Treatment of Fungal Keratitis

MEDICAL THERAPY

The antifungal agents available today are mostly fungistatic, requiring a prolonged course of therapy. Although models of Aspergillus and Candida have been established, there are no reliable animal models of Fusarium keratitis. Fungi considered to be ocular pathogens are rarely encountered among the systemic mycoses. Thus, the therapeutic principles valid for systemic fungal infections may not apply to the cornea (O’Day DM 1987). In vitro antifungal sensitivities often are performed to assess resistance patterns of the fungal isolate. However, in vitro susceptibility testing may not correspond with in vivo clinical response because of host factors, corneal penetration of the antifungal, and difficulty in standardization of antifungal sensitivities.

Polyenes

The polyenes include natamycin and amphotericin B. Polyenes disrupt the cell by binding to fungal cell wall ergosterol forming a polyenesterol complex that alters membrane permeability, depleting essential cellular constituents and are effective against both filamentous and yeast forms

Natamycin

Natamycin, available as 5% suspension (Natacyn, Alcon, Texas, USA; Natamet Sun Pharmaceuticals, Mumbai, India; Nata-Cipla Limited, Mumbai, India) is considered the drug of choice for filamentous fungi (O'Day DM 1987). Predominantly fungicidal tetraene polyene antibiotic, derived from Streptomyces natalensis Because of poor penetration, it is effective only in less severe superficial keratitis. (Prajna et al. 2003) conducted a prospective study comparing the efficacy of natamycin 5% and econazole 2% in 112 cases of culture-proved fungal keratitis and found no statistically significant difference between the two drugs. Moreover, natamycin is expensive; the supply is erratic, and often times difficult to obtain.

Amphotericin B

It is produced by a strain of Streptomyces nodosus; can be fungistatic or fungicidal and is available as a systemic preparation. To prepare the topical form, the compound is diluted with dextrose or distilled water to arrive at a 0.15 to 0.5% concentration (Fungizone, Sarabai Piramol, Vadodara,India).It can also be used through the subconjunctival (10 μg), intracameral (5-7.5 μg), intravitreal (10 μg) and intravenous routes (0.1 mg/kg body weight). The penetration of topically applied amphotericin B is poor in cornea with intact epithelium. Topical applications may cause punctate epithelial erosions. The spectrum of activity of amphotericin B covers Candida species (drug of choice) and Aspergillus sp. (Figs 10.1 and 10.2). It is not effective against Fusarium species (O’Day DM, et al 1986).

AZOLE COMPOUNDS

The azole compounds include triazoles: Econazole, clotrimazole, and the imidazoles: fluconazole, itraconazole and voriconazole. Azoles inhibit ergosterol synthesis at low concentrations, and at higher concentrations, they appear to cause direct damage to cell walls.

Triazole

Econazole

Econazole 1% in arachis oil is available as an ophthalmic preparation in India (Aurozole, Aurolab, Madurai, India). Prajna et al have found that the effect of this drug is equal to that of natamycin against filamentous fungi (Prajna et al 2003).

Clotrimazole

Clotrimazole is also available as a 1% topical preparation eye drops and in ointment form (Auroclot, Aurolab, Madurai, India) (Nistin-C, Jawa Pharmaceuticals, India). Mselle treated 12 patients with proven fungal keratitis with clotrimazole but suggested that clotrimazole as monotherapy is not an ideal choice (Mselle J 2001).

Imidazoles

Whereas the imidazoles; miconazole and ketoconazole, have less systemic toxicity, they are inferior to amphotericin B (Meunier-Carpentier F, 1983). Because of relatively reduced systemic toxicity and better corneal penetration, these compounds can be used systemically for keratomycosis. Thomas et al over a period of 10 years (1984-1994) treated 330 cultured- proved fungal keratitis cases with ketoconazole, itraconazole, amphotericin B, and natamycin and found that 69% of patients responded to ketoconazole, 66% to itraconazole, 53% to amphotericin B, and 56% to natamycin. In severe keratitis, it was less than 60% in all the groups. Fusarium is common in this region. Oral fluconazole and ketoconazole are absorbed systemically with good levels in the anterior chamber and the cornea; therefore, they should be considered in the management of deep fungal keratitis (Thomas PA, 2003).

Fluconazole

Fluconazole (Diflucon®, Pfizer NC, Zocon, Conflu), a fungistatic bitriazole is considered a topical and systemic agent in the treatment of fungal keratitis due to Candida and Aspergillus (Avunduk AM et al., 2003). However, fluconazole does not show encouraging results against Aspergillus species and Fusarium species (Rao SK et al., 1997). Panda et al from India compared the effect of natamycin 5%, polyhexamethylene biquanide (PHMB) 0.02%, 1% povidone iodine, and placebo in experimental Aspergillus keratitis in a rabbit model and concluded that PHMB was moderately effective and povidone iodine was not effective (Panda A et al, 2003).

Voriconazole

A new azole antifungal agent, voriconazole, is derived from fluconazole and shows a broader spectrum of activity against Candida, Aspergillus, Scedosporium, Fusarium and Paecilomyces. Jeu et al. described the mechanism of action. (Jeu L et al., 2003). As with other triazole antifungal agents, voriconazole exerts its effect primarily through inhibition of cytochrome P450- dependent 14_ sterol demethylase, an enzyme responsible for the conversion of lanosterol to 14_ demethyl lanosterol in the ergosterol biosynthetic pathway. In head-to-head comparative trials, voriconazole appeared to be as efficacious as amphotericin B for the treatment of invasive aspergillosis. In clinical studies, it was as efficacious as fluconazole and useful against fluconazole-resistant and itraconazole-resistant strains of Candida. Dose adjustment is recommended in patients with hepatic dysfunction. Eighty percent of this drug is hepatically eliminated. Shah et al. conducted an in vitro study to determine the activity of voriconazole compared with other polyene and imidazole antifungal agents against corneal isolates of Scedosporium apiospermum and found that the minimal inhibitory concentration of voriconazole was 0.5 μg/ml, a concentration lower than that of the other imidazoles (Shah KB et al, 2003).

Echinocandins

The echinocandins are caspofungin, micafungin, anidulafungin ( Glucan synthesis inhibitors) Under new antifungal drugs, echinocandins are used for systemic mycoses.The target of the echinocandins is the synthetic cell wall enzyme complex -1,3- beta -D-glucan synthase. Caspofungin (Cansidas; Merck research labs) is a polypeptide antifungal related to pneumocandin B0 The antifungal spectrum is restricted to Candida species and Aspergillus species and is not active against Fusarium species (Denning DW, 2003).

SURGICAL THERAPY

Frequent corneal debridement with a spatula is helpful as it helps to reduce the bulk of the fungal organisms and enhance penetration of the topical antifungal agent. The use of N-butyl cyanoacrylate tissue adhesive in the management of corneal thinning or perforation associated with active fungal keratitis has been reported (Garg P et al, 2003). In a study of 73 patients, 63% showed resolution of infiltration with scar formation. Xie et al, have tried lamellar keratoplasty. Approximately one third of fungal infection fails to respond to medical

Fig. 10.1: Amphotericin B preparation for intravitreal injection

Note: Reconstituted 10 ml solution can be used for one week; also the 1 ml remade up solution placed in a vial and used within a week (The vial must kept at –4°C)

Fig. 10.2: Amphotericin B preparation for topical application (0.1%)

treatment and may result in corneal perforation. (Xie et al, 2002). In these cases, a therapeutic penetrating keratoplasty is necessary. A small number of patients have been treated successfully with a conjunctival flap. The main goals of surgery are to control the infection and to maintain the integrity of the globe. Topical antifungal therapy, in addition to systemic fluconazole or ketoconazole, should be continued following penetrating keratoplasty. The use of topical corticosteroids in the postoperative period remains controversial.Structural integrity and eradication of sepsis is achieved in 80 to 90% of eyes and graft clarity in 36 to 89% (Panda A et al, 1991, Xie L et al, 2001 and Yao YF et al, 2003).

CONCLUSION

Current treatment methods frequently fail to preserve or restore vision after fungal keratitis. Although emerging antifungal agents show promise, therapeutic gaps will probably persist, and further development is necessary. Priorities should be given to develop and undertake drug trials against filamentous fungal keratitis.