for the Candida and
Scedosporium apiospermum 0.50 Aspergillus isolates in this study.
Copyright ß 2004 American Medical Association. All rights reserved. In the experimental rabbit study mentioned earlier,40 topical
*Vitreous penetration of voriconazole is 0.81 (SD 0.31) mg/ml; aqueous penetration, voriconazole halted or reversed the progression of corneal
1.13 (0.57) mg/ml. Data are from Marco et al,14 Ghannoum and Kuhn13 and Espinel- infection by P. lilacinus beyond a single-axis 2 mm diameter in
Ingroff et al.12
{Typically susceptible to voriconazole, with the exception of a single isolate which nine of 10 infected eyes, including three eyes with complete
demonstrated a minimum inhibitory concentration of .16.0 mg/ml.27 resolution of the fungal keratitis.
For this study, voriconazole powder was suspended to
concentrations of 5 and 10 mg/ml. Although much higher doses
concentrations of the drug in the vitreous of 1.12 mg/ml and in
of the drug have been tested intravitreally, the authors
the aqueous of 1.52 mg/ml, again far exceeding MIC90 levels for
concluded that less concentrated topical applications may be
a wide spectrum of pathogens. Due to the breakdown in the
adequate to prevent or treat extension of corneal infection to
blood–aqueous barrier, it is not surprising that a systemically
the deeper eye tissues.
administered drug would achieve higher concentrations in an
infected eye than it did in non-inflamed eyes.
Hariprasad and colleagues also analysed topically adminis-
OCULAR EFFICACY: CLINICAL CASE REPORTS
tered voriconazole in non-inflamed human eyes.37 In this study,
New-generation triazoles have been used in the treatment of
a voriconazole 1% topical solution was used every 2 h for 1 day
fungal infections, generally with considerable success. Many of
prior to planned vitrectomy surgery. The mean concentration of
the patients described in the literature failed treatment with
voriconazole was 6 mg/ml in the aqueous and 0.15 mg/ml in the
conventional antifungal agents, and success was achieved only
vitreous, demonstrating that the drug penetrates well beyond
after initiating a new-generation triazole. Case reports are
the cornea when applied topically. Given that aqueous and
summarised in table 2.
vitreous levels exceed or meet the MIC90 for most pathogens,
one could assume that concentrations on the ocular surface
would be more than sufficient to treat fungal keratitis.
In a case report of an eye with Scedosporium apiospermum
keratitis that went on to corneal transplant, Nulens and
colleagues found that aqueous voriconazole levels following
12 days of oral treatment were about 50% of plasma levels.38 In
a later case report, this team also found that applying
voriconazole topically (1% voriconazole solution at hourly
intervals) resulted in significantly increased drug levels in the
anterior chamber.39 The voriconazole level in the aqueous
humour was 3.2 mg/ml, which was 160% of the level in plasma
(2.0 mg/ml).
In a rabbit model, Sponsel and colleagues also demonstrated
that topical voriconazole penetrates beyond the corneal tissue.40
Rabbit eyes infected with Paecilomyces lilacinus were treated
twice daily with a topical voriconazole solution. When corneal, Figure 2 General in vitro susceptibility profiles of all isolates for each
antifungal drug using a commercially available microdilution antifungal
vitreous and chorioretinal tissues were analysed, tissue con- susceptibility test (Sensititre YeastOne, TREK Diagnostics, Cleveland,
centrations at both doses tested (5 and 10 mg/ml) exceeded the OH). Reprinted from Marangon FB et al. In vitro investigation of
MIC90 for P. lilacinus. Tissue concentrations were highest in the voriconazole susceptibility for keratitis and endophthalmitis fungal
cornea; the chorioretinal concentration was roughly twice as pathogens. Am J Ophthalmol 2004;137:820–5, by permission of the
high as the vitreous concentration. authors and Elsevier.

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Table 2 Summary of clinical case reports of ocular efficacy of new-generation triazoles in the treatment of fungal eye infections
Author Patient Infectious involvement of eye Triazole treatment Outcome
22
Aydin et al 72-year-old male Postcataract Scopulariopsis sp. Salvage treatment Infection resolved; final VA CF
endophthalmitis Intravenous voriconazole and intravenous caspofungin
with intravitreal voriconazole (2.5 mg/0.1 cm3) in a silicone-filled
eye
Breit et al36 66-year-old female Endophthalmitis following Primary ocular treatment, following oral fluconazole for Infection resolved; final VA 20/30
Candida glabrata septicaemia systemic infection
Intravenous voriconazole 200 mg twice daily plus
caspofungin 50 mg daily for 8 days, then oral
voriconazole 200 mg twice daily for 1 week
Breit et al36 42-year-old male Endophthalmitis following Primary ocular treatment, following oral fluconazole for Infection resolved; final VA 20/20
systemic Candida albicans systemic infection
septicaemia Intravenous voriconazole 200 mg twice daily plus
intravenous caspofungin 50 mg daily for 1 week, then
oral voriconazole 200 mg twice daily and intravenous
caspofungin for nine more days
Breit et al36 48-year-old female Bilateral endophthalmitis Salvage treatment Infection resolved; final VA 20/20
following systemic Candida Intravenous voriconazole 200 mg twice daily, then oral OD and 20/30 OS
albicans septicaemia voriconazole 200 mg twice daily for 4 weeks
Breit et al36 48-year-old female Bilateral Candida albicans Primary treatment Infection resolved although not
on transparenteral endophthalmitis Intravenous voriconazole 320 mg twice daily and until after amphotericin B in the
nutrition intravenous caspofungin 50 mg daily for 8 days then oral left eye; final VA 20/25 OD and 20/
voriconazole 200 mg twice daily and intravenous 60 OS
caspofungin 50 mg daily plus intravitreal amphotericin-B
injections
Breit et al36 52-year-old male Candida albicans endophthalmitis Primary treatment Infection resolved; VA 20/100;
with severe vitreous inflammation Intravitreal voriconazole 100 mg/0.1 ml injection, then oral retina remained attached
and subretinal infiltrates voriconazole 200 mg twice daily
Chen et al23 56-year-old male Endogenous Scedosporium Primary treatment Failed to control infection, eye
apiospermum endophthalmitis Intravenous voriconazole (loading dose of 400 mg went on to enucleation
followed by 300 mg twice daily) and oral terbinafine
(250 mg twice daily) and intravitreal voriconazole (10 mg)
Chen et al23 62-year-old male Endogenous Scedosporium Primary treatment Initial control of infection,
apiospermum endophthalmitis Oral voriconazole (200 mg twice daily) and intravenous however, infection reoccurred;
Amphotericin B, later switched to oral terbinafine eye went on to enucleation
(250 mg daily), plus intravitreal voriconazole in a
silicone-oil-filled eye (100 mg)
Durand et al47 64-year-old male Postcataract Fusarium moniliforme Salvage treatment Infection resolved; final VA 20/40
endophthalmitis Oral voriconazole 300 mg twice daily for 6 months
Durand et al47 55-year-old male Postcataract Aspergillus fumigatus Salvage treatment Signs of recurrence until
endophthalmitis Intravitreal amphotericin B, topical amphotericin B caspofungin added; final VA 20/25
with natamycin, and intravenous voriconazole
6 mg/kg q12h 62 doses, then oral voriconazole 200 mg
twice daily for 6 months; another intravitreal amphotericin
injection and intravenous caspofungin also given
Figueroa et al24 44-year-old male Endogenous Scedosporium Salvage treatment Inflammation gone but macular
apiospermum endophthalmitis Oral voriconazole 400 mg twice daily day 1 then 200 mg scar, slight vit. opacity resulted in
twice daily for 3 months CF acuity
Garbino et al45 61-year-old female Postcataract Paecilomyces Salvage treatment Resolution of infection
lilacinus endophthalmitis Oral voriconazole 400 mg twice daily for 3 months
Hernandez Prats et 19-year-old male Post-traumatic Scedosporium Salvage treatment Resolution; enucleation avoided;
al25 apiospermum keratitis Intravenous voriconazole 200 mg twice daily for 2 weeks, eye went on to PK and intraocular
then intravenous plus topical 1% drops q30 min for lens with good VA
2 weeks, then topical q2 hrs plus oral voriconazole
200 mg twice daily for 3 months
Huynh et al26 19-year-old male Post-traumatic Phaeoacremonium Primary treatment Resolution, final VA 6/18
parasiticum endophthalmitis Oral voriconazole 400 mg twice daily for 8 weeks and
intravitreal amophtericin B (0.01 mg/0.1 ml)
Jain et al28 59-year-old female Endogenous Scedosporium Primary treatment Failed to control infection,
apiospermum endophthalmitis Intravenous voriconazole (6 mg/kg) and intravitreal enucleation, later exenteration and
Amphotericin B (5 mg/0.05 ml), then intravitreal death from sepsis
voriconazole (100 mg/0.1 ml)
Jain et al28 37-year-old female Endogenous Scedosporium Salvage treatment Resolution of infection; however
apiospermum endophthalmitis Intravenous voriconazole (4 mg/kg) and intraviteal patient developed a retinal
voriconazole (100 mg/0.1 ml) detachment
Jain et al28 21-year-old female Endogenous Scedosporium Salvage treatment Failed to control infection; went on
apiospermum endophthalmitis Intravenous Amphotericin B, intravitreal Amphotericin B to CNS infection and death
(5 mg/0.05 ml), then weekly intravitreal Itraconazole
(5 mg/0.05 ml)
Continued

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Table 2 Continued
Author Patient Infectious involvement of eye Triazole treatment Outcome
Jang et al27 63-year-old female Candida chorioretinitis Primary treatment Resolution of infection by
Intravenous voriconazole 6 mg/kg twice daily on day 1, 1 month, BCVA 20/29 both eyes
then 3 mg/kg twice daily for 3 days, then oral
voriconazole 200 mg twice daily for 11 days
Jhanji et al51 69-year-old female Postcataract Fusarium Salvage treatment Resolution of infection by
endophthalmitis Failure of natamycin and topical amphtericin B, then 1% 1 month, BCVA 20/60 at
topical and oral voriconazole 4 months
Jones et al52 52-year-old female Aspergillus niger keratitis Salvage treatment Resolution of infection by
Failure of topical amphotericin B, then 1% topical and 5 weeks, BCVA of 20/30
oral voriconazole
Kim et al46 65-year-old female Refractory Aspergillus fumigatus Salvage treatment Infection began to resolve in
scleritis from scleral buckle Oral voriconazole 200 mg twice daily 1 week
infection
Klont et al39 23-year-old male Fusarium solani keratitis, sudden Salvage treatment Infection resolved but cornea did
onset Intravenous voriconazole 6 mg/kg on day 1, then 4 mg/kg not remain clear due to endothelial
twice daily plus topical voriconazole 1% every 1 h for decompensation
2 weeks, then oral voriconazole 200 mg twice daily plus
topical eight times a day for another 2 weeks
Kramer et al29 22-year-old female Endogenous Aspergillus terreus Intravenous voriconazole and intravitreal amphotericin B Resolution of infection with VA 6/
endophthalmitis Salvage with intravitreal voraconazole (100 mg/0.1 ml) 15
Marangon et al4 NA Fusarium keratitis Primary treatment Failed to control infection; went on
Topical voriconazole for 3 weeks + to corneal transplant
Marangon et al4 NA Colletotrichum keratitis Primary treatment Failed to control infection; ulcer
Topical voriconazole 1% every 1 h for 18 days resolved with natamycin
Nehemy et al30 60-year-old male Postcataract Verticillium sp. Oral voriconazole and intravitreal voriconazole Resolution of infection; final VA
endophthalmitis (133 mg/0.1 ml) 20/40
Nulens et al38 47-year-old male Scedosporium apiospermum Salvage treatment No recurrence of infection
keratitis with 2 mm central Oral voriconazole 6 mg/kg twice daily on day 1, then
infiltrate and severe AC 4 mg/kg twice daily for 3 months
inflammation
Polizzi et al50 56-year-old male Severe ulcerative Fusarium Salvage treatment Improvement in 5 days; resolution
solani keratitis Intravenous voriconazole 400 mg twice daily on day 1, in 20 days
then 300 mg twice daily for 14 days, plus topical
voriconazole 2% seven times daily, then oral
voriconazole 200 mg twice daily for 1 month
Reis et al43 16-year-old female Severe ulcerative Fusarium Salvage treatment Early recurrence was resolved by
solani keratitis Intravenous voriconazole 6 mg/kg twice daily on day 1, oral/topical combination
then 4 mg/kg twice daily for 10 days, then oral voriconazole
6 mg/kg twice daily, intracameral injection 10 mg/0.1 ml,
and topical voriconazole 1% every half hour for 8 weeks
Sen et al31 61-year-old male Postcataract Aspergillus niger Salvage treatment Resolution of infection with VA
endophthalmitis Intravitreal vorazonazole (50 mg/0.1 ml) and topical 20/400
voriconazole 1%
Sen et al31 62-year-old male Endogenous Scedosporium Salvage treatment Resolution of infection with VA
apiospermum endophthalmitis Intravitreal voraconazole (50 mg/0.1 ml) and topical 20/120
voriconazole 1%
Sen et al31 50-year-old female Endogenous Fusarium Salvage treatment Resoultion of infection; VA LP
endophthalmitis Intravitreal and intracameral voraconazole (50 mg/0.1 ml)
and topical voriconazole 1%
Sen et al31 61-year-old male Postcataract Aspergillus flavus Salvage treatment Resolution of infection; VA LP
endophthalmitis Intravitreal voraconazole (50 mg/0.1 ml) and topical
voriconazole 1%
Sen et al31 60-year-old male Postcataract Aspergillus flavus Salvage treatment Resolution of infection with VA
endophthalmitis Intravitreal voraconazole (50 mg/0.1 ml) and topical 20/60
voriconazole 1%
Scott et al44 57-year-old female Bleb-associated Lecythophora Salvage treatment Resolution of infection; Final VA
mutabilis endophthalmitis Intraocular voriconazole 50 mg injection and oral 20/80
voriconazole 200 mg twice daily, then injection of
voriconazole 200 mg into AC and bleb
Sponsel et al40 42-year-old female Invasive Fusarium solani keratitis Salvage treatment Significant improvement at
and endophthalmitis Oral posaconazole 200 mg four times daily and topical 1 week, PK and phaco required
posaconazole 10 mg/0.1 ml every 1 h but good prospects for visual
rehab
Tu et al42 48-year-old male Contact-lens-related Fusarium Salvage treatment Resolution of infection after failing
solani keratitis Intravenous voriconazole (320 mg twice daily) then switched voriconazole treatment, PK 62,
to oral voriconazole 200 mg twice daily, intracameral final VA CF after last graft
(50 mg/0.1 ml) and intravitreal (50 mg/0.1 ml) voriconazole rejection
Then, posaconazole 200 mg four times daily and topical
amphotericin B
Continued

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Table 2 Continued
Author Patient Infectious involvement of eye Triazole treatment Outcome
Tu et al42 29-year-old male Fusarium keratitis Salvage treatment PK 62, resolution of infection
Oral voriconazole 200 mg twice daily and topical voriconazole
switched to oral posaconazole 200 mg four times daily and
topical posaconazole after systemic toxicity to voriconazole
Tu et al42 43-year-old female Contact-lens-related Fusarium Salvage treatment Resolution of infection, PK 61,
keratitis Intravenous voriconazole 200 mg twice daily and topical awaiting another PK
voriconazole plus intravitreal voriconazole (10 mg/0.1 ml)
switched to posaconazole 400 mg twice daily because of
hepatotoxicity
Varma et al32 39-year-old female Bilateral Candida retinitis Salvage treatment Improvement; patient died of
Oral voriconazole 4 mg/kg daily cardiorespiratory arrest prior to
full resolution
Verma et al49 45-year-old female Postlaser in situ keratomileusis Salvage treatment PK 63 and poor visual result
Fusarium solani keratitis Oral voriconazole 400 mg daily
Zarkovic and 9-year-old female Post-traumatic Scedosporium Salvage treatment Resolution of infection with final
Guest34 apiospermum endophthalmitis Oral voriconazole and intravitreal injection of voriconazole VA 6/12
50 mg/0.1 ml, then intravitreal injection of voriconzole
200 mg/0.1 ml
AC, anterior chamber; BCVA, best corrected visual acuity; CF, counting fingers; CNS, central nervous system; LP, light perception; OD, left eye; OS, right eye; PK, penetrating
keratoplasty; VA, visual acuity.

We identified four case reports involving the use of intravitreal voriconazole. A single injection of 200 mg/0.1 ml
posaconazole.41 42 A 42-year-old with invasive Fusarium solani (four times the recommended intravitreal dose) was given.
keratitis and endophthalmitis was successfully treated with The degree to which resolution of the infection was achieved
posaconazole after high doses of amphotericin B (both topical and the speed of recovery after months of failed treatment in
and intravenous), natamycin and ketoconazole failed to stop some cases are remarkable.45 46 Two small series have been
the infection from spreading. At 16 months, the prognosis for reported with notably good visual outcomes.
eventual lens replacement and visual rehabilitation of the eye Durand and colleagues reported on the successful use of
appeared very good. voriconazole in two cases of postcataract surgery fungal
Tu et al recently reported three cases of Fusarium ocular endophthalmitis.47 The first case was a man with postcataract
infections.42 The first case developed Fusarium keratitis and extraction Fusarium endophthalmitis. The infection persisted
endophthalmitis and was treated with a combination of topical, despite removal of the intraocular lens, three vitrectomies and
intracameral, intravitreal and systemic amphotericin B and five intravitreal injections of amphotericin B. Treatment with
voriconazole. Because of the unresponsive nature to the oral voriconazole (300 mg, twice daily) for 6 months resolved
infection, the patient was switched to posaconazle with the inflammation and improved vision in the eye from 20/80 to
resolution of the infection. The two other cases reported 20/40.
developed Fusarium keratitis and one developing endo- The second case was a man with postcataract surgery
phthalmitis. Both were initially treated with topical and intraocular inflammation later diagnosed to be Aspergillus
systemic voriconazole before developing systemic complica- fumigatus endophthalmitis. Intravitreal amphotericin B and
tions from treatment (elevated liver enzymes) and were systemic voriconazole (6 mg/kg intravenously q12h 62 doses,
switched to posaconazole with a rapid resolution of the then 200 mg orally twice daily) were given, but there were signs
infectious process. of recurrence after 1 week. Intravenous caspofungin was added,
There have been at least 36 cases reported involving and the eye improved. Vision improved from counting fingers to
treatment with voriconazole. The first such case report was 20/80 at 6 months and 20/25 at 23 months. Previous research
published by Reis and colleagues in 2000. They treated a 16- had shown that caspofungin may act synergistically with
year-old whose keratitis had been deteriorating for months and voriconazole against Aspergillus in systemic infections,48 and
was later shown to be Fusarium species.43 The recurrent Durand’s case is the first to support this combination approach
infection was treated with topical amphotericin B and systemic in an ocular setting.
fluconazole and itraconazole, to no avail. Intravenous vorico- Researchers at the Barnes Retina Institute and the Cullen Eye
nazole produced a significant improvement, and the infection Institute reported on a series of seven eyes of five patients with
was finally resolved after adding topical voriconazole. confirmed Candida endophthalmitis infections.36 A variety of
Many of the subsequently published cases were also routes of administration and dosing regimens were employed in
essentially rescue attempts, in which voriconazole therapy the series, including intravenous and oral voriconazole, with or
was attempted as a last resort after a long clinical course with without caspofungin, and intravitreal injection of voriconazole.
prior failure of other agents. Scott and colleagues treated a Five of the eyes in this series had excellent final visual acuities
patient with bleb-associated fungal endophthalmitis.44 Prior to of 20/30 or better. Interestingly, three patients in the series
culture results, the patient was treated with antibiotics and developed fungal endophthalmitis or experienced progressive
corticosteroids. Once the fungal nature of the infection was worsening of the disease while being treated with fluconazole.
clear, the patient received three intravitreal injections of This is evidence that fluconazole was ineffective against the
amphotericin B, lensectomy with two vitrectomies, oral and pathogens involved or did not achieve therapeutic concentra-
topical ketoconazole, oral fluconazole, and intraocular (one tions in the vitreous.
injection of 50 mg) and oral (200 mg twice daily) voriconazole. As noted above, there is some debate about whether
The patient was finally treated successfully with high-dose voriconazole achieves the MIC90 to be effective against

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Review

Fusarium species, the most common aetiology in fungal keratitis. The availability of multiple routes of voriconazole adminis-
Two Fusarium cases (one oral, one topical), described below, tration, including topical and intravitreal solutions that can be
have been reported in which voriconazole therapy was not prepared by a compounding pharmacy, provides the clinician
effective. with flexibility and creativity in managing these difficult eye
Verma and colleagues treated postlaser in situ keratomileusis infections. Effective oral or topical medications that can be self-
keratitis in a 45-year-old woman with oral voriconazole administered are important, as ophthalmology is primarily
(400 mg daily) without success.49 Despite intensive treatment practised in the outpatient setting. Additionally, the cost
with a variety of agents, including voriconazole, the patient savings by avoiding hospitalisation for administration of older-
went on to require three penetrating corneal grafts, with a poor generation intravenous antifungals are important.
visual result in the end. Fusarium solani was subsequently grown Voriconazole is rapidly metabolised, so one should consider
from the initial corneal button. following a single intravitreal injection with oral or topical
Marangon and colleagues noted that, even though voricona- administration in order to maintain therapeutic intraocular
zole did very well in their in vitro susceptibility analysis, it was concentrations and increase efficacy.
not effective in clinical use in two of their patients with The new-generation triazoles provide ophthalmologists with
keratitis, one Fusarium species and the other Colletotrichum.4 In much-needed new weapons in the arsenal of treatments against
both of these cases, topical treatment with a 1% solution failed fungal eye disease. We believe there is sufficient evidence in the
to control the infection. literature to support treatment with voriconazole prophylacti-
On the other hand, in the Durand and Reis cases and at least cally in patients at high risk for developing fungal keratitis or
two others,48 50–52 voriconazole was effective in treating Fusarium endophthalmitis. When a fungal aetiology is known or strongly
infections. In some cases, oral voriconazole may not produce suspected, oral voriconazole may be considered as first-line
sufficient concentrations of drug in corneal tissues. The Klont therapy or used as an adjunct to other antifungal treatment.
and Reis cases suggest a beneficial effect of adding topical Intravitreal injections of voriconazole have been reported in case
voriconazole to systemic treatment in Fusarium keratitis. reports with some success and no reports of toxicity, but more
There have now been at least 12 reported cases in the use of data should be obtained before any conclusions can be drawn
intravitreal voriconazole in the treatment of fungal endophthal- from this route of administration. Obviously, given the
mitis. Organisms treated with this route of administration variability of fungal eye infections, the clinician should use
include Candida,36 Aspergillus,29 Scedosporium,23 28 31 34 Fusarium31 judgement regarding the route of voriconazole administration.
and Verticillium.30 Dosages used ranged from 100 mg/0.1 ml to
200 mg/0.1 ml. In those eyes with endogenous Scedosporium, Acknowledgements: The authors wish to thank Pfizer pharmaceuticals for providing
outcomes were typically poor, with two of seven eyes leading to funding to support the research and editorial services of Jan Beiting and Hospicom.
The authors would also like to acknowledge the Research to Prevent Blindness
enucleation. Three patients eventually died from systemic Organization, New York.
sepsis. Given the immunosuppressed nature of these patients,
Funding: Funding was received from Pfizer for technical research assistance in
and the 90% mortality of disseminated Scedosporium, the preparing this manuscript. SMH’s research was supported by an unrestricted grant
abysmal outcomes in these patients are not surprising. In those from the Research to Prevent Blindness Organization, New York, NY.
eyes with postoperative fungal endophthalmitis, a combination Competing interests: SMH, WFM and TKL have no competing interests. WES has
of oral, intravenous and intravitreal voriconazole successfully received grants from Pfizer and other competing organisations such as Fujisawa. JRG
controlled the infection. In those eyes that were successfully has received grants from Merck, Pfizer and Schering. He is also on the Merck and
treated, there were no signs of retinal toxicity. Schering advisory board.

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Voriconazole in the treatment of fungal eye

infections: a review of current literature
S M Hariprasad, W F Mieler, T K Lin, et al.

Br J Ophthalmol 2008 92: 871-878

doi: 10.1136/bjo.2007.136515

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