Side effects include nausea, vomiting, diarrhea, thrombocytopenia, anemia, leukopenia, hepatotoxicity, and, rarely, bowel perforation.

Fluconazole, miconazole, ketoconazole, and itraconazole are azole derivates. Intraocular penetration is highest for fluconazole and lowest for itraconazole [24]. Fluconazole has excellent oral bioavailability and a relatively long half-life (mean, 25 h) in humans, permitting once-a-day administration. Its clinical toxicity (rigors, fever, vomiting, and renal failure) is less than that of amphotericin B. With its broadspectrum antifungal activity, fluconazole is effective in the treatment of experimental cryptococcal meningitis, systemic and ocular Candida infection, and systemic aspergillosis. The dose of fluconazole for treatment of fungal chorioretinitis without endophthalmitis is 200– 400 mg/day in two divided doses. Several species of Candida other than C. albicans, such as

C. krusei and C. glabrata, as well as Aspergillus and Fusarium species, are known to be resistant to fluconazole. In these cases, itraconazole may be used. Itraconazole has a low toxicity profile and is active against Candida, Aspergillus,

Coccidioides immitis, Cryptococcus neoformans,Histoplasmacapsulatum,andBlastomyces dermatitidis [25]. Available data suggest that none of the azole derivatives are as effective as amphotericin B. Furthermore, antagonism occurs in the anti-Candida effect of amphotericin B and ketoconazole when these two drugs are used in combination. The use of ketoconazole in combination with amphotericin B is not recommended because exposure of C. albicans to ketoconazole may make the organism resistant to amphotericin B [26].

The indications for vitrectomy in patients with fungal chorioretinitis and endophthalmitis are advanced cases with extensive vitreous involvement and poor response to systemic antifungal therapy [27].

Although vitrectomy poses some risks, it does have potential benefits, such as:

•Debulking of inflammatory and infectious material from the vitreous

•Acquisition of a larger sample for laboratory study

•Potential for concentrating the sample by centrifugation or filtration to give a better yield on culture

•An opportunity for intravitreal injection of antifungal agents

•Removal of the scaffolding for vitreoretinal traction bands and epiretinal membranes that can contribute to late-developing macular pucker and retinal detachment

Aspergillus Retinitis

Aspergillus is second in frequency to Candida as a cause of fungal intraocular inflammation. Aspergillus species exists as a saprophytic fungus common in soil and decaying organic matter. Although more than 100 species have been identified, the majority of human illnesses are caused by Aspergillus fumigatus and Aspergillus niger and, less frequently, by Aspergillus flavus and Aspergillus clavatus. Even though exposure to Aspergillus is universal, infection in humans is uncommon. Aspergillus can normally be isolated from the skin and mucous membranes including the conjunctiva. The most common mode of transmission of fungal spores to the human host is via inhalation into the pulmonary alveoli and paranasal sinuses [28]. In the debilitated patient, however, Aspergillus invades and disseminates and may produce lesions in the lung, brain, kidney, gastrointestinal tract, myocardium, liver, spleen, and occasionally the eyes. Reported ocular involvement includes subretinal, serous retinal detachments; choroidal, subretinal, and vitreoretinal granulomas; and abscess formation. Primary anterior segment involvement is rare. Exogenous Aspergillus endophthalmitis can occur following penetrating ocular wounds or ocular surgery.

Risk Factors

•Intravenous drug abuse is the most common risk factor associated with endogenous Aspergillus endophthalmitis (EAE). The organisms enter the bloodstream directly from contaminated drugs, needles, or syringes [29].

Fig. 9.14 (a) Histopathology of Aspergillus chorioretinitis. (b) Special stains revealed evidence of Aspergillus. (Reprinted with permission from Arévalo JF, Fernández

CF, Mendoza AJ. Chapter 41: Fungal infections. In: Retinal Imaging. Huang D, Kaiser PK, Lowder CY, Traboulsi EI, eds. Philadelphia: Mosby Elsevier: 2006; 366–774)

•Immunosuppression and debilitating diseases, such as [30]:

–Organ transplantation

–Myeloproliferative disorders

–Bronchopulmonary aspergillosis and chronic bronchitis in chi1dren

–Bronchial carcinoid and systemic corticosteroid use

•Prematurity.

•Miliary tuberculosis.

•Alcoholism.

•Goodpasture syndrome.

•Aspergillus endocarditis on prosthetic or natural cardiac valves.

Pathogenesis

Aspergillus has a predilection for invasion of blood vessels producing thrombosis, hemorrhage, infarction, and suppuration (Fig. 9.14). Vascular involvement is the major cause of death. Hematogenous dissemination to the eye can occur following hyphal penetration of blood vessels with an initial choroidal lesion. The infection then spreads to the overlying retina, with progressive abscess formation. Eventually the vitreous is invaded, and finally the anterior segment becomes involved [31]. Septate dichotomously branching hyphae can be found throughout the eye. This also explains the recalcitrance of infection to intravenous amphotericin B, given the absence of patent ocular vessels for drug delivery and the poor intraocular penetration of the drug.

Clinical Features

The ocular presentation and findings are often characteristic and provide possible diagnostic clues. The patients come to the office with rapid onset of pain and severe visual loss. Photophobia, pain, and iridocyclitis may occur, although the anterior segment is often quiet. Some patients present as a marked vitreous haze, a white mass in the vitreous, or a white pupil. The chorioretinal compromise characteristically involves the central macula. A large macular abscess and retinal pseudohypopyon formation are suggestive of the diagnosis (Fig. 9.15). A confluent yellowish macular infiltrate begins in the choroid and subretinal space. The retinal involvement may range from subretinal or subhyaloid infiltrates to fullthickness retinal necrosis (Fig. 9.16). Serous or exudative retinal detachment, intraretinal hemorrhages, choroidal or vitreous abscess, intravitreal granulomata, and posterior scleritis (Fig. 9.17) are also frequent [32].

Diagnosis

Disseminated aspergillosis is often a difficult clinical diagnosis to confirm. High clinical index of suspicion assisted by microbiological and histopathological evaluation helps in arriving at a correct diagnosis, thereby aiding successful treatment. Serologic tests are unreliable whereas blood cultures are usually negative even in fulminant cases. Even in patients with pulmonary involvement, sputum cultures are rarely positive. Invasive culture techniques (e.g., biopsies)

are helpful. Early recognition of intraocular aspergillosis may hasten diagnosis and improve prognosis. Awareness of Aspergillus’ propensity to cause retinal and choroidal infarction may improve the ophthalmologist’s ability to diagnose this visionand life-threatening event.

Fig. 9.15 Man with a history of intravenous drug abuse had vitritis and retinal pseudohypopyon formation due to Aspergillus. (Reprinted with permission from Weishaar PD, Flynn HW Jr, Murray TG, et al. Endogenous Aspergillus endophthalmitis. Clinical features and treatment outcomes. Ophthalmology. 1998;105:57–65)

Intraocular infection with Aspergillus species is difficult to distinguish from the other causes of endophthalmitis on the basis of clinical appearance alone [33]. In addition, Aspergillus species cannot be differentiated, with certainty, from other fungi on histopathological examination.

It has been suggested that a definitive diagnosis of Aspergillus infection is possible only by isolating and identifying the organism after culturing. In culture, all Aspergillus species have septate, dichotomously branching hyphae with conidiophores (stalks) bearing conidia at their ends. They are best identified using periodic acid Schiff or Gomori methenamine silver stain, but may also be seen with Gram stain or hematoxylin and eosin. Aspergillus species rapidly grow on Sabouraud agar and Czapek solution agar. Colonies are initially flat, white, and filamentous but become pigmented within 48 h with the production of conidia (Fig. 9.18).

Anterior chamber aspirates are usually of no value for isolation of the fungus. Despite the presence of hyphae on the surface of the iris, negative anterior chamber aspirates can be reported [34]. Direct examination and culture of vitreous specimens provide a better chance for isolation of the fungus, confirming the role for early vitrectomy in cases of Aspergillus

Fig. 9.16 (a) Yellowish subretinal lesion nasal to the optic disk surrounded by fluid secondary to Aspergillus infection in chronic leukemia. (b) Histology of the fellow enucleated eye confirming Aspergillus infection. (Reprinted

and modified with permission from Machado Od Ode O, Gonçalves R, Fernandes EM, et al. Bilateral Aspergillus endophthalmitis in a patient with chronic lymphocytic leukemia. Br J Ophthalmol. 2003;87:1429–1430)