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

2. 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 ㎛
Septae - may be divided into compartments by cross-walls
branching and apical extension

3. Fungi vs. Bacteria and Viruses

4. 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

5. 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.

6. 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

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

8. Sites and Mechanism of Action

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

10. Polyenes
natamycin

11. 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

12. 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.

13. 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.

14. 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.

15. Azoles
MICONAZOLE

17. 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

18. 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

19. 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.

20. Echinocandin

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

23. 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.

24. 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

25. Clinical Spectra of Activity

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

27. 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