257 FUNGAL ENDOPHTHALMITIS

between 28 and 45% of cases. Infection typically begins as a chorioretinitis. On histopathology, Candida endophthalmitis is characterized by small foci of retinal and uveal infection and suppurative granulomatous inflammation with multiple small foci of suppurative vitritis and infection. In contrast, Aspergillus endophthalmitis is most often localized to the subretinal and subretinal pigment epithelial spaces, and is associated with foci of deep retinal necrosis or chorioretinitis, vascular invasion, and a single larger area of suppurative vitritis. These characteristics are consistent with the clinical findings that visual recovery is less common with Aspergillus and positive vitreous cultures are more often obtained with

Candida.

DIAGNOSIS

Clinical signs and symptoms

Fungal endophthalmitis presentation varies depending upon the:

●Size of the intraocular inoculation;

●Patient’s relative immunocompetency;

however, days to weeks later, fungal endophthalmitis develops in spite of continuous systemic antifungal treatment. For this reason, some authorities recommend repeat examination of patients with candidemia two weeks after an initial negative exam.

Laboratory findings

A thorough history and ophthalmologic examination often strongly suggest the causative pathogen. Obtaining a fungal culture prior to the initiation of antifungal therapy is essential; this may be the only way to determine the identity of the infectious filamentous fungus or yeast while allowing for drug sensitivity testing, if necessary. Fungal culture may not be necessary in those cases where systemic cultures have already isolated the pathogen.

Acquisition of vitreous fluid either by aspiration alone (i.e. vitreous tap) or during vitrectomy provides a higher yield than aqueous fluid from the anterior chamber. In the Endophthalmitis Vitrectomy Study, there was no added benefit of vitrectomy over aspiration alone. However, diagnostic vitrectomy is preferable to vitreous tap because aspiration without vitrectomy induces traction at points of vitreoretinal adhesion and may

gal agents during the initial infection period.

Most often, patients present 7 to 14 days after inoculation with:

●Conjunctival injection;

●Varying levels of pain (mild or absent);

●Often only mildly decreased vision.

The presentation of fungal endophthalmitis is typically more indolent than that seen with bacterial endophthalmitis, with a slower onset and more chronic course. Anterior chamber reaction, including hypopyon, and vitritis with whitish plaques on the pars plana, lens capsule or intraocular lens may develop. Alternatively, the eye may be white and quiet. Typically, exogenous endophthalmitis excites more pronounced pain and anterior segment inflammation, while endogenous endophthalmitis produces less pain and a quieter anterior segment.

More fulminant infections may cause:

●Fibrinous membranes in the anterior chamber;

●Vitreous veils, snowballs, and/or calcific plaques in the posterior segment.

Endogenous fungal endophthalmitis may also be associated with:

●White, fluffy retinal infiltrates;

●Retinal hemorrhages.

Funduscopy of Candida endophthalmitis characteristically reveals focal white superficial retinal lesions associated with a fluffy white overlying vitritis. Multiple white-centered superficial retinal hemorrhages can also be seen. Subretinal infiltrates sometimes coalesce into a white subretinal nodule. In contrast, Aspergillus endophthalmitis produces a more severe chorioretinitis, with more rapidly progressing larger lesions, as well as vasculitis and areas of retinal necrosis and retinal hemorrhage. A large yellow macular infiltrate often develops, with preretinal or subretinal exudative layering to form a pseudohypopyon of the posterior pole. Other fungi may produce a chorioretinitis similar to that seen with Candida.

Often, initial examination of patients at risk for fungal endophthalmitis by an ophthalmologist may be unremarkable;

capped and taken directly to the microbiology laboratory for smears and inoculation of culture media. The vitrectomy canister is sealed and sent for vacuum filtration or centrifugation. If only a small amount of vitreous is available, tryptic soy broth (usually used for swabs) can be drawn into the specimen syringe along with a small air bubble, and mixed.

Smears are best prepared by placing one drop of each specimen on a glass slide and using a spatula to spread in a circular area 1 cm in diameter. These are then left to dry and carried to the microbiology laboratory for fixation and staining. Gomori’s methenamine silver (GMS) and calcofluor white, and Acridine Orange stains may be used to stain for organisms. Blood agar and Sabouraud’s dextrose agar containing gentamicin are the preferred culture media. One drop of specimen can be placed in brain heart infusion broth warmed to room temperature. Two specimen drops are placed on a calcium alginate swab, which can then be placed in the bottom of a Thioglycolate broth warmed to room temperature. Aspirates may also be sent for PCR for fungal DNA if available to facilitate early preliminary identification.

In every case, fungal cultures should be incubated at least 4 to 6 weeks for observation. Some laboratories routinely discard cultures that have no growth after 48 hours, but some fastidious organisms may be quite slow growing; cultures for suspected fungal endophthalmitis discarded before 28 days may be falsely read as negative.

TREATMENT

Therapy for fungal endophthalmitis may be instituted medically and/or surgically. Initially, removal of infecting exogenous agents (e.g. indwelling catheter), treatment of an external fungal infection (e.g. keratitis), and/or treatment of systemic conditions that may predispose to endogenous endophthalmitis (e.g. neutropenia secondary to chemotherapeutics) is warranted.

Medical

Medical therapy may be ocular or systemic. Prior to instituting therapy, however, aqueous and vitreous cultures are sent to microbiology for sensitivities.

Ocular

Ocular therapy for fungal endophthalmitis may be:

●Topical;

●Subconjunctival;

●Intravitreal.

Topical ophthalmic antifungal agents, while effective for fungal keratitis or scleritis (e.g. natamycin 5% ophthalmic suspension), do not provide adequate intravitreal drug levels required for the treatment of endophthalmitis. Poor vitreous penetration is also seen following subconjunctival deposition of antifungal agents. In addition, this route of administration has a higher risk of local side effects, such as pain at the site of injection. Intravitreal injection is then performed. Amphotericin B (5 μg in 0.1 mL) may be effective for most forms of fungal endophthalmitis. If a patient has not undergone pars plana vitrectomy (PPV), then the half-life of intraocular amphotericin B is approximately one week, and one should not repeat injection until that time has elapsed. In contrast, if a patient has undergone PPV, the drug is cleared within 24 hours of administration.

Systemic

Systemic therapy may be:

●Parenteral;

●Oral.

Intravenous drugs currently available for fungal endophthalmitis include:

●Amphotericin B;

●Fluconazole.

Both agents are effective against a wide spectrum of fungi and act by binding to sterols in fungal cell membranes, increasing cell membrane permeability and causing leakage of cell contents leading to cell death. Amphotericin B is given intravenously in doses of 0.5 mg/kg/day or 1 mg/kg every other day in a single infusion over 4 hours. The patient also must be premedicated with ibuprofen and diphenhydramine for some of the uncomfortable side effects. Fluconazole is a third-generation imidazole that may be administered either parenterally or orally in doses ranging from 200 mg to 400 mg/day.

In the past, the most effective oral agents against fungal endophthalmitis have been:

●Flucytosine is effective against Candida and Cryptococcus species, particularly when added to amphotericin B. However, resistance has been noted in over 50% of fungal isolates tested against the drug. In addition, there have been side effects reported, the most serious of which is pancytopenia; others include elevated liver function tests and hepatomegaly;

●Fluconazole has good antifungal activity, but after several weeks the physician must be aware of clinical depression setting in, which may necessitate discontinuance of the drug;

synthetic derivative of fluconazole, differing from this drug by the addition of a methyl group to the propyl backbone and by the substitution of a triazole moiety with a fluoropyrimidine group. These structural changes result in a higher affinity for the fungal enzyme lanosterol 14-a-demethylase, thus preventing the conversion of lanosterol to ergosterol. Since ergosterol is essential to fungal cell membrane synthesis, depletion causes disruption of the membrane and cell lysis. Voriconazole has demonstrated greater activity against all Candida and Aspergillus species than all other antifungals currently available. Also, all endemic fungal pathogens, such as Fusarium, Histoplasma,

Blastomyces, Paracoccidioides, and Cryptococcus species, are fully susceptible to voriconazole.

Voriconazole achieves therapeutic concentrations in both the aqueous and vitreous both after oral and intravitreal administration. Examination of the safety of intravitreal use of voriconazole showed: normal adult rats were injected with differing concentrations of voriconazole in one eye while the fellow eye was injected with saline, thus serving as a control. Serial electroretinogram (ERG) measurements of maximum scotopic b-wave, bmax, intensity needed for half saturation, I0.5, and saturated a-wave amplitude were measured in all eyes. Determination was made that there was no statistically significant difference in these parameters recorded between control eyes and voriconazole-injected eyes in any concentration groups. Histologic examination with light microscopy did not reveal any retinal abnormality in the eyes with 5 to 25vμg/mL intravitreal voriconazole. No statistically significant difference was noted between eyes treated with different concentrations of voriconazole versus the fellow control eyes treated with saline in terms of ERG findings. Thus, because of its broad spectrum of coverage, low MIC90 levels for the organisms of concern, good tolerability, and excellent bioavailability with oral administration, voriconazole may represent a major advance in the prophylaxis or management of both exogenous and endogenous fungal endophthalmitis.

Surgical

In most cases of fungal endophthalmitis, pars plana vitrectomy may be helpful to:

●Retrieve vitreous samples for culture of the causative organisms;

●Remove the bulk of infective material;

●Sterilize the vitreous cavity;

●Improve aqueous circulation into the vitreous to circulate therapeutic drug molecules and to wash out offending fungal elements.

When there is no specific vitreous pathology, one must search for fungal elements to culture from all sites. Often, centrifugation or filtration of vitreous specimens can concentrate organisms and improve the chances of obtaining a positive culture. In cases of recurrent infection or inflammation in patients with an intraocular lens, removal and culture of the intraocular lens implant and the entire capsular bag should be considered to