Review

Endogenous Candida 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 and endophthalmitis are complications of systemic candidiasis with extension of the fungal pathogens to the and . 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 , 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- , 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 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 and blurred vision that may be venous drug use [17–19], as well as neutropenia, which is the most associated with ocular discomfort and [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 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 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 (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 creamy white lesion at the level of the retina and 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 , 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 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 [33], presumably because some patients only and, from there, Candida spreads into the vitreous [17]. The have transient or intermittent fungemia. Martinez-Vazques and inflammation is usually suppurative in nature with formation colleagues reported seven (47%) positive cultures in 15 cases of of multiple small vitreous abscesses [17], but a combination of suspected C. albicans endophthalmitis complicating intra- granulomatous and suppurative inflammation has also been venous drug abuse [35]. The yield of positive cultures from vitre- described [9]. Small foci of retinal damage are seen with ous samples is usually low in cases with fungal endophthalmitis. Candida retinitis compared with extensive retinal necrosis with In a retrospective study by Tanaka and colleagues, positive Aspergillus infection [17]. cultures were found in only 38% of vitreous specimens in

676 Expert Rev. Anti Infect. Ther. 4(4), (2006) Endogenous Candida endophthalmitis

used combined PCR assay and restriction A B fragment length polymorphism analysis with different oligonucleotide primers to detect fungi in vitreous fluid and identify the specific Candida spp. causing the infection. Of four studied eyes, PCR products were found in three eyes and only those that tested positive with PCR responded to antifungal therapy, whereas the PCR-negative specimen was also negative by culture and did not respond to antifungal drugs [40].

Early detection Published rates of endophthalmitis complicating candidemia vary widely and this is probably owing to differences in the patient population studied and prophylac- tic/systemic treatment regimens used. The consequences of unrecognized endo- phthalmitis are severe, which warrants Figure 1. (A) Macrosection of an eye showing Candida abscesses. (B) Histopathological section showing an abscess in choroid invading the retina and with vitreous cells. formal ophthalmological assessment after detection of candidemia. An initial nega- patients with endogenous fungal endophthalmitis. The authors tive review should be followed by another at 2 weeks. In a pro- attributed these results to several factors, including culture spective study of 31 patients with candidemia, the incidence of techniques and presurgical antimicrobial treatment [19]. chorioretinitis was found to be 26% (eight patients), with 16% Specimens for vitreous cultures obtained during vitrectomy (five patients) diagnosed on their initial ocular consultation and surgery may be more sensitive in making the diagnosis than three patients diagnosed within a 2-week period of their first those obtained by vitreous needle biopsy. In a recent report that review. The authors reported no evidence of ocular candidiasis included 14 patients with fungal endophthalmitis, four cases in other patients who continued to be examined for up to who had a negative culture when the sample was taken via a 24 weeks [8]. As Candida endophthalmitis could be initially needle tap were found to be positive when another biopsy was mistaken for noninfective [30,41], ophthalmologists need taken during vitrectomy [36]. This may in part be explained by to maintain a high index of suspicion for patients with intra- fungal infection starting in the choroid and extending through ocular inflammation and a history of systemic immunosuppres- the retina to the posterior part of the vitreous. Pathogens are sion, intravenous drug use or recent history of invasive surgical thus present mainly in the opacified vitreous near the retina procedures [41]. Clinicians involved in the management of and can only be sampled during vitrectomy from posterior patients with candidemia should be aware of the potential for vitreous near the retina and not by vitreous tap that aspirates anterior and central vitreous [36]. Detection of C. albicans DNA in intraocular fluid can be carried out using PCR assay. This method has been shown to be sensitive and rapid and overcomes the limitations of vitreous fluid culture [37]. It also does not require viable organisms and can be performed on a small sample volume [38]. With routine cultures, the likelihood of obtaining positive culture results from the aque- ous humor is much less than those from the vitreous [39,40], but PCR may be able to detect Candida DNA in aqueous samples taken through an anterior chamber paracentesis, which is an easier and less-invasive procedure when compared with vitreous aspiration or biopsy. Rapid detection of non-albicans spp. by PCR would permit the proper selection of antimicrobial treatment, as in species that are expected to be azole-resistant. However, PCR may detect DNA from live or dead organisms and this should be remembered when interpreting results in Figure 2. Hypopyon in an eye with intraocular Candida infection. patients already receiving treatment. Okhravi and associates

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A B

Figure 3. (A) Creamy white lesion classic of intraocular Candida. (B) Puff ball appearance of Candida infection extending into the vitreous. eye involvement. Early consideration of ophthalmological the fungal cell membrane, resulting in increased cell evaluation should be given and is essential if the patient has membrane permeability and, ultimately, cell death [44]. The visual symptoms or the eye is red. drug exhibits wide antifungal activity [45], although limited activity has been reported against some of the non-C. albicans Treatment spp. [46–49]. This drug is available commercially as AMB deoxy- Patients with Candida chorioretinitis need to have the type and cholate (D-AMB) since combining the drug with sodium extent of their disease diagnosed, any complications detected deoxycholate, a bile salt carrier, increases its aqueous solubility. and any underlying systemic cause or risk factor defined. Treat- The drug is given as an intravenous infusion in dextrose over ment should be instituted as soon as the diagnosis is made, in several hours in a dose of up to 1.5 mg/kg/day in severe cases, collaboration with the treating physician, with the aim to treat although a dosage above 1 mg/kg is often associated with high both the systemic and ocular candidiasis. Therapy should be toxicity. When given parenterally, it is highly protein bound continued until complete resolution of visible lesions. There are and distributes poorly to body fluids and tissues. Although the no randomized controlled trials on the duration of therapy for presence of intraocular inflammation enhances AMB penetra- fungal . Clinical guidelines recommend courses of tion into the eye, systemically delivered AMB (even as lipid 6–12 weeks of therapy to ensure complete eradication of the formulations) does not achieve therapeutic concentrations in systemic disease as well as any residual fungus in the eye [42]. the eye and is therefore not effective in the management of Candida retinitis extending into the vitreous [50,51]. The Systemic antifungal therapy Systemic antimycotic agents can be used to treat ocular candidiasis, as well as the A B systemic infection. However, once the fungus has penetrated the blood–eye barrier and crossed Bruch’s membrane into the retina, the infection is then no longer confined to the choroid, so drugs that cross the blood–retinal barrier and achieve high intraocular levels must be used [43], usually in combination with intravitreal therapy when the vitreous is involved. AMB is a polyene that binds to the ergosterol of the fungal cell Figure 4. (A) occurring in an eye treated for Candida endophthalmitis with systemic membrane forming an ergosterol–AMB fluconazole. (B) Ultrasound showing fixed detached retina in patient with Candida endophthalmitis without vitrectomy. complex. This complex forms pores in

678 Expert Rev. Anti Infect. Ther. 4(4), (2006) Endogenous Candida endophthalmitis

systemic toxicity of AMB is a serious disadvantage. Nephro- humor after oral or intravenous administration [49,59,61]. In toxicity is the main problem encountered and frequently leads contrast to AMB, this drug is well tolerated by most patients, to dose reduction or cessation of therapy [52]. Other side with fewer side effects, but hepatotoxicity may rarely be seen, effects include hypokalemia, fever and severe hypotension. especially in patients with AIDS [62,63]. Lipid formulation of AMB aims to optimize therapy with In a meta-analysis of several prospective studies that AMB as these compounds are associated with fewer side effects, compared fluconazole with AMB, Kontoyiannis and colleagues greater therapeutic index and higher distribution of the drug to proved that there was little difference in efficacy in the treat- infected tissues [53,54]. In addition, they may have better ment of systemic candidiasis due to C. albicans [64]. However, intraocular penetration than standard AMB. Goldblum and given the superior penetration of this azole into the vitreous, it colleagues studied the ocular penetration of two different types is the preferred systemic drug for the treatment of intraocular of lipid formulated AMB, namely, AMB lipid complex (ABLC) candidiasis [50,51]. Although fluconazole has been used for the and liposomal AMB (L-AMB), as compared with D-AMB in a treatment of systemic Candida infection for more than a dec- rabbit model. Results showed that, after intravenous adminis- ade, increasing drug resistance does not appear to pose a signif- tration, AMB concentration in the aqueous and vitreous icant problem [1,65]. In patients with candidemia, less than 1% humor was highest with L-AMB in inflamed eyes. After 1 week of fungal isolates exhibited resistance to fluconazole, with little of treatment, the AMB concentration in the vitreous was 0.47 difference in the susceptibility to fluconazole in 1999–2000 ± 0.21 µg/ml with L-AMB, 0.27 ± 0.18 µg/ml with ABLC (97.9%) compared with that detected in 1994–1995 (94%) [1]. and 0.16 ± 0.04 µg/ml with D-AMB. Intraocular distribution Resistance of C. albicans to fluconazole is currently estimated to was highly dependent on the presence of intraocular inflam- be less than 5% [65]. Although it was originally suggested that mation and no intravitreal AMB was detected in the absence there was a deleterious interaction between fluconazole and of uveitis [55]. In practice, AMB is injected directly into the AMB in an animal model, studies in humans have indicated vitreous in most patients with Candida endophthalmitis to that combined therapy with fluconazole and AMB is not antag- bypass the blood–retinal barrier, and is not given systemically onistic compared with fluconazole monotherapy and may be to treat intraocular infection. associated with an improved outcome [66,67]. The 5-flucytosine antimetabolite selectively inhibits fungal Ketoconazole and itraconazole are drugs that belong to the cell division. It is well absorbed orally and, although it may be triazole and imidazole groups, respectively. Both drugs can be administered by intravenous infusion, it is associated with administered orally and are effective against Candida spp., but higher toxicity and should only be used if the oral route is not isolates of C. glabrata may be resistant to itraconazole [19,68]. available. After uptake into fungal cells, the drug is deaminated These agents are used in mucocutaneous disease, but variable into 5-flurouracil and then phosphorylated into 5-flurodeox- absorption and blood levels make them unreliable in the uridine monophosphate, which in turn inhibits the enzyme management of systemic candidiasis. Itraconazole has good thymidylate synthetase, which is needed for DNA synthesis [56]. activity against Aspergillus spp., unlike ketoconazole and As the deamination step required for its activation occurs fluconazole [69]. Savani and colleagues studied the ocular pene- specifically inside fungal cells, systemic toxicity of the drug is tration of several azole compounds in an animal model and usually low. However, bone marrow depression and alteration showed a greater ocular distribution of fluconazole than both of liver function may be encountered. 5-flucytosine achieves itraconazole and ketoconazole. For all three drugs, intravitreal therapeutic concentrations in the vitreous and aqueous humor concentrations were higher in inflamed eyes compared with after oral administration [57] and is active against Candida and eyes with no induced uveitis [70]. Cryptococcus spp. and some strains of Aspergillus spp. It is usually used in combination with other antifungal agents as Intravitreal therapy acquired resistance develops quickly if used alone. Concurrent The rationale for the use of intravitreal injections of antifungal therapy with AMB and 5-flucytosine is synergistic and can be agents is to achieve a high intraocular level of the drug and used in severe cases of endophthalmitis [58]. simultaneously limit drug-related systemic toxicity. Drawbacks Fluconazole is a triazole antifungal agent that works by of this modality include the likelihood of retinal toxicity and inhibiting the fungal enzyme cytochrome P450, which is injury to intraocular structures. Furthermore, as fungal endo- involved in the synthesis of ergosterol. As a result, ergosterol phthalmitis is usually part of a systemic infection, intravitreal synthesis decreases and 14α-methylated sterols accumulate, injections alone are insufficient to manage the systemic with increase in the cell membrane permeability and, sub- candidiasis, but are used in addition when the eye is involved. sequently, cell death [59]. The drug is active against most yeasts, AMB is the most common antifungal agent given by this including C. albicans, C. parapsilosis and C. tropicalis. C. gla- route, although other antifungal agents have been investigated brata has reduced susceptibility to fluconazole with rates of for intravitreal injection [71–74]. The recommended dose of resistance to itraconazole and fluconazole at 10.7 and 15.2%, AMB is 5–10 µg in 50–100 µl [75]. Since the drug can cause respectively [1], while isolates of C. krusei are intrinsically resist- focal retinal necrosis, injection should be carried out slowly into ant to fluconazole [60]. Fluconazole achieves good concentra- the central vitreous cavity and as far as possible from the retinal tions in the cerebrospinal fluid, and vitreous and aqueous surface [76]. The number of injections needed is not

www.future-drugs.com 679 Sallam, Lynn, McCluskey & Lightman standardized but depends mainly on the severity of infection, colleagues, one patient with severe C. albicans endophthalmitis the clinical response of the patient to initial treatment and was treated successfully with intravitreal in addition to systemic whether vitreous has been removed or not, since ocular clear- voriconazole and no sign of retinal toxicity was seen up to ance of the drug is enhanced after vitrectomy [77]. Although 4 months postinjection [15]. Several other reports have also fluconazole can be given intravitreally (100 µg) and scleral demonstrated the safety and efficacy of intravitreal voriconazole implants containing fluconazole were found to be useful in a in cases of fungal endophthalmitis due to Aspergillus and rabbit model, neither are used in most clinical centers [78]. Verticillium spp. [84–86]. Posaconazole is a new triazole antifungal agent currently being Newer azole drugs investigated for treating systemic mycotic infections [87,88]. The Voriconazole is a new-generation triazole, approved recently for drug has an extended spectrum against most fungal pathogens, the treatment of serious infection by Aspergillus, Fusarium, including fluconazole-resistant Candida and refractory cases of Paecilomyces spp. and resistant Candida spp. [79]. The drug has Fusarium and Aspergillus infection [89]. Posaconazole has excel- an excellent pharmacokinetic profile with 96% oral bio- lent bioavailability after oral administration and appears to availability and achieves a peak plasma concentration in 2–3 h achieve high concentrations in both aqueous humor and vitre- after oral dosage [80]. In one study, after two oral doses (400 mg, ous [87,90]. To date, the exact role of posaconazole in treating administered 12 h apart), aqueous and vitreous levels were intraocular fungal infection has not been determined. Sponsel found to be greater than the minimum concentration required and colleagues published the report of a patient with contact to inhibit 90% of growth (MIC90) of most fungi with the lens-related Fusarium solani and endophthalmitis that concentrations in the aqueous and vitreous equal to 53 and resolved completely with systemic and topical posaconazole, 38.1%, respectively, of the plasma drug concentration [81]. despite being resistant to AMB and ketoconazole [90]. Furthermore, in another study, 1 week of intravenous treat- ment with voriconazole was shown to result in higher intra- Echinocandins ocular concentrations and achieved a level exceeding 18-times Caspofungin belongs to a new class of antifungal agents known the MIC90 of C. albicans [15]. Voriconazole use may be associ- as echinocandins, which selectively target the fungal cell wall [91]. ated with skin rash and photosensitivity as well as disturbance The drug is approved currently in the USA and Europe for the of liver function. Importantly, when this is given systemically, treatment of invasive aspergillosis resistant to AMB and transient visual disturbances (photopsia, disturbed color vision itraconazole and can only be given parenterally. and blurring of vision) are seen in approximately a third of the In a prospective trial comparing caspofungin and AMB for patients with no evidence of ocular involvement, but these are the treatment of invasive candidiasis, both drugs were shown to reversible and do not necessitate drug withdrawal [82]. be equally effective. No patients in the caspofungin group and In an in vitro study of the susceptibility of pathogens causing only one patient in the AMB group developed new ocular and endophthalmitis in South Florida, lesions while receiving treatment. Fewer drug-related side Marangon and colleagues found that nearly all isolates were effects were experienced by patients receiving caspofungin [92]. sensitive to voriconazole, while susceptibility to AMB and Several animal studies have demonstrated excellent drug fluconazole was 76.5 and 60%, respectively. For Candida spp., distribution into the eye of the related drug micafungin after MIC90 values for voriconazole were much lower than that of systemic administration [93]; however, clinical experience with AMB (0.5 µg/ml), fluconazole (0.5 µg/ml) and others. In this caspofungin in endophthalmitis is limited. Few case reports study, Candida spp. were the most common cause of endo- describe its use in individual cases of C. glabrata and Fusarium genous endophthalmitis, with C. albicans responsible for endophthalmitis, whether alone or combined with other anti- 53.5% of the Candida cases [13]. Breit and colleagues published fungal agents [14,84]. As discussed previously, Breit and colleagues a review series of five patients with endogenous Candida endo- achieved good results with a combination of voriconazole and phthalmitis who were managed successfully with systemic vori- caspofungin in a series of patients with endophthalmitis due to conazole alone or in combination with caspofungin. Only one C. albicans, C. glabrata and C. guilliermondii [15]. Other drugs patient with bilateral disease experienced treatment failure that from this group are emerging [94]. necessitated intravitreal AMB in either eye, although three of these patients had organisms that were resistant to systemic Intravitreal steroids fluconazole [15]. The use of intraocular steroid injection in the management of Voriconazole has been considered recently for intravitreal fungal endophthalmitis is controversial, but is not undertaken injection. Gao and colleagues investigated the safety of inject- by most ophthalmologists. Although in an animal study, Coats ing the drug into the vitreous of a rodent model [83]. Their data and Peyman showed that injecting dexamethasone in the vitre- showed that intravitreal concentrations of 25 µg/ml or less were ous increased significantly the rate of vitreous clearance when not associated with any retinal toxicity that could be detected combined with AMB [95], clinical use in cases of exogenous by electrophysiological and histological examination. They fungal endophthalmitis failed to show any significant difference suggested that a dose of 100 µg could be used safely for intra- in visual or anatomical outcome in the dexamethasone-plus vitreal injection in humans [83]. In the paper by Breit and group [96]. In addition, steroids may interfere with monocyte

680 Expert Rev. Anti Infect. Ther. 4(4), (2006) Endogenous Candida endophthalmitis cell activity on fungal pathogens that may potentiate the incidence of ocular infection appears to be decreasing owing to infection [97]. No controlled trial data exist, and it is unlikely the recent trend of early systemic treatment of deep tissue that such a trial would be undertaken. fungal infection and prophylaxis with fluconazole in high-risk situations. Typically, the disease presents as a focal white fluffy Ocular surgery infiltrate in the choroid and retina that may break into the Surgical removal of the vitreous gel (vitrectomy) is indicated in vitreous. Lesions are usually associated with vitritis and vitreous eyes with fungal endophthalmitis that have severe vitreous abscesses may be seen. The diagnosis is usually made on clinical involvement. Early vitrectomy may be indicated for lesions grounds and requires a high index of suspicion. It may be involving the fovea and also in patients with poor visual acuity at confirmed by laboratory investigation, but the yield of positive presentation. Vitrectomy is typically both diagnostic and thera- blood and vitreous cultures is generally low. Both intravitreal peutic in patients with Candida infection. Removal of the vitreous and systemic treatment are used for treatment of Candida decreases the fungal load and thus increases the effect of the anti- chorioretinitis and endophthalmitis, but still there is no univer- fungal drugs and provides a specimen for laboratory studies and sal agreement regarding the specific indications for either form culture. Most surgeons would opt to inject an antifungal drug of treatment. Systemic antifungal drugs are needed to manage intravitreally at the conclusion of the surgery [36]. In addition, coexisting candidemia and preference is given to drugs that vitrectomy decreases the late-onset development of retinal mem- penetrate the blood–retinal barrier when lesions extend into the branes and tractional retinal detachment due to vitreous contrac- retina and vitreous. Vitrectomy and intravitreal AMB are tion that can occur during the healing stage (FIGURE 4) [98]. Rarely, indicated for cases with severe vitreous involvement. Early choroidal neovascularization may complicate Candida endo- vitrectomy appears to decrease the incidence of late retinal phthalmitis and can result in late-onset visual loss. Management is detachment and improve the visual outcome. Intravitreal vori- with laser photocoagulation or surgical excision [99,100]. conazole may offer a new treatment option to manage Candida endophthalmitis but further evaluation is needed. Outcome Visual prognosis in endogenous endophthalmitis depends on Expert commentary the virulence of the organism, the location of the fungal abscess Candida chorioretinitis should be considered in the differential and the degree of ocular damage before the start of effective diagnosis of posterior uveitis or endophthalmitis in an immuno- treatment [16]. Retinal detachment consequent to vitreous compromised host or a patient who has recently had intravenous contraction in nonvitrectomized eyes and the development of lines or is an intravenous drug abuser. The diagnosis is usually fibrotic membranes distorting the macula are an important straightforward on clinical examination, but vitreous biopsy or, cause of visual loss after settling of the infection. In addition, preferentially, a diagnostic and therapeutic vitrectomy may be choroidal neovascular membranes may develop at the site of needed in selected patients to confirm or rule out the diagnosis. healed scars. Patients with Candida endophthalmitis generally Although not available routinely, PCR studies of vitreous have a better visual outcome than those due to Aspergillus infec- specimens appear to be very sensitive and can compensate for tion, which tend to involve the macula and are usually associ- the shortcomings of vitreous and aqueous humor cultures. ated with more extensive retinal damage [17,30,41]. In two Successful management depends on early diagnosis and prompt reports, more than 80% of patients with Candida endo- treatment, as well as close collaboration between physicians and phthalmitis had a final visual acuity of 6/60 or more [19,30], with ophthalmologists. All patients with candidemia should have a better visual acuity in eyes that underwent early vitrectomy and formal ophthalmological assessment. When visual symptoms or intravitreal injection of antifungal drugs [36,101]. It is important a are present, this is urgent. In the absence of ocular to remember that patients with candidemia have a high overall symptoms, ocular examination should occur within 1–2 weeks. mortality rate, which may approach 50% [101,102], which Repeat evaluation at 2 weeks is required in patients seen initially reflects the extent and severity of fungal infection, as well as within a few days of a positive blood culture. Management is their underlying medical problems [41]. usually tailored to the degree and severity of ocular involvement. Early lesions confined to the choroid are outside the blood–reti- Conclusions nal barrier and can be treated as for systemic infection with Candida chorioretinitis is the most common cause of endo- drugs, such as AMB. Flat lesions involving the retina with mini- genous endophthalmitis seen in clinical practice. Although mal overlying vitritis need initial systemic treatment with drugs, uncommon, the disease is serious and frequently sight threaten- such as fluconazole, that achieve a high therapeutic level in the ing. All but a few cases of ocular candidiasis are seen in patients eye and also need to be watched carefully. Fluconazole can be with risk factors for candidemia, and thus, they are at risk of used without deleterious drug interaction with AMB when death due to concomitant infection of vital organs, such as the systemic involvement necessitates continuing AMB. Lesions heart or brain. Important predisposing factors for systemic extending into the vitreous are best managed with vitrectomy candidemia include systemic immunosuppression, recent inva- and intravitreal AMB injection in addition to systemic flucon- sive procedures and intravenous drug abuse. Although Candida azole. Voriconazole should be considered for the management of is an increasingly prevalent cause of nosocomial infection, the ocular candidiasis in the following situations: fungal isolates

www.future-drugs.com 681 Sallam, Lynn, McCluskey & Lightman from blood/eye that are likely to be or known to be not suscepti- be promising but further trials are needed before it should ble to fluconazole, especially when resistance is demonstrated by replace fluconazole as systemic treatment for fungal endo- in vitro testing, as with C. krusei and C. glabrata and patients phthalmitis, which is cheaper, more readily available and has who develop intraocular involvement while receiving a full stood the test of time. The role of caspofungin remains systemic treatment dose of fluconazole. Caspofungin and uncertain at the present time. emerging echinocandins should be considered as salvage therapy Further development of intravitreal medications continues or if toxicity prevents the use of other agents [103]. and newer drugs will be coming into clinical practice. Atten- tion should also be given to the analysis of the pathophysiology Five-year view during the healing process of Candida endophthalmitis, as The area that will be the focus of most research activity during clinical experience shows that retinal traction due to formation the next 5 years is probably the development of new systemic of surface membranes remains an important cause of visual fail- agents that can penetrate the blood–retinal barrier and achieve ure in treated eyes. Development of therapeutic agents that high therapeutic levels in the vitreous, perhaps avoiding the modulate cellular activity and extracellular matrix proliferation need for additional intravitreal therapy. Voriconazole appears to could, at least theoretically, improve the visual outcome.

Key issues

• Candida albicans is the most common cause of fungal endogenous endophthalmitis. • Candida endophthalmitis is seen mainly in immunocompromised patients, after invasive medical procedures and in intravenous substance misusers. • Neutrophils appear to be the most important defensive mechanism against dissemination of Candida infection and this may explain the low incidence of Candida retinitis in AIDS patients with severe immunosuppression. • All patients with candidemia should have a dilated ophthalmological examination shortly after diagnosis for early detection of ocular involvement. • Diagnosis is mainly clinical and treatment requires cooperation with other physicians involved in the management of the patient. • The sensitivity of standard cultures for the detection of Candida in the vitreous is still relatively low and candidemia may be intermittent, thereby remaining undetected by blood cultures. • PCR of aqueous and vitreous samples is a recent method that may become useful in patients with an unclear diagnosis. • Incidence is decreasing owing to the trend of prophylaxis in patients at high risk and early initiation of antifungal agents in patients with systemic candidiasis. • Fluconazole remains the systemic drug of choice for intraocular candidiasis as it crosses the blood–retinal barrier and is effective against most of the endophthalmitis-causing Candida spp. • Early vitrectomy and intravitreal antifungal agents appear to improve the visual prognosis. • Further studies are needed to define the indications for the newer antifungal agents.

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Fax: +44 207 251 9350 [email protected]

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