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Treatment of endogenous endophthalmitis due to Candida species

Treatment of endogenous endophthalmitis due to Candida species
Authors:
Marlene L Durand, MD
Carol A Kauffman, MD
Section Editors:
Jennifer E Thorne, MD, PhD
Daniel J Sexton, MD
Deputy Editor:
Keri K Hall, MD, MS
Literature review current through: Dec 2022. | This topic last updated: Apr 07, 2022.

INTRODUCTION — Candida species are a common cause of fungal endophthalmitis. This infection arises in two distinct ways:

The endogenous form follows candidemia, with hematogenous seeding of the eye. Fungi usually first seed the highly vascular choroid, then infection typically progresses through the retina into the vitreous. The aqueous is sometimes involved as well.

The exogenous form follows trauma, eye surgery, or progression of fungal keratitis (corneal infection). Fungi are directly inoculated into the aqueous and/or vitreous. (See "Treatment of exogenous endophthalmitis due to Candida species".)

The management of endogenous endophthalmitis due to Candida species will be reviewed here. The epidemiology, pathogenesis, clinical manifestations, and diagnosis of fungal endophthalmitis are discussed separately. The management of exogenous endophthalmitis due to Candida species and endophthalmitis due to molds are also presented elsewhere. Bacterial endophthalmitis, Fusarium keratitis, and candidemia and other types of Candida infection are also discussed elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis" and "Treatment of exogenous endophthalmitis due to Candida species" and "Treatment of endophthalmitis due to molds" and "Bacterial endophthalmitis" and "Treatment and prevention of Fusarium infection", section on 'Keratitis' and "Management of candidemia and invasive candidiasis in adults" and "Overview of Candida infections".)

DEFINITION — The terminology of Candida endophthalmitis may be confusing. The term "endophthalmitis" means infection within the eye and in general implies infection of the vitreous and/or aqueous (figure 1). Endogenous Candida endophthalmitis often presents first as chorioretinitis with minimal vitritis (vitreous inflammation) then later progresses to produce vitreous and sometimes aqueous infection. The term "ocular candidiasis" is used to describe this spectrum of infection, and some articles in the literature reserve the term "Candida endophthalmitis" only for cases in which the vitreous and/or aqueous are involved. However, the majority of publications include the entire spectrum, including chorioretinitis, in the term "Candida endophthalmitis," so we will follow this convention. We will note the distinction between chorioretinitis alone and Candida infection that extends to involve the vitreous throughout this topic because the approach to therapy differs between these two conditions.

TREATMENT — No controlled trials of treatment regimens for endogenous Candida endophthalmitis have been performed. The evidence comes from case reports and small observational studies. In addition, studies of the treatment of candidemia have provided insights regarding the choice of therapy for endogenous Candida endophthalmitis. (See "Management of candidemia and invasive candidiasis in adults".)

The approach to treatment must take into account the site and stage of infection, the pharmacology of the available antifungal agents, and existing clinical experience [1,2]. Therapeutic approaches include:

Systemic antifungal agents

Intravitreal antifungal agents

Surgical removal of the vitreous (vitrectomy)

Our recommendations are generally in keeping with the 2016 Infectious Diseases Society of America guidelines for the management of candidiasis [3].

In general, patients who have only chorioretinitis can be treated with a systemic antifungal agent alone. For patients whose lesions threaten the macula or exhibit mild to moderate vitritis, many ophthalmologists will use intravitreal injections of antifungal agents in combination with systemic antifungal therapy in order to attain immediate high concentrations of the agent in the posterior compartment of the eye (figure 1). For patients who have moderate to heavy vitritis, vitrectomy and intravitreal injection of antifungal agents along with systemic therapy is almost always necessary.

The overall prognosis for Candida endophthalmitis has improved but only if the infection is diagnosed early and managed appropriately. Close follow-up by an ophthalmologist is required. (See 'Outcomes' below.)

Approach to treatment — Treatment of endogenous Candida endophthalmitis varies depending on whether only chorioretinitis is present, whether the macula is threatened, and the degree of vitritis. Patients with this condition should be evaluated and treated by both an ophthalmologist who has been trained to manage this condition (eg, a retina specialist) and an infectious diseases specialist. The systemic antifungal doses recommended below are intended for patients with normal renal function.

Endogenous endophthalmitis without vitritis

For patients with extramacular chorioretinitis without extension into the vitreous, we recommend the following treatment course:

For Candida species that are susceptible to fluconazole and voriconazole, systemic therapy with oral fluconazole (800 mg [12 mg/kg] loading dose, then 400 to 800 mg [6 to 12 mg/kg] orally daily) OR voriconazole (400 mg [6 mg/kg] intravenously [IV] every 12 hours for two doses, then 300 mg [4 mg/kg] IV or orally every 12 hours) can be used. For fluconazole-susceptible isolates, fluconazole is preferred over voriconazole.

Most patients infected with a fluconazole-resistant species can be treated with systemic voriconazole, as discussed below:

-For C. krusei, which is inherently resistant to fluconazole, voriconazole should be used as nearly all strains are still susceptible. There have been rare reports of voriconazole resistance in patients with C. krusei infections who have received prolonged voriconazole therapy [4,5].

-For C. glabrata isolates that are fluconazole resistant, voriconazole should be used only if the isolate is shown to be susceptible. It is important to note that cross-resistance between fluconazole and voriconazole is common among C. glabrata isolates, and patients infected with this species should be followed carefully for their response to treatment.

-In patients who present acutely, the IV formulation of voriconazole is recommended initially prior to switching to oral therapy. Oral therapy at a dose of 200 to 300 mg orally twice daily can be used following an initial response to the IV formulation.

-In patients with a subacute presentation who are being managed as outpatients, the voriconazole loading dose can be given orally (400 mg [6 mg/kg] twice a day for two doses), followed by an oral maintenance dose of 200 to 300 mg (3 to 4 mg/kg) twice daily.

-It is important to measure serum trough concentrations of voriconazole four to seven days after initiating therapy to ensure that adequate concentrations have been achieved to allow success and to avoid high concentrations that have been associated with adverse events. Although debate remains over the optimal target concentration, available data suggest a therapeutic range between 2 and 5 mcg/mL. In patients with concentrations that are too high or too low, the serum concentration should be rechecked four to five days after adjusting the dose. (See "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)

For fluconazole- and voriconazole-resistant isolates, liposomal amphotericin B (3 to 5 mg/kg IV daily) is recommended. Flucytosine (100 mg/kg orally daily in four divided doses) can be added for species that are susceptible to this agent.

It is likely that patients who have only chorioretinitis without vitreous involvement will respond to therapy with other agents, such as echinocandins, but there is little clinical experience using this approach. We do not generally recommend echinocandin therapy. If an echinocandin is considered in cases of chorioretinitis without vitritis (eg, in patients intolerant of other therapeutic options), it should only be used if frequent ophthalmic examinations can be performed and if improvement is documented on therapy.

For patients who have macular involvement with or without extension into the vitreous, we suggest an intravitreal injection of amphotericin B deoxycholate (5 or 10 mcg in 0.1 mL sterile water) or voriconazole (100 mcg in 0.1 mL sterile water or normal saline) in order to quickly achieve high local antifungal concentrations, in addition to systemic therapy, as noted above.

Endogenous endophthalmitis with vitritis — In patients with endogenous Candida endophthalmitis with moderate to heavy vitritis, vitrectomy should be performed in addition to intravitreal injection of antifungal agents. In those with light to moderate vitritis, vitrectomy may not be required, although intravitreal injection of antifungal agents may be indicated. An ophthalmologist should perform frequent dilated ophthalmic exams to follow the progression of the infection. Systemic antifungal therapy is required in all cases.

We recommend the following treatment course for moderate to heavy vitritis:

Vitrectomy and

Intravitreal injection of amphotericin B deoxycholate (5 or 10 mcg in 0.1 mL sterile water) or voriconazole (100 mcg in 0.1 mL sterile water or normal saline) and

Systemic therapy as listed above (see 'Endogenous endophthalmitis without vitritis' above)

Intravitreal injection of amphotericin B or voriconazole may need to be repeated, typically 48 hours or more after the initial injection if there is no clinical improvement.

The management of exogenous endophthalmitis caused by Candida species is discussed separately. (See "Treatment of exogenous endophthalmitis due to Candida species".)

Duration of systemic therapy — The optimal duration of systemic antifungal therapy for Candida endophthalmitis is unknown but is typically four to six weeks [3]. Treatment should continue until all active eye lesions have resolved as determined by serial dilated ophthalmic examinations. The length of treatment will depend on the rapidity of resolution of active eye lesions. Patients who have vitreous involvement generally require a longer duration of therapy than those who have only chorioretinitis.

Systemic antifungal therapy — Patients who have only chorioretinitis respond better to systemic antifungal therapy alone than those with vitreal involvement [6,7]. At this early stage of the infection, systemic therapy is probably adequate without intravitreal injection of antifungal agents. In patients who have endophthalmitis as a manifestation of disseminated candidiasis, it is essential that systemic therapy be given to treat other involved organ systems. (See "Management of candidemia and invasive candidiasis in adults".)

Experience in treating ocular candidiasis has accumulated with amphotericin B with or without flucytosine, voriconazole, and fluconazole. When choosing an antifungal agent, it is important to determine the risk of fluconazole-resistant Candida isolates, such as Candida krusei and most Candida glabrata isolates.

Amphotericin B and flucytosine — Liposomal amphotericin B (3 to 5 mg/kg IV daily) has replaced amphotericin B deoxycholate (0.7 to 1 mg/kg IV daily) in most cases in which the latter agent was used for candidemia, given lower renal toxicity with liposomal amphotericin B. Amphotericin B deoxycholate with flucytosine (100 mg/kg orally per day in four divided doses) was previously used as one of the preferred treatments for Candida endophthalmitis [3].

Two major drawbacks of amphotericin B deoxycholate are that it achieves poor levels in the vitreous [6] and that it has significant systemic toxicities, particularly nephrotoxicity. There are limited data on the penetration of the lipid formulations of amphotericin into the eye. One study in rabbits that had inflamed eyes noted higher concentrations in both the aqueous and vitreous with infusions of liposomal amphotericin B when compared with either amphotericin B deoxycholate or amphotericin B lipid complex [8]. A study that included 4 patients with fungal endophthalmitis receiving 200 to 250 mg per day of IV liposomal amphotericin found that levels in aqueous and vitreous were only 0.09 and 0.17 percent of serum levels, respectively [9]. In contrast, flucytosine achieves excellent concentrations in the eye. However, it can cause concentration-dependent bone marrow toxicity, which commonly occurs in patients with renal insufficiency. (See "Pharmacology of amphotericin B", section on 'Adverse effects' and "Pharmacology of flucytosine (5-FC)", section on 'Adverse effects'.)

Fluconazole — Fluconazole has much less toxicity than amphotericin B and achieves concentrations in the vitreous in humans that are approximately 70 percent of that in the plasma [10,11]. Increasing numbers of reports have shown the benefit of fluconazole for the treatment of Candida endophthalmitis [11-15]. However, failures have also been reported [16]. In animal models of Candida endophthalmitis, amphotericin B was superior to fluconazole in one study [17] but not in another [18]. In many of the case reports, the doses of fluconazole (100 to 200 mg orally daily) were likely too low.

Voriconazole — Voriconazole is being used with increasing frequency for Candida endophthalmitis [1,19-21]. This agent achieves approximately 40 percent of serum concentrations in the vitreous in noninflamed eyes, is available for intravenous or oral administration, and is active against many species of Candida, including some strains of C. glabrata and almost all strains of C. krusei that are resistant to fluconazole [22]. Voriconazole has an additional advantage of being active against molds, such as Aspergillus spp, which can also cause endophthalmitis [23-26]. Because cross-resistance occurs between fluconazole and voriconazole for C. glabrata isolates, susceptibility testing is recommended to guide therapy. Increasing resistance to voriconazole among strains of C. glabrata is worrisome and may decrease the usefulness of this agent for treating endophthalmitis due to C. glabrata. (See "Antifungal susceptibility testing", section on 'Indications for testing'.)

In a treatment trial evaluating the efficacy of voriconazole versus amphotericin B followed by fluconazole for candidemia in 370 patients, a post-hoc analysis of outcomes of the subset of patients who had Candida ocular infections noted a favorable response in 29 of 31 evaluable patients (93.5 percent) [21]. The favorable response rate in the voriconazole group was similar to what was observed among patients treated initially with intravenous amphotericin B for three to seven days, followed by oral fluconazole. However, 13 of 44 patients (30 percent) in the voriconazole group and 6 of 16 patients (38 percent) in the amphotericin/fluconazole group were not evaluable because they died or had no follow-up eye examination. Only 4 of the 31 evaluable patients in the voriconazole group had extension of infection into the vitreous, whereas 27 had chorioretinitis, which is typically easier to treat.

In a review of several published reports that included seven patients who had Candida endophthalmitis treated with voriconazole, visual acuities in the six survivors ranged from 20/20 to 20/100 [1]. It is not possible to firmly state that voriconazole was solely responsible for improved visual outcomes, since several of these patients were given other systemic antifungal agents or had intravitreal injection of voriconazole or amphotericin B.

Posaconazole — Posaconazole has been used in very few patients with ocular fungal infections. Concentrations in the vitreous appear to be low [1]. Currently, it is not recommended as treatment for Candida endophthalmitis.

Isavuconazole — Successful treatment with oral isavuconazole has been reported in a single case of Candida dubliniensis endophthalmitis in a patient who failed fluconazole and was intolerant to amphotericin [27]. Data for ocular concentrations of isavuconazole are limited [28,29].

Echinocandins — The echinocandins do not achieve adequate concentrations in the vitreous, and their role in treating Candida ocular infections is unclear. It is possible that they could treat chorioretinitis without vitreous extension, but only a few case reports have addressed this, and both failure and success have been noted [1,30,31]. Echinocandins may achieve good levels in the highly vascular choroid, but data are sparse in humans. A study of eight eyes in seven patients who were receiving IV micafungin and who were scheduled for vitrectomy (six eyes) or enucleation (two eyes) reported mean micafungin concentrations of 21 mcg/mL in the plasma but, 30 to 90 minutes later, only 0.08 mcg/mL in aqueous samples and 0.10 mcg/mL in vitreous samples [32]. Micafungin concentrations in other ocular structures were measured in one enucleated eye and showed reasonable levels in the choroid (5.8 mcg/mL; 34 percent of the plasma level) but lower levels in the retina (1.20 mcg/mL; 7 percent of the plasma level) and vitreous (0.15 mcg/mL; 0.88 percent of the plasma level). Currently, given their poor penetration into the vitreous, echinocandins cannot be recommended as treatment for Candida endophthalmitis with vitritis, and their role in treating chorioretinitis alone is unclear [1].

It has been suggested that one might gain a sense of the success of echinocandin therapy for treating Candida endophthalmitis by assessing the response to therapy of the few patients with ocular involvement who were included in the large randomized treatment trials of echinocandins for candidemia and invasive candidiasis. A total of 1028 patients received echinocandins in five randomized controlled treatment trials, and 21 were stated to have endophthalmitis [33-37]. Twelve patients (57 percent) were said to have had resolution of the eye infection. Unfortunately, in none of these trials were specific data reported with regards to the extent of ocular involvement (vitritis versus chorioretinitis) or use of intravitreal injections and/or vitrectomy.

Intravitreal antifungal agents and vitrectomy — A few patients with vitritis have had a successful outcome documented with systemic antifungal therapy alone, but failure rates are high [12,15,19]. In patients with endogenous Candida endophthalmitis with moderate to heavy vitritis, vitrectomy should be performed, but, in those with light vitritis, vitrectomy may not be required. For severe vitritis, the best therapeutic strategy appears to be vitrectomy, intravitreal injection of amphotericin B (5 or 10 mcg in 0.1 mL sterile water), or voriconazole (100 mcg in 0.1 mL sterile water or normal saline) and systemic antifungal therapy [11,12,15]. Early vitrectomy may be important for a favorable outcome [12]. In at least one study of 12 patients with Candida endophthalmitis, good outcomes were reported in the seven patients who underwent early vitrectomy (within one week), but poor visual outcomes were noted in four of five patients in whom vitrectomy was delayed or not performed [12]. The extent of vitreal involvement was not detailed in this report.

Vitrectomy entails the use of a vitrector, an instrument inserted into the vitreous that simultaneously cuts and aspirates much of the gel-like vitreous out of the eye. During this process, another cannula infuses a physiologic saline solution into the vitreous cavity (figure 2). Vitreous samples are sent for stains and culture. (See "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis", section on 'Diagnosis'.)

Intravitreal injections may be performed with or without vitrectomy and are given at the end of the procedure when vitrectomy is performed. High doses of intravitreal amphotericin B deoxycholate are toxic to the retina, but an intravitreal injection of 5 or 10 mcg (in 0.1 mL sterile water) appears to be safe and may be repeated several days later if evidence of intraocular infection persists on serial examinations. Patients have received cumulative intravitreal doses of 30 mcg amphotericin B deoxycholate without apparent retinal toxicity [38]. Increasingly, voriconazole is used for intravitreal injection. The usual dosage of voriconazole for intravitreal injection is 100 mcg in 0.1 mL sterile water or normal saline, giving a final concentration in the vitreous of about 25 mcg/mL.

More than one intravitreal injection may be necessary. The second injection is usually given at least 48 hours later.

OUTCOMES — It is difficult to determine exactly the visual outcomes in patients with endogenous Candida endophthalmitis, due at least in part to the fact that many studies include both patients with chorioretinitis alone and patients who also have vitreal involvement [2,39]. In general, patients who have chorioretinitis alone have better outcomes than those who also have vitritis. It also appears that overall outcomes have improved compared with those reported several decades ago [21]. (See 'Voriconazole' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Candidiasis".)

SUMMARY AND RECOMMENDATIONS

Candida species are a common cause of fungal endophthalmitis. This infection arises in two distinct ways:

The exogenous form follows trauma or a surgical procedure on the eye with direct inoculation of the organism into the anterior chamber.

The endogenous form follows candidemia with hematogenous seeding of the eye, typically starting with the choroid.

Regardless of the route of infection, if untreated, both forms progress to more extensive involvement of the eye and irreversible loss of vision. (See 'Introduction' above.)

Treatment of endogenous Candida endophthalmitis varies depending on whether only chorioretinitis is present, whether the macula is threatened, and whether there is extension into the vitreous. Chorioretinitis usually responds to systemic antifungal therapy alone, whereas eyes with marked vitritis usually require systemic antifungal therapy, vitrectomy (surgical removal of the vitreous), and intravitreal injection of an antifungal agent. (See 'Approach to treatment' above and 'Definition' above and 'Treatment' above.)

Endogenous endophthalmitis without vitritis — In patients with extramacular chorioretinitis without extension into the vitreous, we recommend systemic antifungal therapy targeted to the susceptibility of the pathogen (Grade 1C). The antifungal doses recommended below are intended for patients with normal renal function. (See 'Endogenous endophthalmitis without vitritis' above.)

For Candida species that are susceptible to fluconazole and voriconazole, systemic therapy with oral fluconazole (800 mg [12 mg/kg] loading dose, then 400 to 800 mg [6 to 12 mg/kg] orally daily) OR voriconazole (400 mg [6 mg/kg] intravenously [IV] every 12 hours for two doses, then 300 mg [4 mg/kg] IV or orally every 12 hours) can be used. For fluconazole-susceptible isolates, fluconazole is preferred over voriconazole.

Most patients infected with a fluconazole-resistant species can be treated with systemic voriconazole. (See 'Endogenous endophthalmitis without vitritis' above.)

For fluconazole- and voriconazole-resistant isolates, liposomal amphotericin B (3 to 5 mg/kg IV daily) is recommended; flucytosine (100 mg/kg orally daily in four divided doses) can be added for species that are susceptible to this agent.

In patients who have macular involvement, in addition to systemic antifungal therapy, we recommend an intravitreal injection of an antifungal agent to quickly achieve high local concentrations (Grade 1C); either amphotericin B deoxycholate (5 or 10 mcg in 0.1 mL sterile water) or voriconazole (100 mcg in 0.1 mL sterile water or normal saline) may be used. (See 'Endogenous endophthalmitis without vitritis' above.)

Endogenous endophthalmitis with vitritis — Patients with marked vitreous inflammation (vitritis) require a vitrectomy in addition to intravitreal and systemic antifungal therapy. Vitrectomy may also be indicated when vitritis is worsening despite intravitreal and systemic antifungal therapy. An ophthalmologist (usually a retina specialist) should follow the patient closely and determine the degree of vitritis and response to therapy. Minimal vitritis generally does not require vitrectomy, but vitrectomy is usually indicated for moderate to severe vitritis. The antifungal doses recommended below are intended for patients with normal renal function. We use the following approach:

We recommend vitrectomy and intravitreal injection of an antifungal agent (Grade 1C); appropriate antifungal agents for intravitreal injection include amphotericin B deoxycholate (5 or 10 mcg in 0.1 mL sterile water) or voriconazole (100 mcg in 0.1 mL sterile water).

In addition, we recommend a systemic antifungal agent targeted to the susceptibility of the pathogen (Grade 1C):

For Candida spp susceptible to fluconazole and voriconazole, fluconazole (800 mg [12 mg/kg] loading dose, then 400 to 800 mg [6 to 12 mg/kg] orally daily) or voriconazole (400 mg [6 mg/kg] IV every 12 hours for two doses, then 300 mg [4 mg/kg] IV or orally every 12 hours) can be used. If the organism is susceptible to fluconazole, that agent is preferred. In patients who present acutely, the IV formulation of voriconazole is recommended initially prior to switching to oral therapy. Oral voriconazole can be used following an initial response to the IV formulation. Fluconazole is the preferred agent for fluconazole-susceptible isolates.

Most patients infected with a fluconazole-resistant species can be treated with systemic voriconazole, as discussed above.

For Candida isolates that are resistant to fluconazole and voriconazole, liposomal amphotericin B (3 to 5 mg/kg IV daily) is recommended. Flucytosine (100 mg/kg orally per day in four divided doses) can be added for species that are susceptible to this agent. (See 'Endogenous endophthalmitis with vitritis' above.)

Duration — The optimal duration of systemic antifungal therapy for Candida endophthalmitis is unknown but is typically four to six weeks. Serial dilated ophthalmic examinations are necessary to help determine the ultimate duration of therapy beyond two weeks. Patients who have vitreous involvement generally require a longer duration of therapy than those who have only chorioretinitis.

Exogenous endophthalmitis — The treatment of exogenous Candida endophthalmitis is discussed separately. (See "Treatment of exogenous endophthalmitis due to Candida species".)

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