Fungal endophthalmitis Leila Rezaei vitreoretinal surgeon Assistant professor

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Fungal endophthalmitis Leila Rezaei, vitreoretinal surgeon Assistant professor of Kermanshah university of medical science

Fungal endophthalmitis Leila Rezaei, vitreoretinal surgeon Assistant professor of Kermanshah university of medical science

q Fungal Endophthalmitis, a serious, sight-threatening infection, is often a complication of intraocular surgery,

q Fungal Endophthalmitis, a serious, sight-threatening infection, is often a complication of intraocular surgery, systemic infection, and ocular trauma. q Endogenous, Follows Fungemia, with Hematogenous seeding of eye. q Exogenous, Follows Eye surgery, or Fungal Keratitis.

Ø The most common organisms in fungal endophthalmitis are: Candida spp, Aspergillus spp, Coccidioides

Ø The most common organisms in fungal endophthalmitis are: Candida spp, Aspergillus spp, Coccidioides spp, Blastomyces spp, Cryptococcus spp, Histoplasmosis spp.

v The common causes for: ü Endogenous FE: ü Post-traumatic FE: ü FE secondary

v The common causes for: ü Endogenous FE: ü Post-traumatic FE: ü FE secondary to keratitis: Candida albicans Aspergillus niger Fusarium solani

v The causative species is often difficult to diagnose because of poor growth in

v The causative species is often difficult to diagnose because of poor growth in culture. v The diagnosis is usually based on clinical history and presence of characteristic features in posterior segment. v Choice of drugs is not routinely based on laboratory susceptibility testing of fungal isolates.

Treatment of Fungal Endophthalmitis • Treatment is also difficult, resulting from: Drug resistance, Antifungal

Treatment of Fungal Endophthalmitis • Treatment is also difficult, resulting from: Drug resistance, Antifungal drug toxicity, Poor bioavailability of systemically administered drugs. • Intravitreal antibiotics are a mainstay of treatment for fungal endophthalmitis.

Systemic Antifungal Agents v Amphotericin B v Flucytosine v Azole compounds Fluconazole Itraconazole Voriconazole

Systemic Antifungal Agents v Amphotericin B v Flucytosine v Azole compounds Fluconazole Itraconazole Voriconazole Posaconazole v Echinocandins Caspofungin Micafungin Anidulafungin 0. 6– 1 mg/kg/day IV 50 to 150 mg/kg/day oral 400– 1600 mg/day oral or IV 400– 800 mg/day oral or IV 6 mg/kg/day oral or IV 400– 800 mg/day oral or IV 50 mg/day IV 50– 100 mg/day

Intravitreal Antifungal Agents Amphotericin B 5– 10 μg/0. 1 ml Voriconazole 0. 1 mg/0.

Intravitreal Antifungal Agents Amphotericin B 5– 10 μg/0. 1 ml Voriconazole 0. 1 mg/0. 1 ml Caspofungin 0. 1 mg/0. 1 ml Fluconazole (experimental) Flucytosine (experimental)

 • The drug should be given slowly in the central vitreous space, as

• The drug should be given slowly in the central vitreous space, as a bolus of even very small doses near the retina may result in retinal necrosis. • The drug has been found to reach the retinal surface in a few hours. • The frequency with which intravitreous injections can be given safely has not been determined and is different for each agent.

 • The elimination half-life of a drug in a vitreus cavity depends on

• The elimination half-life of a drug in a vitreus cavity depends on 2 pathways: 1) Anterior route passage into aqueous, 2) Posterior route by active transport across retina. • In inflamed eye, mechanism of active transport across retina is compromised, resulting in increased half-lives of drugs eliminated primarily through a posterior route.

q Increased retinal toxicity to routinely used doses of intravitreal antibiotics was demonstrated in

q Increased retinal toxicity to routinely used doses of intravitreal antibiotics was demonstrated in eyes filled with silicone oil. ü This was possibly due to reduction of the preretinal space. ü Using one quarter of the nontoxic dose could prevent retinal toxicity. ü Animal studies indicate that drug clearance is more rapid after vitrectomy.

Intravitreal Amphotericin B Ø Intravitreal Amphotericin B: 5– 10 μg, is generally nontoxic. Ø

Intravitreal Amphotericin B Ø Intravitreal Amphotericin B: 5– 10 μg, is generally nontoxic. Ø Intraocular toxicity from highly concentrated amphotericin B: Severe Noninfectious Panophthalmitis and Retinal Necrosis.

Intraocular Injection of Amphotericin-B § After intraocular injection, half-life : 9. 1 days. §

Intraocular Injection of Amphotericin-B § After intraocular injection, half-life : 9. 1 days. § Repeat injection: every 1 week § The half-life is further decreased by vitreous removal. (only 1. 8 days in vitrectomized eyes)

Intraocular Injection of Amphotericin-B a. 50 mg vial in 10 cc Aqua (=5 mg/cc)

Intraocular Injection of Amphotericin-B a. 50 mg vial in 10 cc Aqua (=5 mg/cc) b. take 0, 1 cc (=0, 5 mg) and dilute with 9, 9 cc Aqua (=0, 05 mg/cc) c. draw in tuberculin syringe for intravitreal injection d. inject 0, 1 cc (=0, 005 mg=5μg) into the vitreous cavity. Ø Physicians should examine the color of Amphotericin B solution prior to intraocular administration. Ø If the solution appears to be Yellow, the medication should not be injected.

Liposomal Amphotericin B • Liposomal Amphotericin B is a lipid-associated formulation of the Amphotericin

Liposomal Amphotericin B • Liposomal Amphotericin B is a lipid-associated formulation of the Amphotericin B. • Liposome incorporation reduces the toxicity of Amphotericin B by at least fourfold. • route in the rhesus mon

Intravitreal Fluconazole • Fluconazole penetrates ocular tissues well, achieving levels in the retina/choroid that

Intravitreal Fluconazole • Fluconazole penetrates ocular tissues well, achieving levels in the retina/choroid that are equal to serum levels, and aqueous and vitreous humor levels ≥ 70% of serum levels. • Intravitreous injection of Fluconazole is probably not necessary because of its good intraocular penetration. • Intravitreal Fluconazole has been tested in animal models, but does not appear to be any more effective than intravitreal Amphotericin B and is thus rarely used clinically.

Intravitreal Voriconazole Ø Broad spectrum of action. Ø Intravitreal Voriconazole has been shown to

Intravitreal Voriconazole Ø Broad spectrum of action. Ø Intravitreal Voriconazole has been shown to be less toxic to the retina than intravitreal Amphotericin B. Ø Based on animal models, intravitreal Voriconazole (VCZ) appears to be nontoxic up to doses of 100 μg. üDosage: 50 – 100 μg/0. 1 cc

a. 200 mg vial in 20 cc Aqua (=10 mg/cc) b. take 1 cc

a. 200 mg vial in 20 cc Aqua (=10 mg/cc) b. take 1 cc (=10 mg) and dilute with 19 cc Aqua (=0, 5 mg/cc) c. draw in tuberculin syringe for intravitreal injection d. inject 0, 1 cc (=0, 05 mg) into the vitreous cavity.

The half-life: 2. 5 hours. Supplementation of intraocular Voriconazole to maintain therapeutic levels is

The half-life: 2. 5 hours. Supplementation of intraocular Voriconazole to maintain therapeutic levels is required in clinical settings. Voriconazole is eliminated primarily through the retina, thus half-life of drug is increased in fungal endophthalmitis.

Intravitreally Implantable Voriconazole Delivery System Ø The therapeutic effect of intravitreal VCZ DDS on

Intravitreally Implantable Voriconazole Delivery System Ø The therapeutic effect of intravitreal VCZ DDS on fungal endophthalmitis appears to be significantly better than intravitreal injection of VCZ. ü The optimal dose of VCZ in the DDS in studies was 1. 2 mg.

Combination therapy with intravitreal Amphotericin B and Voriconazole could be a novel treatment strategy

Combination therapy with intravitreal Amphotericin B and Voriconazole could be a novel treatment strategy in the management of Endophthalmitis caused by Filamentous fungus.

Intravitreal Miconazole • Intravitreous injection of Miconazole has been used to treat endogenous Pseudallescheria

Intravitreal Miconazole • Intravitreous injection of Miconazole has been used to treat endogenous Pseudallescheria boydii infection of the eye that was resistant to Amphotericin B.

Intravitreal Ketoconazole • Intravitreal Ketoconazole has been reported safe in a rabbit model, but

Intravitreal Ketoconazole • Intravitreal Ketoconazole has been reported safe in a rabbit model, but its use has not been reported in humans.

Intravitreal Micafungin • In rabbits, intravitreal injection of 15 μg Micafungin was nontoxic, but

Intravitreal Micafungin • In rabbits, intravitreal injection of 15 μg Micafungin was nontoxic, but its use has not been reported in humans.

Intravitreal Corticosteroids • Intravitreal corticosteroids (e. g. , Dexamethasone 400 μg) may be a

Intravitreal Corticosteroids • Intravitreal corticosteroids (e. g. , Dexamethasone 400 μg) may be a helpful adjunct in some patients with fungal endophthalmitis, by reducing inflammation. • Generally, corticosteroids should be withheld until proper antimicrobials have been initiated, especially in patients with suspected fungal disease.

Conclusion For the treatment of fungal endophthalmitis, intravitreal injection of Amphotericin B is therapy

Conclusion For the treatment of fungal endophthalmitis, intravitreal injection of Amphotericin B is therapy of choice. The recommended dose ranges from 5 to 10 μg/0. 1 ml and may be repeated weekly. In vitrectomised patients, the dosing regimen should be reduce to every 3 or 4 days. The length of treatment and the total dosage are based on the extent of disease and its response to therapy.

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