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

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

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

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

The causative species is often difficult to diagnose because of poor growth in culture. The diagnosis is usually based on clinical history and presence of characteristic features in posterior segment. 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 drug toxicity, Poor bioavailability of systemically administered drugs. Intravitreal antibiotics are a mainstay of treatment for fungal endophthalmitis.

Systemic Antifungal Agents Amphotericin B 0.6–1 mg/kg/day IV Flucytosine 50 to 150 mg/kg/day oral Azole compounds Fluconazole 400–1600 mg/day oral or IV Itraconazole 400–800 mg/day oral or IV Voriconazole 6 mg/kg/day oral or IV Posaconazole 400–800 mg/day oral or IV Echinocandins Caspofungin 50 mg/day IV Micafungin 50–150 mg/day IV Anidulafungin 50–100 mg/day

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 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 2 pathways: Anterior route passage into aqueous, 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.

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

Intravitreal Amphotericin B Intravitreal Amphotericin B: 5–10 μg, is generally nontoxic. 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. 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. 50mg vial in 10cc Aqua (=5mg/cc) b. take 0,1cc (=0,5mg) and dilute with 9,9cc Aqua (=0,05mg/cc) c. draw in tuberculin syringe for intravitreal injection d. inject 0,1cc (=0,005mg=5μg) into the vitreous cavity. Physicians should examine the color of Amphotericin B solution prior to intraocular administration. 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 B. Liposome incorporation reduces the toxicity of Amphotericin B by at least fourfold. route in the rhesus monkey.

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 Broad spectrum of action. Intravitreal Voriconazole has been shown to be less toxic to the retina than intravitreal Amphotericin B. Based on animal models, intravitreal Voriconazole (VCZ) appears to be nontoxic up to doses of 100 μg. Dosage: 50 – 100 μg/0.1 cc

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

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 The therapeutic effect of intravitreal VCZ DDS on fungal endophthalmitis appears to be significantly better than intravitreal injection of VCZ. 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 in the management of Endophthalmitis caused by Filamentous fungus.

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 its use has not been reported in humans.

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 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 the therapy of choice. The recommended dose ranges from 5 to 10 μg/0.1ml 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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