가톨릭대학교 의과대학 안과 및 시과학 교실 서울성모병원 장동진 ANTIFUNGAL DRUGS 가톨릭대학교 의과대학 안과 및 시과학 교실 서울성모병원 장동진

Fungus more than 70,000 species  but only two basic types Yeasts Molds(filamentous) single cells, usually round or oval in shape 3 – 15 ㎛ reproduce by budding Hyphae - branching cylindrical tubules diameter from 2 - 10 ㎛ Septae - may be divided into compartments by cross-walls branching and apical extension

Fungi vs. Bacteria and Viruses

Fungi vs. Bacteria and Viruses Classified as eukaryotic cells internal membrane system dividing the cell into different regions membrane-enclosed organelles DNA contained in a membrane bound nucleus rigid cell wall polysaccharides and chitin determines the organism’s shape

more challenging to develop antimicrobials with selective toxicity. The complexity of fungal organisms a closer similarity to mammalian cells more challenging to develop antimicrobials with selective toxicity.

Eye Infections Only a small number of fungi The most common ocular fungal pathogens yeast - Candida molds - Aspergillus, Fusarium, Curvularia virtually every eye structure including the cornea, sclera, conjunctiva, lens, ciliary body, vitreous, and the entire uveal tract Predisposing factors contact lenses, topical steroids, trauma, compromised immune system

Clinical Features Satellite lesion Feathering margin Midstromal infiltration Feathering margin Dry rough texture Satellite lesion

Sites and Mechanism of Action

Four main classes of antifungals Polyenes amphotericin B natamycin Pyrimidines(antimetabolites) Flucytosine Azoles voriconazole, posaconazole, ketoconazole, itraconazole, f luconazole, miconazole Echinocandins caspofungin,micafungin,anidulafungin

Polyenes natamycin

Polyenes Natamycin Amphotericin B Well tolerated, less irritating than amphotericin B Not effective for deep stromal infection Amphotericin B Not commercially available as a topical formulation Good corneal penetration with topical use Corneal toxicity increases with topical concentrations over 0.15% Oral use not affective: poor ocular bioavailability Side effects nephrotoxicity, agranulocytosis, liver dysfunction, thrombocytopenia, leukopenia, electrolyte imbalance, anemia, headache, nausea, vomiting, malaise, weight loss, phlebitis, fever, chills antagonism with miconazole

Evidences Three of 4 patients who failed to respond to initial treatment with 5% topical natamycin, followed by 2% topical the ketoconazole and systemic ketoconazole underwent repeated amphotericin B intracameral injections and had complete resolution of the ulcer (Kuriakose et al.). Three patients with culture proven Aspergillus flavus corneal ulcers and hypopyon who did not respond to 5% topical natamycin, 0.15% amphotericin B solution, or oral itraconazole, received intracameral amphotericin B injections and had complete resolution of the ulcer and hypopyon (Kaushik et al.). Intracameral injection of amphotericin B may have a role in management of severe fungal keratitis not responding to topical treatment.

Evidences A rabbit model for Candida albicans compared the efficacy of topical amphotericin B with four other antifungal agents. Amphotericin B and 5% natamycin were the most effective, 1% miconazole and 1% flucytosine were effective but inferior to the polyenes, and 1% ketoconazole was not effective (O’Day et al.). Topical amphotericin B appears to be very effective against Candida keratitis.

Evidences A prospective nonrandomized study compared the efficacy of 1% itraconazole drops with 5% natamycin for monotherapy of fungal keratitis. In patients with Fusarium keratitis, 79% responded favorably to natamycin compared with 44% to itraconazole (p <.02). Both treatments were well tolerated with no obvious adverse effects reported (Kalavathy et al.). 5% natamycin is the treatment of choice for treating filamentous fungal keratitis. Natamycin is more effective than itraconazole for treating Fusarium keratitis but is not effective in treating deep stromal infections.

Azoles MICONAZOLE

Azoles Voriconazole Excellent bioavailability Miconazole Topical side effects of burning, itching, tearing Good ocular penetration with topical and subconjunctival use Toxic conjunctival necrosis may occur with subconjunctival use Ketoconazole Fungistatic activity, therapy response generally slow inappropriate for severe or progressive fungal disease Itraconazole Topical not effective for severe infections, penetrates cornea poorly Penetrates all eye tissues poorly with oral administration Fluconazole Very good bioavailability, low toxicity

Evidences MIC: Minimum inhibitory concentration A prospective nonrandomized study that evaluated aqueous and vitreous voriconazole concentrations after oral administration in 14 patients scheduled for elective pars plana vitrectomy showed therapeutic MIC concentrations in the vitreous and aqueous against a wide range of organisms, including Aspergillus and Candida (Hariprasad et al.). Oral voriconazole appears to reach therapeutic aqueous and vitreous levels in the noninflamed human eye. MIC: Minimum inhibitory concentration

Evidences A retrospective record review of fungal isolates associated with fungal keratitis and endophthalmitis evaluated the MICs of common fungal pathogens against amphotericin B, fluconazole, ketoconazole, flucytosine, itraconazole, and voriconazole. Voriconazole showed the highest susceptibilities for Aspergillus, Candida, and Fusarium (Marangon et al.). Voriconazole has demonstrated high susceptibilities for Aspergillus, Candida, and Fusarium.

Echinocandin

Micafungin Caspofungin Topical not commercially available Report of 3 cases of yeast keratitis treated successfully with topical micafungin Caspofungin Scant ocular treatment information

Evidences Case report of 2 patients with exogenous Fusarium and Aspergillus endophthalmitis successfully treatment using voriconazole, and voriconazole and caspofungin in combination (Durand et al.). A retrospective review of 5 patients with Candida endophthalmitis showed that 4 of 5 patients had resolution with IV and oral voriconazole. Oral, IV and intravitreal voriconazole, and voriconazole in combination with caspofungin, may be efficacious in treating both endogenous and exogenous endophthalmitis.

Evidences A case report of 3 patients originally treated with topical corticosteroids, who did not respond to initial treatment with topical azoles and polyenes, reported resolution of Candida ulcers with topical 0.1% micafungin (Matsumoto et al.). Topical micafungin shows potential as a treatment for fungal keratitis

Clinical Spectra of Activity

Limits of antifungal treatment significant side effects a narrow antifungal spectrum of activity poor tissue penetration fungal resistance

Fungal resistance Polyene Azoles Echinocandins replace ergosterol with certain precursor sterols Azoles accumulation of mutations in ERG11, the gene coding for the 14-a-sterol demethylase. Cross-resistance is conferred to all azoles Increased azole efflux by both ATP-binding cassette (ABC) and major facilitator superfamily transporters Increased production of C14-a-sterol demethylase Echinocandins mutations in a conserved region of the FKS1 gene coding for amino acids Phe 641-Asp 658 FKS1p is an essential component of the 1,3-b-D-glucan synthase complex