Review Endogenous Candida endophthalmitis Ahmed Sallam, William Lynn, Peter McCluskey and Sue Lightman† Intraocular Candida infections, although uncommon, represent an important clinical problem owing to the potential for visual loss, which can be bilateral. Candida chorioretinitis and endophthalmitis are complications of systemic candidiasis with extension of the fungal pathogens to the uvea and retina. Early diagnosis and prompt management significantly affect the visual prognosis for these patients. This review evaluates the current literature on Candida endophthalmitis and includes discussion on CONTENTS presentation, diagnosis and management strategies. New systemic and intravitreal antifungal agents are also reviewed in the context of the management of intraocular Etiology & pathogenesis fungal infection. Pathology Expert Rev. Anti Infect. Ther. 4(4), 675–685 (2006) Presentation & clinical features Etiology & pathogenesis detected in blood cultures [10] has decreased Diagnosis Candida spp. form part of the human flora the incidence of ocular complications dramati- Early detection where they exist as commensals on the cally [11]. In part, this may also be due to the mucosal surface of the respiratory, gastro- superior ocular penetration of fluconazole (as Treatment intestinal and female genital tracts. Distur- compared with amphotericin B [AMB]), which Outcome bance of the body’s immune system is gener- is now used more frequently as antifungal proph- Conclusions ally required for these organisms to become ylaxis in high-risk situations and also in the Expert commentary pathogenic. Candida is the most common systemic treatment of candidal endophthalmitis. cause of nosocomial fungal infection and, Candida chorioretinitis and endophthalmitis Five-year view although there is a recent trend towards an occur predominantly as a result of candidemia Key issues increase in the non-albicans spp., Candida seeding the eye, although cases occurring in References albicans is still the most common organism otherwise healthy individuals have been very Affiliations isolated in candidemia [1–3]. In a large pro- rarely reported [12]. While C. albicans is the spective study of more than 1000 patients with most common form of fungal endogenous candidemia, Chen and colleagues reported endophthalmitis [13], other Candida spp. may that C. albicans was the most common species rarely cause this [14–16], with not much differ- (50.4%), followed by Candida tropicalis ence in the pattern of prevalent species noted (20.5%), Candida parapsilosis (14.2%) and in systemic candidemia. Uncommonly, †Author for correspondence Department of Clinical Candida glabrata (12.0%). There were Candida infection may occur after penetrating Ophthalmology, Institute of 0–2 isolates of Candida krusei per year [1]. trauma or intraocular surgery and this type of Ophthalmology, Moorfields Eye The incidence of endogenous fungal endo- intraocular inflammation is referred to as Hospital, City Road, London phthalmitis in patients with candidemia has exogenous endophthalmitis. EC1V 2PD, UK been reported to range from 9 to 45% [4–9]. Risk factors for the development of candi- Tel.: +44 207 566 2266 Fax: +44 207 251 9350 However, data from Feman and colleagues demia and endogenous fungal endophthalmi- [email protected] showed that, in patients with disseminated tis are related mainly to suppression of the fungal disease, Candida chorioretinitis and antifungal immune mechanisms or to pro- KEYWORDS: amphotericin B, Candida, endophthalmitis occurred in approximately cedures that increase the risk of blood-borne caspofungin, chorioretinitis, 2.5% of their cases. This low figure may signify infection. Well-established factors include: endogenous endophthalmitis, fluconazole, intravitreal therapy, that the current trend for prophylaxis and immunosuppressive diseases, such as uncon- vitrectomy, voriconazole prompt early treatment when Candida is trolled diabetes mellitus, cancer, therapy with www.future-drugs.com 10.1586/14787210.4.4.675 © 2006 Future Drugs Ltd ISSN 1478-7210 675 Sallam, Lynn, McCluskey & Lightman broad-spectrum antibiotics and immunosuppressive drugs, Presentation & clinical features major surgery, especially intra-abdominal surgery, intravenous Patients with ocular Candida infection usually present with a hyperalimenation, indwelling intravenous catheters, and intra- subacute onset of floaters and blurred vision that may be venous drug use [17–19], as well as neutropenia, which is the most associated with ocular discomfort and photophobia [11]. Early common underlying condition associated with fungemia [20]. In or peripheral fungal lesions may be asymptomatic, with a retrospective study involving 46 patients with fungal endo- patient’s referral for ocular consultation being on the basis of a phthalmitis, neutrophil counts equal to or less than positive blood culture or diagnosis of systemic fungal infec- 500 cells/ml were noted in approximately 70% of patients [19] tion. In a report that reviewed cases of culture-positive endo- and neutropenia was also shown to be associated with a poor genous endophthalmitis, Binder and colleagues showed that, response to antifungal treatment [21]. C. albicans endophthalmi- in cases with yeast infection, nearly half the patients did not tis can also be seen in the postpartum period or after abortion, have any detectable associated infectious focus beyond the presumably as a complication of transient candidemia [22,23]. blood, whereas the most common additional infectious focus Despite the very high incidence of mucosal candidiasis, among these patients was urinary tract infection, seen in 30% Candida retinitis is very uncommon in HIV-infected patients of cases [30]. in the absence of other risk factors [24,25]. In a large retrospective Conjunctival injection and inflammation in the anterior series of 1163 HIV-infected patients, Jabs reported a single chamber with or without a hypopyon may be present (<0.1%) case of Candida retinitis in a patient who was an intra- (FIGURE 2). Inflammatory cells may also be deposited at the back venous drug user. He attributed this low incidence to the fact of the cornea (keratitic precipitates). The hallmark for the that immunity against systemic candidiasis is not dependent on diagnosis of Candida chorioretinitis is the presence of a fluffy cell-mediated immunity, in contrast to cytomegalovirus creamy white lesion at the level of the retina and choroid that infection (e.g., retinitis) or cryptococcal infection. Instead it is usually associated with vitreous haze (FIGURE 3A) [4]. The depends mainly on neutrophil cellular activity, which is not lesions are commonly multiple and can be bilateral, hence the severely disturbed in HIV infection [24]. importance of examining both eyes even in patients with Newborns with low birth weight and prolonged hospital stay uniocular symptoms. Progression of an active lesion is noted are at risk of developing candidemia. Although the occurrence by forward protrusion into the vitreous cavity, a sign first of ocular infection is very unusual in this age group [26], close described by Villafont and colleagues in 1964 [31]. The follow-up of newborns who survive candidemia is still essential inflammation may extend into the vitreous and sometimes as, rarely, preterm infants with successfully treated candidemia intravitreal puff ball-like lesions are seen, which represent may develop a fungal abscess in the crystalline lens, as a result vitreous abscesses (FIGURE 3B). of sequestration of Candida. The organisms then escape the Nonspecific lesions, such as intraretinal hemorrhages, nerve effect of systemic antifungal drugs [27]. In addition, Candida fiber layer infarcts and white centered hemorrhages (Roth sepsis was found to be associated independently with pro- spots) may be seen in the fundus in 10–20% of patients with gression of retinopathy of prematurity and the need for surgical candidemia. The presence of these lesions is not diagnostic and intervention in extremely low-birth-weight neonates [28]. may be caused by either ocular candidiasis or associated Fungal infections may cause release of proinflammatory systemic disease [4,32,33]. Serial ophthalmological examination is cytokines that aggravate retinal neovascularization in usually helpful to determine the nature of these lesions [33]. retinopathy of prematurity [29]. Retinal vascular occlusion may occur with fungal infection In contrast to deep and disseminated fungal infection, the [19,34] and is usually associated with poor visual outcome [19]. presence of superficial fungal infection is not itself a risk for developing ocular infection. Feman and colleagues found no Diagnosis cases of fungal endophthalmitis or chorioretinitis among the The diagnosis of Candida endophthalmitis is usually based on 32 patients with superficial fungal infection examined [11]. How- the appearance of the typical fundus lesion(s) in a patient with ever, Candida endophthalmitis may develop in patients receiving disseminated Candida infection or significant risk factors. In antifungal therapy, as they may have a resistant organism [11]. this context, isolation of the organism from urine, blood or other suspected sites such as intravenous lines and indwelling Pathology catheters supports the presumptive diagnosis. Positive Candida The choroid is the primary site of infection in the eye with blood cultures occur in only 50–75% of patients with Candida secondary involvement of the retina (chorioretinitis) (FIGURE 1) endophthalmitis