Leber first documented fungal keratitis in 1879 [7, 8]. Fungal keratitis has preponderance in males with a male to female ratio of 2.25:1 [9]. Molds are far more common than yeast [10]. Patients with ocular trauma were 5.33 times more likely to develop microbial keratitis [11]. The association of trauma was higher for fungal and parasitic keratitis. Out of all fungal keratitis, 81.9 % was caused by trauma [11]. The reason is obvious in that trauma was more often associated with outdoor occupation (e.g. agriculture and manual labor).

Treating fungal keratitis is a laborious process often requiring months.

A literature search using “Fungal keratitis”, “Cladosporium” and “ophthalmic antifungal agents” as keywords in relevant databases (including Medline, Cochrane Library, and PubMed) was performed.

Common agents including their dosages and side effects were gathered and organized (Table 2). Fungal keratitis can be both treated by medical or surgical therapy. The efficacy of medical treatment depends on the penetration of the agent into the aqueous humor and achieving therapeutic levels. Apart from the deep penetration into the cornea by the fungi and the single commercially available antifungal agent (natamycin), resistance to treatment also plays a part. The formation of biofilm is considered to be the cause of resistance [12, 13]. A systemic review of medical interventions for fungal keratitis in the Cochrane Database (updated in 2012) concluded that there is no evidence suggesting that any particular drug or combination of drugs is more effective than another [14]. However, literatures have been emerging to support the use of second generation triazoles, such as voriconazole [6, 15]. Visual acuity and infiltrate size are predictors of worse clinical outcomes. Patients with infiltrates and hypopyon are less likely to respond to medical treatment [16, 17].

Table 2 Common topical agents for fungal keratitis Full size table

In a general sense, triazoles were used for yeasts and amphotericin B was used for molds. A good initial treatment would be a combination of natamycin 5 % drops and amphotericin B 0.15 % drops. Additional topical, subconjunctival and or systemic treatment could then be considered depending on the depth and severity of the infection and the culture result. The treatment regimen should be adjusted according to the clinical progression based on biomicroscopic signs, repeated corneal scrapings and tolerance of medications. It is also important to put the patient’s compliance into account.

Amphotericin B alters the stability of the membrane by binding to ergosterol and forms pores. It is insufficiently absorbed from the GI tract and due to its poor ocular penetration, administration of higher doses via the intravenous route is needed [4]. Amphotericin also binds to mammalian cholesterol albeit with lower affinity. Thus explaining its side effects. It causes chills and fever and it is notorious for its nephrotoxicity [4]. It is the drug of choice for Candida keratitis. Though also effective against filamentous fungi, it has no activity against Fusarium sp..

Natamycin is the only ophthalmic agent approved by the Food and Drug Administration. It also binds to ergosterol. However, it does not alter the membrane permeability. In stead, it prevents the ergosterol-dependent fusion of vacuoles and membrane fusion and fission [18]. It has good activity against Candida, Aspergillus and Fusarium spp. Though being used as a standard care, the penetration is poor and the bioavailablity is only about 2 % after topical administration [19]. It is therefore not the drug of choice for deep, severe infection.

Corticosteroids (imidazoles or triazoles) inhibit sterol demethylation of lanosterol to ergosterol in fungal membranes. Fluconazole is a safe agent that can be administered orally, intravenously, subconjunctivally or topically. The penetration is well with few side effects [20]. It is limited by its narrow spectrum of antifungal activity. It is inactive against Aspergillus and Fusarium spp. Miconazole has a broad spectrum of activity however, it is toxic systematically and could lead to epithelial erosions topically. It is used as a second-line agent to natamycin [21].

Voriconazole was first tested for retinal toxicity in rodent animal models [22]. No electroretinographic or histological abnormality was reported with an intravitreal voriconazole concentrations up to 25 μg/mL. Voriconazole has an excellent susceptibility profile against both yeasts and molds. It does not depend on the state of the epithelial surface [23]. The ocular penetration of voriconazole after two 400mg doses of voriconazole 12 h apart was measured at 1.13 μg/mL (53 % of plasma levels) [24]. The safety profile of voriconazole has been reviewed [25]. Visual disturbances including photophobia and/or color change and skin rashes were mild and transient. Even with continued therapy, they typically resolve within 1 month. Oral and IV formulations were approved by FDA for deadly fungal infections in 2002. The broad spectrum of antifungal activity includes species that are resistant to other antifungal agents [24]. In the high-risk group population for developing fungal keratitis or endophthalmitis, voriconazole can also be used as a prophylactic agent [24].

Despite the recent advancement in diagnosis and treatment of fungal keratitis, 15–27 % require surgery [26]. Surgical mode of treatment includes debridement, penetrating keratoplasty, evisceration, bandage contact lens and corneal transplantation. Surgical intervention is carried out in a significantly larger number of patients with fungal keratitis compared to bacterial and parasitic keratitis thus indicating the poor response of fungal keratitis to medical treatment [11].

In conclusion, voriconazole could be a good choice for refractory fungal keratitis. We were able to control the Cladosporium keratitis by combining oral and topical voriconazole.