Treatment of exogenous endophthalmitis due to Candida species

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

●The exogenous form follows trauma, eye surgery, or progression of fungal keratitis (corneal infection). Fungi are directly inoculated into the aqueous and/or vitreous.

●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. (See "Treatment of endogenous endophthalmitis and chorioretinitis due to Candida species".)

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

DEFINITION — The term "endophthalmitis" means infection involving the vitreous and/or aqueous humors (figure 1). Exogenous endophthalmitis signifies that the infection was introduced into the eye from the "outside," either by trauma, eye surgery, or extension of corneal infection (keratitis).

TREATMENT — Exogenous endophthalmitis is treated with an intraocular injection of an antimicrobial agent into the vitreous. An intracameral injection (into the aqueous) may be given in cases with significant anterior segment infection. A vitrectomy (surgical debridement of the vitreous) may be performed in cases with significant vitritis or that fail to improve with intravitreal injections. Surgical removal of any foreign material (eg, artificial intraocular lens) may be necessary. Adjunctive systemic antifungal therapy is given in most cases.

Our recommendations are generally in keeping with the 2016 Infectious Diseases Society of America (IDSA) guidelines for the management of candidiasis [1].

Approach to treatment

Exogenous endophthalmitis with vitritis — We suggest the following treatment course:

●Vitrectomy (when there is significant vitritis or failure to improve with intravitreal injections alone) 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 antifungal therapy – 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 200 to 300 mg [3 to 4mg/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 and susceptible to voriconazole (nearly all cases), voriconazole should be used.

•For C. glabrata isolates that are fluconazole resistant, voriconazole should be used 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 levels 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 mg/L. 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 'Voriconazole'.)

For patients who have an IOL who fail to improve after the therapeutic regimen described above (vitrectomy, intravitreal amphotericin B or voriconazole injection, and systemic azole therapy), the IOL will likely need to be removed, and repeat intravitreal injections of amphotericin B deoxycholate (5 mcg in 0.1 mL sterile water) or voriconazole (100 mcg in 0.1 mL sterile water or normal saline) given.

Exogenous endophthalmitis with primarily aqueous involvement — In cases of exogenous Candida endophthalmitis in which the aqueous is the major site of intraocular infection (eg, from contiguous spread of fungal keratitis), intracameral (into the anterior chamber) injection of voriconazole (50 mcg in 0.1 mL of sterile water) should be administered. Intracameral amphotericin B deoxycholate (5 mcg in 0.1 mL sterile water) may be given instead of intracameral voriconazole for voriconazole-resistant strains of Candida. Even in cases in which only the aqueous appears to be involved clinically, 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) should be considered. Such cases may have occult infection of the vitreous. Repeated intracameral or intravitreal injections may be given, usually separated by at least two days. The necessity and timing of repeat injections is determined by the ophthalmologist based on the eye's response to therapy.

If concurrent keratitis is present, topical antifungal agents (topical voriconazole 1% or topical amphotericin B deoxycholate 0.15% in sterile water) should be given. Topical voriconazole penetrates the cornea and can achieve therapeutic levels in the aqueous [2], so the addition of frequent topical voriconazole eyedrops (in addition to intracameral and systemic therapy) may be beneficial in treating aqueous infections due to voriconazole-susceptible strains of Candida. Corneal transplantation is sometimes required to control a fungal keratitis that has extended into the aqueous.

In addition to intracameral antifungal therapy, systemic voriconazole or fluconazole should be given for susceptible strains, even for cases in which only the aqueous is involved. Dosing is discussed above. (See 'Exogenous endophthalmitis with vitritis' above.)

The management of endogenous endophthalmitis caused by Candida species and endophthalmitis caused by molds are presented separately. (See "Treatment of endogenous endophthalmitis and chorioretinitis due to Candida species", section on 'Treatment' and "Treatment of endophthalmitis due to molds", section on 'Treatment Modalities'.)

Duration of therapy — The optimal duration of antifungal therapy for exogenous Candida endophthalmitis is unknown but is typically several weeks, depending on resolution of lesions as determined by serial ophthalmic examinations [1].

Intraocular therapy — In cases in which the aqueous is primarily involved (eg, acute Candida endophthalmitis after corneal transplantation), either amphotericin B deoxycholate or voriconazole may be injected intracamerally (into the anterior chamber) (figure 1). Intracameral injection of amphotericin B deoxycholate has been used for many years for fungal endophthalmitis [3] and appears to be effective [4,5]. The usual dose of amphotericin B deoxycholate for intracameral use is 5 mcg in 0.1 mL sterile water. There may be transient increase in eye pain, hypopyon, or intra-aqueous inflammation in some eyes after amphotericin B injection, but this resolves by 24 to 48 hours [4,5]. Several studies have reported effective use of intracameral voriconazole at doses ranging from 12.5 mcg to 100 mcg per 0.1 mL [6-8]. Intracameral doses of 100 mcg of voriconazole have been used repeatedly in some eyes without any apparent toxicity [7], but we prefer a dose of 50 mcg due to the limited experience with intracameral voriconazole and because this dose produces sufficiently high levels in the aqueous to treat Candida species.

Once the infection is known to be due to Candida spp, we prefer to use intracameral voriconazole rather than amphotericin B deoxycholate, given the potential toxicity of the latter agent. However, in cases in which rapid improvement does not occur with voriconazole, we favor switching to amphotericin B deoxycholate. Efficacy studies comparing intracameral administration of these two agents have not been performed.

Intracameral voriconazole has been shown to have a half-life of only 22 minutes in an experimental rabbit model [9], so topical voriconazole 1% solution can be used to prolong the drug level in the aqueous. Application of 1% voriconazole ophthalmic solution (eyedrops) every 2 hours for 24 hours prior to scheduled eye surgery produced high levels in the aqueous in one study of 13 patients [10]. In cases of exogenous Candida endophthalmitis resulting from Candida keratitis, the keratitis should also be treated with antifungal eyedrops. Topical voriconazole eyedrops (1%) are preferred in these cases since topical voriconazole penetrates the cornea and achieves good levels in the aqueous, whereas topical amphotericin B does not.

It is important to note that intracameral injections of voriconazole or amphotericin B deoxycholate do not produce significant levels in the vitreous, so intravitreal injections of voriconazole or amphotericin B deoxycholate should also be given in any case of exogenous endophthalmitis if vitreous involvement cannot be excluded [11].

Therapy should include vitrectomy and intravitreal injection of an antifungal agent when the vitreous shows severe involvement. Vitrectomy entails the use of a vitrector, an instrument inserted into the vitreous that simultaneously cuts and aspirates much of the 4 mL of gel-like vitreous into a canister (figure 2). Intravitreal amphotericin B deoxycholate (5 or 10 mcg in 0.1 mL sterile water) or intravitreal voriconazole (100 mcg in 0.1 mL sterile water or normal saline) may be used, the latter only for voriconazole-susceptible isolates. Most Candida species are susceptible to voriconazole, however [12].

When infection has resulted from cataract surgery with IOL implantation, it is often necessary to remove the IOL. Candida may produce a chronic inflammation in the aqueous after cataract surgery, with symptoms persisting for months and misdiagnosed as a noninfectious anterior uveitis; cure nearly always requires removal of the IOL in these cases in addition to other antifungal therapy [13]. Antifungal drugs can suppress but cannot always cure the infection without removal of the IOL. This is likely related to the development of a biofilm, which some Candida species readily form on the implant. When antifungal agents are stopped in cases in which the IOL is left in place, relapse is a possibility [14].

If endophthalmitis has followed corneal transplantation with an infected donor cornea, repeat transplantation, along with intracameral voriconazole or amphotericin B deoxycholate, is usually indicated at the onset of endophthalmitis.

Systemic antifungal therapy — In addition to intraocular therapy, we recommend systemic azole therapy, based on the efficacy of systemic azoles in treating endogenous Candida endophthalmitis. (See "Treatment of endogenous endophthalmitis and chorioretinitis due to Candida species".)

Specific recommendations for systemic antifungal therapy are provided above. (See 'Approach to treatment' above.)

Fluconazole achieves concentrations in the vitreous in humans that are approximately 70 percent of that in the plasma [15,16]. Fluconazole has shown efficacy in a rabbit model of exogenous Candida endophthalmitis [17]. Voriconazole has activity against C. krusei and some fluconazole-resistant C. glabrata as well as other common Candida species, and it achieves adequate levels in the eye [18,19]. Because C. glabrata isolates can demonstrate cross-resistance to both fluconazole and voriconazole, susceptibility testing should be performed, and the response to therapy should be monitored closely. (See "Management of candidemia and invasive candidiasis in adults".)

We generally do not recommend systemic amphotericin B for exogenous Candida endophthalmitis because it achieves poor levels in the aqueous and the vitreous [20] and has known systemic toxicities. The value of systemic echinocandins for treating exogenous Candida endophthalmitis is unknown, but it is unlikely that they would be effective because of the poor intraocular concentrations achieved with these agents.

OUTCOMES — Reports on the outcome of therapy for exogenous Candida endophthalmitis vary from vision restored to normal to light perception only. There are too few cases reported to have a firm idea of outcomes, although one series of 15 patients reported visual acuities of at least 20/60 in one-half of the patients, most of whom did not have the artificial intraocular (IOL) lens removed [21]. A series that included five patients with post-cataract surgery Candida endophthalmitis, all of whom had the IOL removed as part of treatment, reported visual outcomes of 20/50 or better in all patients [22].

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

●Mechanism of infection – Candida species are common causes of fungal endophthalmitis, but most cases are endogenous, meaning they develop from hematogenous seeding of the eye during candidemia. Exogenous Candida endophthalmitis, in which Candida is inoculated into the aqueous and/or vitreous via the ocular surface, is less common (figure 1). Exogenous Candida endophthalmitis occurs most commonly after eye surgery (eg, cataract surgery, corneal transplantation) or penetrating eye trauma but may also occur as an extension of Candida keratitis (corneal infection). (See 'Introduction' above.)

●Management – Patients with exogenous Candida endophthalmitis require aggressive multimodality therapy to control infection and preserve vision. We use the following approach:

•Intraocular antifungal therapy

-For patients with exogenous Candida endophthalmitis with vitreous involvement, we recommend intravitreal injection of an antifungal agent (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) for all cases. Intravitreal injections may be repeated, usually after two days or more. We recommend vitrectomy in cases with marked vitritis or in cases failing intravitreal injections (plus adjunctive systemic therapy).

-For patients with exogenous Candida ocular infection with primarily aqueous involvement, we recommend intracameral injection of an antifungal agent (Grade 1C); either amphotericin B deoxycholate (5 mcg in 0.1 mL sterile water) or voriconazole (50 mcg in 0.1 mL sterile water or normal saline) may be used. In addition, in patients with exogenous Candida endophthalmitis resulting from Candida keratitis, we also recommend administration of voriconazole eyedrops (1 percent) (Grade 1C). Some patients with endophthalmitis resulting from severe Candida keratitis may also require corneal transplantation.

•Systemic antifungal therapy – For all patients with exogenous Candida endophthalmitis, we recommend systemic azole therapy targeted to the susceptibility of the pathogen (Grade 1C); many patients can receive fluconazole, but some require voriconazole.

•Foreign body management – All foreign bodies (eg, intraocular lenses placed during cataract surgery) should be surgically removed if primary treatment fails. (See 'Approach to treatment' above.)

●Endogenous endophthalmitis – The management of endogenous endophthalmitis caused by Candida species and endophthalmitis caused by molds is presented separately. (See "Treatment of endogenous endophthalmitis and chorioretinitis due to Candida species" and "Treatment of endophthalmitis due to molds".)