antifungal agents in ophthalmology
DESCRIPTION
Fungal infections of eye cause one of the most dangerious infections. Accurate diagnosis and proper institution of anti-fungal therapy is essential. Here we discuss the various anti-fungal agents available to be used in ophthalmology.TRANSCRIPT
Polyenes
1st effective antifungals Bind preferentially to ergosterol in the
fungal plasma membrane > alters membrane permeability > disrupts the fungal cell
Use is restricted due to insolubility, irritation on application and instability
Nystatin
1st polyene antibiotic in 1950 Derived from Streptomyces noursei Affective against Candida infections Topical ointment 100,000 IU, 4-5
times/day Allergic hypersensitivity reactions
Amphotericin B Streptomyces nodosus Insoluble in water, unstable at 37 degree Degrades rapidly is exposed to light Effective against Candida, Aspergillus,
Cryptococcus, Coccidioides, Sporothrix, Blastomycosis, Histoplasma, Mucormycosis
Topical/s.c./intracameral/i.v. Topical – 0.075%-0.3% hourly S.c. 0.8-1.0mg 1-2 doses i.v. 1-1.5mg/kg/day in 5% dextrose over 4 hrs with
pretreatment with hydrosortisone Adverse reactions: anaphylaxis, headache, nausea,
vomoting, fever, nephrotoxicity
Natamycin Only antifungal commercially available for
topical administration Derived from Streptomyces natalenses Most effective against filamentous fungi Also for fusarium, aspergillus and most of
other fungi 5% topical suspension drops 4-6 times/day Adverse reactions: irritation, burning, PEK,
allergic reactions
Imidazoles
1st imidazole was Clotrimazole Inhibition of fungal ergosterol synthesis Interference with mitochondrial oxidative
and peroxisomal enzymes resulting in accumulation of lethal by-products
Affinity for fungal cytochrome P450
Clotrimazole Chlorinated trityl imidazole Borad antifungal activity Specially for aspergillus Also for Candida, fusarium, penicillium,
clasporium and actenomyces 1% eye drops to be used hourly Sckin cream 1% well tolerated by eye Poorly soluble in water Can not be given parenterally Irritation, punctate keratopathy, hepatotoxicity,
diarrhoea
Miconazole Phenethyl imidazole Broad spectrum Causes alteration in fungal cell wall >
induces permeability changes 1% Topical instilled every hourly Sub conj 5-10mg every 48 hrs for 2-3
doses Conjunctival injection, PEE, pruritus,
erythema, local irritation
Econazole
Dichlorimidazole Broad spectrum Low toxicity Interference with membrane sterol
formation 1% ointment and drops 4-6times daily Effective in only superficial infections of
the eye
Ketoconazole Highly effective for treatment of keratomycosis Inhibits ergosterol synthesis More water soluble Enhanced absorption capacity Affective against Candida, Aspergillus, Fusarium Oral: 200-800mg/24hrs single daily dose for a week Topical 1-5% drops Reactions: relatively safe, GIT upset, abnormal LFT,
hypersensitivity Reversible hepatotoxicity Topical well tolerated
Fluconazole 1st antifungal with good pharmacokinetic profile
& relative low side effect Water soluble Exhibits low binding to proteins Most effective against yeasts. Also few dimorphic fungi Most important application : systemic use in
Candida endophthalmitis in combination with Amphotericin B
Oral 200-600mg/day for 3 weeks for candida and 10-12 weeks in cryptococcus infection
Topically 0.3% eye drop every 4hrly
Voriconazole Good bioavailability Good tolerability Good therapeutic concentrations Completely inhibits ergosterol synthesis, more
effectively than fluconazole Commonly used for invasive systemic and ocular
infections specially aspergillosis and candidiasis 200-400mg BD with maintaininace with half dose Transient visual disturbances, fever, rash, vomiting,
headache, abdominal pain, rare but serous hepatotoxicity
Faster and deeper penetration Highly effective in fungal keratitis with
deep abscess Outclasses all other antifungals IV 100ug at conc of 1000ug/ml in
candida endophthalmitis – non-toxic to retina
Itraconazole Well distributed in lipid-rich tissues Lack of intravenous preparation Primarily for aspergillus, histoplasma,
blastomycosis, onychomycosis Moderate for candida & fusarium Orally 200mg BD for a week Topically – to be freshely prepared Subconj is safe GI upset and hypersensitivity
FLUCYTOSINE Fluorinated pyrimidine Effective against Candida, Cryptococcus,
Aspergillus, Clasporium, Penicillium Transported across fungal cell membrane by a
specific permease In cell it is deaminated to fluorouracil that blocks
fungal thymidine synthesis Orally 50-150mg/kg/day divided in 4 doses for a
week Topically 1% drops every hourly Not used alone as poor penetration in certain fungal
cell membranes Topically causes irritation, itching, burning.
Systemically causes nausea, vomiting, diarrhoea
Caspofungin Inhibits 1,3 beta glucan synthase Disrupts the integrity of fungal cell wall Administered IV Effective for invasive aspergillosis,
candidemia Initial dose 70mg iv-infusion followed by
50mg iv daily Relatively low incidence of side effects
including GI disturbances, headache, fever, anemia, hypokalemia, tachycardia, hypersensitivity
SILVER COMPOUNDS
Silver Sulphadiazine Highly effective against Candida,
Aspergillus, Fusarium Topically well tolerated Fungistatic For both superficial and deep infections 1% drops hourly Local irritation, FB sensation, tching
NEWER HORIZONS TERBINAFINE (LAMISIL)
AllylamineBroad spectrum, highly effectiveLow toxicity, high cure ratesPrimary fungicidal action even at low concHighly selective for single fungal enzymeHighly lipophilicMycological cure achieved before clinical cure250mg/day for 2-4 weeksTopical 1% ointmentSystemic side effect include GI upset, skin reactions,
taste disturbances, liver dynfunction, blood disorders.
Topical may cause irritaiton, itching, redness
Caspofungin