Endogenous Candida albicans endophthalmitis in a 28-year-old male with a history of intravenous drug abuse. Note vitreous haze from vitritis, vitreous white fluffy lesions, and edematous optic disc (a). At 6 months, favorable clinical response after vitrectomy, one intravitreal amphotericin B injection, and systemic fluconazole treatment (b)
Possible sources of infection have been explored. In the mid-1980s, in France, an outbreak of candidiasis followed the introduction on the drug market of a new brown heroin , which had poor water solubility. This drug had to be dissolved in lemon juice or another acidic solvent. The hypothesis that the lemon juice used to dissolve the heroin might have been contaminated with Candida albicans carried by drug users was suggested [31, 32]. Moreover, lemon juice has been shown to be a good growth medium for yeasts [33, 34]. However, it has also been suggested that yeasts may be present in saliva used for drug dissolution or transmitted by needle licking before injecting the heroin [24, 26]. Finally, endogenous Candida endophthalmitis may occur rarely in healthy, immunocompetent patients without any risk factors .
Contrary to superficial fungal infections, disseminated candidiasis, especially ocular infections such as Candida chorioretinitis or endophthalmitis, is uncommon among HIV-infected patients. An explanation would be that immunity against systemic candidiasis is not dependent on cell-mediated immunity, but depends mainly on neutrophil cellular activity, which is not severely disturbed in HIV infection [36, 37].
In the USA and Europe, an ophthalmic examination is recommended for all candidemic patients to rule out intraocular involvement . In the current era of widespread prophylactic antifungal therapy, ocular fungal infection is rare, and some studies highlighted that the usefulness of routine ophthalmic consultations for all fungemic patients is relatively low [12, 13].
19.4 Clinical Features
19.4.1 Systemic Disease
Superficial mycoses include oropharyngeal, vaginal and cutaneous candidiasis, and paronychia and onychomycosis. Invasive candidiasis can involve virtually any organ and hence have a variety of clinical manifestations. Candida species may cause endocarditis, vertebral osteomyelitis, meningitis, cerebral abscess, endophthalmitis, septic arthritis, involvement of the kidney, pneumonia, etc. This is why a positive blood culture for Candida species should always be considered and antifungal therapy is nowadays recommended for any episode of candidemia [14, 38].
A syndrome was reported in heroin addicts treated for systemic Candida albicans infections including cutaneous lesions (scalp nodules and pustulosis in hairy zones), ocular localizations (mainly chorioretinitis), and osteoarticular involvement (vertebrae, costal cartilage, knees, and sacroiliac) .
19.4.2 Ocular Disease
Patients may be asymptomatic and patients who are seriously ill may not be able to voice any visual changes. In other cases, symptoms are due to chorioretinal or vitreous involvement and may include floaters and blurred vision and scotoma, without pain in early stages. A red painful eye with photophobia arises from anterior uveitis and decreased vision resulting from macular chorioretinal involvement or dense vitritis. Candida chorioretinitis lesions are initially located at the level of the choroid and/or retina and spread into the vitreous cavity in the late phase. Early, the characteristic findings are creamy, white, well-circumscribed lesions, associated or not with retinal hemorrhages or perivascular sheathing, associated with overlying vitreous cellular inflammation. Lesions may be singular or multiple and posterior or peripheral. Occlusive retinal vasculitis is an uncommon complication of Candida infection . Retinal hemorrhages may surround small necrotic lesions and appear similar to Roth spots. The vitreous exudates may assume a “string-of-pearls” or fluff ball appearance (Fig. 19.2). Chorioretinal lesions may become difficult to see at the late stage due to vitritis.
Candida albicans endophthalmitis. Note typical fluff ball appearance of vitreous exudates (a) and “pseudo” Roth spots (b)
The anterior segment initially may be normal. Over time, patients may develop anterior uveitis with ciliary injection, non-granulomatous keratic precipitates, posterior synechiae, flare, cells, and, in severe cases, hypopyon (Fig. 19.3). Resolution of the acute chorioretinitis may result in permanent pigmentary scarring. Epiretinal membrane, vitreoretinal traction, macular hole, choroidal neovascularization, or retinal detachment may occur. Rare cases of spontaneous healing have been described [40–42].
Candida albicans endophthalmitis following a gastrointestinal surgery. Note the hypopyon (a). At 7 days, favorable clinical response after vitrectomy, one intravitreal amphotericin B injection, and systemic fluconazole treatment (b)
Unlike endogenous fungal endophthalmitis, the vast majority of fungi identified in exogenous cases are molds. However, Candida species may be isolated in such situations, up to 29.8 % in a recent study . In comparison with bacterial endophthalmitis, exogenous fungal endophthalmitis often presents with a latency period of weeks to months after intraocular inoculation with insidious course . Typically, there are infiltrates in the anterior vitreous and fibrinous exudate in the anterior chamber. Confirmation of clinically fungal exogenous endophthalmitis is obtained by aspiration of aqueous humor and vitreous for microbiological analysis. Twenty-two isolates from patients with postsurgical endophthalmitis due to Candida parapsilosis as a result of exposure to a contaminated ocular irrigating solution were published by McCray et al. .
On fluorescein angiography, active lesions were early hypofluorescent and progressively became totally hyperfluorescent. Active choroidal inflammations appear as hypofluorescent spots on indocyanine green angiography without additional lesions than in fluorescein angiography .
OCT can clearly show the progression of chorioretinal lesions. Thus, OCT findings can show early lesions as a dome-shaped protrusion of the outer retina and pigment epithelium, then lesions involve the inner retinal layer as a hyper-reflective lesion, and finally, late-stage lesions appear like well-circumscribed, hyper-reflective, dome-shaped elevation overlying the retina with dense shadowing obscuring the underlying structures . OCT can also demonstrate large fluffy balls extending into the vitreous body and dense vitritis (Fig. 19.4). Hence, OCT is useful for monitoring progression of Candida endophthalmitis and its response to therapy, as well as in retinal complication detection.
Endogenous Candida albicans chorioretinitis in a patient with a history of indwelling central venous catheter in the context of pancreatic cancer (blood cultures were positive). Note creamy white lesions in the right (a) and the left eye (b). Ocular coherence tomography (OCT) findings show a well-circumscribed, hyper-reflective, dome-shaped elevation overlying the retina with dense shadowing obscuring the underlying structures in the right eye (c) and a lesion of the outer retina and pigment epithelium in the left eye (d). At 2 months, favorable clinical response after systemic fluconazole treatment in the right eye (e) and in the left eye (f). OCT findings show persistent vitreoretinal traction in the right eye (g) and a paramacular chorioretinal thinning in the left eye (h)
It is important to maintain a high index of suspicion of endogenous Candida ocular infection. Actually, the diagnosis of Candida endophthalmitis is usually based on the appearance of typical fundus lesions in a patient with disseminated Candida infection or significant risk factors. However, Candida blood culture may be negative even when disseminated disease is present, presumably because some patients only have transient or intermittent fungemia . In this way, Martinez-Vazques et al. reported seven blood-positive cultures in 15 cases (47 %) of C. albicans endophthalmitis in intravenous drug abusers . Moreover, isolation of Candida species from at least one extra-digestive site (urine, mouth, throat, upper and lower respiratory system, postoperative aspiration, or other suspected sites such as intravenous lines and indwelling catheters) supports the presumptive diagnosis . Candida colonization is a reliable independent risk factor for candidemia [50, 51] and a colonization index (number of colonized sites/number of sampled sites) >0.5 is associated with an increased risk of candidemia with identification of the same Candida species in the colonized sites and bloodstream .
Vitreous biopsy can help to confirm the diagnosis of endophthalmitis. However, the yield of positive cultures from vitreous samples is variable, ranging from 26 to 68 % in literature [18, 27, 53, 54]. Vitreous specimens obtained by vitrectomy might be more sensitive than specimens obtained by needle biopsy, probably because the majority of Candida is present in vitreous near the retina and only sampled during vitrectomy from posterior vitreous near the retina and not by vitreous tap . Henderson et al. confirmed that anterior chamber tap for culture was a poor diagnostic method in an experimental model . Furthermore, polymerase chain reaction (PCR) has shown to be of high specificity for fungal detection in vitreous , even though PCR on humor aqueous seems to be not as sensitive as on vitreous . Hence, PCR may allow a rapid diagnosis of fungal endophthalmitis. The use of serologic tests for circulating antibodies or antigens may be useful in providing a presumptive diagnosis of invasive fungal infection. However, the utility of these approaches remains to define in fungal endophthalmitis .
It is important to keep in mind that an infectious disease expert should be consulted because a complete medical workup for other sites of involvement is needed.
19.5.1 Differential Diagnosis
The differential diagnosis of Candida endophthalmitis includes endogenous bacterial endophthalmitis, endogenous endophthalmitis caused by other fungal organisms, toxoplasmic retinochoroiditis, primary intraocular lymphoma, and herpes virus family retinitis, in particular cytomegalovirus, multifocal choroiditis, and posterior uveitis.
Four major categories of systemic antifungal agents used in candidiasis can be distinguished: the polyenes (amphotericin B deoxycholate and its lipid formulations), the triazoles (fluconazole, itraconazole, voriconazole, and posaconazole), the echinocandins (caspofungin, anidulafungin, and micafungin), and the flucytosine. It is important to keep in mind that in fungal endophthalmitis treatment, achieving adequate concentrations of antifungal agents in the choroid, retina, and vitreous is crucial to success.
Amphotericin B has long been considered the standard of therapy for intraocular fungal infections. Very few resistances were described and only Candida lusitaniae is frequently resistant to amphotericin B . However, several studies noted the poor penetration of both amphotericin B deoxycholate (AmB-d) and its lipid formulations into the vitreous [61, 62]. Furthermore, amphotericin B use has been limited due to its systemic adverse effects, such as nephrotoxicity, fever, and hypotension. Amphotericin B has been injected directly into the vitreous as adjunctive treatment in severe fungal endophthalmitis [63, 64]. However, toxicity to the retina has been reported in rabbits with doses between 1 and 10 μg [65–67]. Experimental studies suggested reduced toxicity with intravitreal injections of liposomal amphotericin B [68, 69]. Amphotericin B intravitreal injection doses typically administered in humans are 5 or 10 μg/0.1 mL.
Flucytosine ocular penetration appears to be good, but this drug should not be used as monotherapy due to its propensity for the selection of resistant organisms. Hence, flucytosine is an adjunctive agent that can be used in combination with amphotericin B for the treatment of Candida endophthalmitis. Flucytosine is active against most Candida species, with the exception of C. krusei .
Fluconazole, an older generation of triazole, is most commonly used in ocular candidiasis due to its excellent efficacy, its low toxicity, and its good intraocular penetration [70–72]. Studies in humans have shown good response rates associated with amphotericin intravitreal injection  or not [73–76]. However, fluconazole had a limited spectrum of antifungal activity, and resistances were noted in immunosuppressed hosts who received long-term treatment. Fluconazole is active against all Candida species, except C. krusei, some strains of inherently resistant C. glabrata, and strains of C. albicans, which acquired resistance. Fluconazole treatment failures have been reported in endophthalmitis, even in cases of Candida albicans [77, 78]. Fluconazole is available in both intravenous and oral formulations.
Itraconazole has broader activity, but suffers from irregular absorption. It is not usually used in such cases. Furthermore, oral itraconazole has limited penetration into eyes with fungal endophthalmitis .
Voriconazole is a second-generation triazole available since 2002 with an extended spectrum of activity, including C. krusei, C. glabrata, and certain molds. Although voriconazole was highly active against C. glabrata, resistance to voriconazole has been reported. Moreover, voriconazole inhibited 90 % of clinical isolates of Candida species at a concentration six to eight times less than that determined for fluconazole . Voriconazole is available in both intravenous and oral formulations. Voriconazole has excellent oral bioavailability achieving therapeutic aqueous and vitreous levels in the noninflamed human eye . Despite these advantages, only a small number of patients who had Candida endophthalmitis treated with systemic voriconazole are described in the literature [82–84]. The most common adverse effects of voriconazole reported are disturbances of vision (photopsia, disturbed color vision, and blurring of vision), skin rashes, and elevations in hepatic enzyme level. The patients should be warned of the risk of photosensitization. The potential for drug interactions with voriconazole is high.
Voriconazole is also considered for intravitreal injection. Experimental studies showed no significant toxicity [85, 86], suggesting that an intravitreal voriconazole concentration up to 25 μg/mL is safe and that a dose of 100 μg could be used safely for intravitreal injection in humans . Several reports have been published about the safety and efficacy of intravitreal voriconazole in fungal endophthalmitis [82, 87]. Voriconazole intravitreal injections may be safer than amphotericin B injections and may immediately achieve high vitreal concentrations .
Like voriconazole, posaconazole has excellent in vitro activity against most Candida species. However, very few data are available concerning its interest in fungal endophthalmitis management [89, 90].
Echinocandins ocular penetration is very poor in animal studies [91–93]. Furthermore, clinical failure of caspofungin in the management of Candida albicans endophthalmitis associated with poor vitreous penetration has been reported .
Currently, no clear guidelines exist about the role of early vitrectomy in ocular candidiasis management. Vitrectomy may be useful to decrease infection load, to increase intraocular diffusion of systemic antifungal treatment, to limit healing vitreous retraction, and to provide vitreous samples for the analysis of intraocular fluid. Some studies suggest that early vitrectomy may be useful in reducing the risk of retinal detachment [54, 95]. Furthermore, antifungal drug intravitreal injection may be performed at the conclusion of the surgery. However, evidences for vitrectomy remain modest. Moreover, early vitrectomy in an infected eye could lead to specific complications, such as retinal detachment or intraocular hemorrhage. In this context, early vitrectomy might be considered for patients with severe vitritis or in patients with no clinical improvement despite the antifungal treatment [27, 82].
Finally, systemic corticosteroids should be avoided in Candida endophthalmitis .
Although there are no prospective studies for the treatment of Candida endophthalmitis, recommendations exist. Current Infectious Diseases Society of America (IDSA) guidelines for the management of endogenous Candida endophthalmitis published in 2009 and current European Society of Clinical Microbiology and Infectious Diseases guidelines for ocular candidiasis published in 2012 still recommend intravenous AmB-d and oral flucytosine, possibly with vitrectomy and intravitreal AmB-d, as therapy for patients with sight-threatening infections or when the susceptibility of the isolate is unknown. They also recommend fluconazole alone for less severe cases [14, 96]. Nowadays, newer antifungals are changing this conventional approach to ocular candidiasis. Recently, recommendations have been suggested concerning Candida endophthalmitis treatment encouraging an increased role for fluconazole and voriconazole and a decreased role for AmB-d . In these recommendations, either fluconazole (12 mg/kg loading dose, then 6–12 mg/kg daily) or voriconazole (6 mg/kg for 2 doses, then 4 mg/kg twice daily) may be used. Intravitreal injection of antifungal agents (voriconazole or AmB-d) should be considered if there is significant vitritis and, in cases of macular involvement, to achieve high vitreal concentrations as quickly as possible. It is recommended that treatment should be continued for at least 4–6 weeks, until complete resolution of visible lesions.
The visual outcome of Candida endophthalmitis is variable, depending on the stage of the disease. Previous studies have reported variable visual outcomes, with 15–60 % of eyes developing severe visual loss [55, 97]. Data from a more recent review by Sallam et al. indicated that a third of patients (33 %) develop severe visual loss (visual acuity of <20/200) and 50 % of patients develop visual loss (visual acuity worse than 20/40). In this study, poor initial visual acuity and centrally located lesions were associated with an increased risk of permanent visual loss. The authors suggested that early vitrectomy within 1 week of presentation significantly reduced the risk of retinal detachment, but had no effect on final visual outcomes . Furthermore, patients with candidemia have a high overall mortality rate, which may approach 50 %, associated with the severity of fungal infection and with their underlying medical problems.
Fungal endophthalmitis is a sight-threatening disease most commonly caused by Candida species. Candida endophthalmitis most often results from hematogenous dissemination. Although the use of prophylactic systemic antifungal therapy decreases the prevalence of ocular involvement in fungemia, it is important to be on the lookout for endogenous Candida ocular infection, particularly in immunocompromised or diabetic patients, those with indwelling catheter, or among intravenous drug users. The diagnosis of Candida endophthalmitis is mainly clinical and is usually based on the appearance of typical fundus lesions. Further trials are needed to define the role of voriconazole, a drug with more side effects and drug interactions than fluconazole.
Candida endophthalmitis is a vision-threatening condition.
Endogenous Candida ocular infections may occur in immunocompromised or diabetic patients, those with indwelling catheter, or among intravenous drug users.
Management and treatment should be instituted in collaboration with an infectious disease expert for systemic involvement management.
Current treatments include systemic fluconazole or voriconazole due to their good intraocular penetration, associated or not with early vitrectomy or antifungal intravitreal injection.