Treatment of endophthalmitis due to molds

INTRODUCTION — Endophthalmitis due to molds is uncommon in temperate climates but is common in tropical regions such as India. Fusarium and Aspergillus spp account for most cases of mold endophthalmitis. Mold endophthalmitis often results in loss of vision.

The treatment of endophthalmitis due to molds will be reviewed here. The epidemiology, clinical features, and diagnosis of fungal endophthalmitis are discussed elsewhere. The treatment of endophthalmitis caused by Candida and bacterial species are also presented separately. Fusarium keratitis is also discussed elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis" and "Treatment of endogenous endophthalmitis and chorioretinitis due to Candida species" and "Treatment of exogenous endophthalmitis due to Candida species" and "Bacterial endophthalmitis" and "Treatment and prevention of Fusarium infection", section on 'Keratitis'.)

DEFINITIONS — The term "endophthalmitis" means infection within the eye involving the vitreous and/or aqueous (figure 1).

Endogenous endophthalmitis results from bacterial or fungal seeding of the eye via the bloodstream. In most cases of endogenous mold endophthalmitis, the highly vascular choroid is seeded first, and the infection typically progresses from the "back" of the eye (posterior segment) anteriorly.

Exogenous endophthalmitis means the infection was introduced from the "outside," for example, following eye surgery or trauma or extension of fungal infection of the cornea (termed "fungal keratitis" or "keratomycosis"). In exogenous endophthalmitis, the aqueous is typically infected first and, in some cases, the vitreous is not involved.

TREATMENT MODALITIES — The treatment of mold endophthalmitis typically involves a combination of vitrectomy, intravitreal and/or intracameral (into the anterior chamber) injection of an antifungal agent, removal of foreign materials (eg, intraocular lens), and systemic antifungal therapy [1-4]. Corneal transplantation is indicated in some cases of mold keratitis (corneal infection) that have extended to the aqueous [5]. No controlled trials of treatment regimens for mold endophthalmitis have been performed given its rarity. The evidence regarding the treatment of mold endophthalmitis comes from case reports and case series. Even with therapy, there is a high rate of loss of useful vision, but it appears that the prognosis is improving with the availability of voriconazole. (See 'Prognosis' below.)

Vitrectomy and removal of foreign bodies — Surgical removal of the vitreous, or vitrectomy, is nearly always necessary in mold endophthalmitis [2,4-7]. Vitrectomy entails the use of a vitrector, an instrument inserted into the vitreous cavity that simultaneously cuts and aspirates some of the approximately 4 mL of gel-like vitreous into a canister (figure 2). During this process, a separate cannula infuses balanced salt solution into the vitreous cavity to maintain intraocular pressure. By the end of the case, the canister contains dilute vitreous "washings" (eg, 50 to 100 mL). Vitrectomy decreases the burden of fungi quickly by debriding the vitreous [8]. Samples are obtained during vitrectomy for microbiologic studies, and intravitreal antibiotics are injected at the end of the case. A vitrectomy, which is typically performed with local anesthesia with sedation, may be difficult if there is so much inflammation that the retina surgeon cannot see the retina. In patients too ill for eye surgery, a needle aspiration of the vitreous (for stains and cultures) followed by an intravitreal antibiotic injection should be performed. If the aqueous is primarily involved, then needle aspiration of aqueous plus intracameral antibiotic injection should be performed.

If only the aqueous is involved, as may occur in some cases of keratomycosis, then a vitrectomy may not be necessary. Even in such cases, intravitreal injection of amphotericin B deoxycholate or voriconazole is often given in addition to injection into the aqueous (intracameral injection) due to concern for occult extension of fungal infection into the vitreous. Intravitreal and intracameral injections are discussed below. (See 'Intravitreal antifungal therapy' below and 'Intracameral antifungal therapy' below.)

Successful treatment of mold endophthalmitis also requires removal of any foreign material (eg, an intraocular lens placed during cataract surgery or a foreign body introduced by penetrating eye trauma). Leaving any such foreign material in place may allow persistent infection despite antifungal therapy and nearly always leads to relapse of infection. Leaving an intraocular lens in place in postcataract fungal endophthalmitis is a risk factor for poor visual outcome [9].

Corneal transplantation — Corneal transplantation may be indicated in cases of keratomycosis due to molds in which the infection has extended into the aqueous. This is particularly true in corneas with extensive involvement, corneal melting, impending perforation, and/or poor response to treatment [10]. The treatment of Fusarium keratitis is discussed in greater detail separately. (See "Treatment and prevention of Fusarium infection", section on 'Keratitis'.)

Intravitreal antifungal therapy — Intravitreal injection of either amphotericin B deoxycholate or voriconazole is necessary for nearly all cases of mold endophthalmitis to ensure the rapid achievement of high levels of an antifungal drug inside the eye. No studies have compared the efficacy of intravitreal amphotericin B with intravitreal voriconazole.

Intravitreal amphotericin B deoxycholate has been used for many years; the usual dose is 5 or 10 mcg in 0.1 mL sterile water [11]. Intravitreal voriconazole has been used successfully in a number of cases and appears to have less toxicity than amphotericin B [1,12,13]. The usual dose of intravitreal voriconazole is 100 mcg in 0.1 mL sterile water [11].

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 [14].

Based on animal studies and case series, intravitreal voriconazole also appears to be safe. In vitro toxicity studies of human retinal pigment epithelium cells and primary human ocular nerve head astrocytes, a concentration of voriconazole of 25 mcg/mL vitreous appears to be safe [13]. In a study of rats, a dose of up to 25 mcg per mL vitreous was found to be safe based on electroretinography and histopathology findings [15]. This dose corresponds to an injection of 100 mcg into the adult human vitreous, which has a volume of approximately 4 mL. A dose of 50 to 100 mcg of voriconazole in 0.1 mL sterile water has been used in patients without apparent toxicity [8,12,13,16-20].

Intracameral antifungal therapy — In rare cases in which the aqueous humor is significantly involved, such as in early postcataract surgery mold endophthalmitis or early endophthalmitis due to keratomycosis, an intracameral (into the anterior chamber) injection of amphotericin B deoxycholate or voriconazole should be given. Intracameral amphotericin B deoxycholate has been used for many years to treat exogenous fungal endophthalmitis [21]. More recently, it has been used to treat refractory cases of keratomycosis, including some with extension into the aqueous [22,23]. Increasingly, intracameral and intravitreal voriconazole have been used in place of amphotericin B. The rationale for intracameral injections is discussed in greater detail separately. (See "Treatment of exogenous endophthalmitis due to Candida species", section on 'Intraocular therapy'.)

The usual dose of amphotericin B deoxycholate for intracameral injection is 5 mcg in 0.1 mL sterile water. Transient increase in eye pain (lasting up to 12 hours) and anterior chamber inflammation, including hypopyon, have occurred following intracameral amphotericin B injections [22,24].

The optimal dose of intracameral voriconazole has not been well established, but 50 to 100 mcg in 0.1 mL sterile water is usually used. Intracameral voriconazole has been used without apparent toxicity. In one in vitro study of cultured human ocular cells, a concentration of 250 mcg/mL of voriconazole for 30 days did not appear to cause toxicity either to corneal or endothelial trabecular meshwork cells [25]. In another in vitro study, voriconazole concentrations up to 50 mcg/mL did not decrease the viability of corneal endothelial cells, but concentrations ≥100 mcg/mL led to a reduction in cell viability [26].

Several studies have reported effective use of intracameral voriconazole at doses ranging from 12.5 mcg to 100 mcg in 0.1 mL sterile water [10,12,16]. Intracameral doses of 100 mcg of voriconazole have been used repeatedly in some eyes without any apparent toxicity [10], but we prefer a dose of 50 mcg due to the limited experience with intracameral voriconazole and because this dose produces sufficiently high concentrations in the aqueous.

Intracameral voriconazole has been shown to have a half-life of only 22 minutes in an experimental rabbit model [27], so topical voriconazole 1% solution can be used to prolong the drug level in the aqueous. Topical voriconazole given frequently produces high levels of voriconazole in the aqueous [28].

Topical antifungal therapy — Neither voriconazole 1% solution nor amphotericin B deoxycholate 0.15% solution are commercially available as eye drops, but both have been widely used for treatment of keratomycosis. Their role in the treatment of mold endophthalmitis has not been defined, but topical voriconazole may be indicated as adjunctive therapy in some cases. Topical voriconazole penetrates the intact human cornea, and repeated application may produce therapeutic levels in the aqueous. Two studies of patients with intact corneas reported that repeated doses of topical voriconazole 1% produced therapeutic aqueous levels [29,30].

For topical amphotericin B deoxycholate, no human studies are available. However, studies in rabbits show that topical amphotericin B does not penetrate an intact cornea but does penetrate a corneal debrided of epithelium [31]. It is therefore possible that in patients with keratomycosis-associated endophthalmitis primarily involving the aqueous, amphotericin B eye drops may have some benefit as adjunctive therapy in cases due to voriconazole-resistant fungi.

Systemic antifungal therapy — Systemic antifungal therapy is indicated for endogenous mold endophthalmitis, and the choice of systemic therapy should be based on optimal treatment for invasive fungal infection. The treatment of invasive fungal infections is discussed in detail separately. (See "Treatment and prevention of invasive aspergillosis" and "Treatment and prevention of Fusarium infection".)

In exogenous mold endophthalmitis, vitrectomy and intraocular injections of antifungal agents (amphotericin B deoxycholate or voriconazole) alone may suffice, but the addition of systemic voriconazole is almost always indicated unless the fungus is known to be resistant to azoles. Systemic amphotericin B is not usually given in exogenous endophthalmitis because the significant toxicity of this therapy is usually not justified by the uncertain benefit. In experimental studies, systemic amphotericin B deoxycholate achieves minimal intraocular levels in uninflamed rabbit eyes, although higher levels are achieved in inflamed rabbit eyes when multiple-dose regimens are used over seven days [32]. Liposomal amphotericin may achieve higher vitreous concentrations than other lipid formulations of amphotericin B or amphotericin B deoxycholate [1].

Voriconazole is the treatment of choice for systemic Aspergillus infections; it is also active against Fusarium and these two fungi account for the majority of mold endophthalmitis cases. Voriconazole achieves vitreous levels with oral administration that are nearly 40 percent of plasma levels [33]. In addition to endophthalmitis caused by Aspergillus spp and Fusarium spp, voriconazole has also been used to treat endophthalmitis due to Paecilomyces lilacinus, Scedosporium apiospermum, and Lecythophora mutabilis [18,34-36]. Oral voriconazole, in combination with vitrectomy and intravitreal amphotericin B deoxycholate, was used successfully to treat a case of exogenous Fusarium endophthalmitis and a case of Aspergillus endophthalmitis [37]. The patient with Aspergillus endophthalmitis also received intravenous (IV) caspofungin; it is not clear whether caspofungin contributed to the success of therapy in this case.

It is important to measure serum concentrations of voriconazole four to seven days after initiating systemic 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 of greater than 1 mg/L and less than 5.5 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. Once appropriate levels have been achieved, it is not necessary to recheck them unless there is a change in clinical status or concern for toxicity (eg, transaminitis) or drug-drug interactions. (See "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)

The intraocular concentration of posaconazole has not been studied in animal models and it may not achieve adequate concentrations using the oral suspension. The oral suspension of posaconazole has been used with success as salvage therapy in a few complicated cases of Fusarium keratitis-related endophthalmitis and endophthalmitis that had not responded to therapy with either voriconazole or amphotericin B [38-40]. In one patient successfully treated with both topical and the oral suspension of posaconazole for refractory Fusarium keratitis-related endophthalmitis, the vitreous concentration one week after keratoplasty was approximately 20 percent of the plasma concentration (0.25 mcg/mL in vitreous, 1.2 mcg/mL in plasma), and the aqueous concentration three months later was 0.9 mcg/mL (with plasma level of 1.6 mcg/mL) [39]. It is not clear whether the newer delayed-release posaconazole tablet that is much simpler for patients to take and that results in higher serum concentrations will prove useful for ocular infections.

Isavuconazole has been shown to be noninferior to voriconazole in treating invasive aspergillosis and is also approved for the treatment of mucormycosis [41]. There is limited information about penetration of isavuconazole into the eye. A study in rats demonstrated good levels of the drug following oral administration in most tissues, including the brain and uveal tract [42]. However, studies measuring intraocular levels in humans have not been published. Isavuconazole treatment of mold endophthalmitis has not been reported, but a single case of endogenous Candida dubliniensis endophthalmitis successfully treated with isavuconazole after failing other systemic treatments (fluconazole, amphotericin) has been reported [43]. At this time this agent cannot be recommended for treatment of mold endophthalmitis.

Fluconazole is not recommended because of its poor activity against molds. Itraconazole is not used due to poor penetration into the vitreous. The echinocandins are active against Aspergillus spp but not Fusarium spp or other molds. There are few data on the ability of the echinocandins to cross the blood-eye barrier, but adequate concentrations would be unlikely given the large size of these molecules and the high degree of protein binding. In experiments in rabbits of systemically administered caspofungin and micafungin, these agents were undetectable in the vitreous [44,45]. However, micafungin produced concentrations in the retina-choroid that were comparable with plasma concentrations [45]. An individual case report showed success with caspofungin for a case of postcataract surgery Acremonium endophthalmitis that had failed amphotericin B treatment [46]. Caspofungin plus voriconazole was successful in a case of Aspergillus endophthalmitis [37], but it is not clear that the addition of caspofungin added to the effectiveness of voriconazole. Echinocandins alone are not recommended for the treatment of mold endophthalmitis given the lack of efficacy data, their limited spectrum of activity against molds, and the concern that vitreous concentrations are low.

APPROACH TO TREATMENT — The approach to treatment depends on several factors, including whether the infection is exogenous or endogenous and the infecting agent. With endogenous infections, the treatment depends on whether the patient has a localized ocular infection (versus a systemic infection) at the time of presentation. Most immunocompromised patients have a concurrent systemic fungal infection. In contrast, most patients who have endogenous endophthalmitis as the result of injection drug use developed endophthalmitis as a result of transient fungemia and may not have any other sites of fungal infection. Treatment requires a combination of modalities, which may include vitrectomy, aspiration of the aqueous, removal of any foreign body (eg, intraocular lens), corneal transplantation, injection of an antifungal agent into the vitreous and/or aqueous, topical and systemic antifungal therapy. Specific treatment recommendations are provided below.

Exogenous mold endophthalmitis

Anterior segment involvement only — For patients with endophthalmitis involving only the anterior segment of the eye (figure 1), such as from extension of mold keratomycosis, we suggest the following treatment approach:

●Aspirate the aqueous for stains and cultures. (See "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis", section on 'Diagnosis'.)

●Surgically remove any foreign body, such as an intraocular lens (eg, placed during prior cataract surgery).

●Inject either voriconazole (50 mcg in 0.1 mL sterile water) or amphotericin B deoxycholate (5 mcg in 0.1 mL sterile water) into the aqueous. Voriconazole is preferred for molds such as Aspergillus or Fusarium that are typically susceptible to voriconazole.

●Corneal transplantation may be indicated in cases of keratomycosis due to molds in which the infection has extended into the aqueous. The management of Fusarium keratitis is discussed in detail separately. (See "Treatment and prevention of Fusarium infection", section on 'Keratitis'.)

●Administer topical antifungal drops (voriconazole 1% or amphotericin B deoxycholate 0.15% in sterile water) frequently (eg, hourly) in cases of keratomycosis-related endophthalmitis. Topical voriconazole is preferred for susceptible fungi since it penetrates the cornea well and achieves good concentrations in the aqueous humor.

●Administer systemic voriconazole (6 mg/kg IV every 12 hours for two doses, then 4 mg/kg IV every 12 hours for patients with severe disease), except in those rare cases due to voriconazole-resistant molds. Oral therapy, using 200 mg twice daily on an empty stomach, can be used following an initial response to the IV formulation. In less severe cases, oral voriconazole can be used as initial therapy; the oral loading dose is 400 mg twice daily for two doses, followed by 200 mg twice daily. Some patients may require higher doses than 200 mg twice daily to achieve adequate serum concentrations because of significant interpatient variability in voriconazole serum levels. As noted above, it is important to measure serum concentrations of voriconazole four to seven days after initiating systemic therapy to ensure that adequate concentrations have been achieved to allow success and to avoid high levels that have been associated with adverse events. (See 'Systemic antifungal therapy' above and "Pharmacology of azoles", section on 'Serum drug concentration monitoring'.)

●Even if there is no apparent vitreous involvement, consider injecting voriconazole (100 mcg in 0.1 mL sterile water) or amphotericin B deoxycholate (5 or 10 mcg in 0.1 mL sterile water) into the vitreous since there may be occult vitreous infection.

●Repeat injection of amphotericin B deoxycholate or voriconazole into the aqueous and/or vitreous if no improvement has occurred. Injections may be repeated more than once, but voriconazole is preferred for such repeated injections because intracameral amphotericin B deoxycholate may cause anterior segment inflammation. (See 'Intracameral antifungal therapy' above and 'Vitreous involvement' below.)

Vitreous involvement — For patients with exogenous endophthalmitis involving the vitreous, we suggest the following treatment approach:

●Perform a vitrectomy to decrease the fungal burden and to obtain a sample for stains and cultures (see "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis", section on 'Diagnosis'). In the rare case in which the retina specialist feels that they cannot safely perform a vitrectomy or in patients too ill for eye surgery, a vitreous aspirate should be obtained for stains and cultures, although the diagnostic yield is lower than with vitrectomy. Surgically remove any foreign body, such as an intraocular lens (eg, placed during prior cataract surgery).

●Administer 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). A repeat injection may be indicated after several days if there has been no response to therapy. We favor the first injection to be amphotericin B deoxycholate if the identity of the fungus is unknown, but we prefer voriconazole for subsequent injections if the fungus is susceptible. More than one repeat intravitreal injection may be given.

●If there is involvement of the aqueous, administer an intracameral injection of voriconazole (50 mcg in 0.1 mL sterile water) or amphotericin B deoxycholate (5 mcg in 0.1 mL sterile water).

●Administer systemic voriconazole (6 mg/kg IV every 12 hours for two doses, then 4 mg/kg IV every 12 hours). The IV formulation is recommended for at least the initial few days for patients who have an acute presentation. Oral therapy at a dose of 200 mg twice daily taken on an empty stomach can be used following an initial response to the IV formulation. Some patients may require higher doses than 200 mg twice daily to achieve adequate serum concentrations because of significant interpatient variability in voriconazole serum levels. As noted above, it is important to measure serum concentrations of voriconazole four to seven days after initiating systemic therapy to ensure that adequate concentrations have been achieved to allow success and to avoid high levels that have been associated with adverse events (see "Treatment and prevention of invasive aspergillosis", section on 'Voriconazole'). If the fungus is resistant to voriconazole, or has recurred despite maximal therapy (eg, repeated intravitreal injections of amphotericin B deoxycholate or voriconazole, vitrectomy, removal of all foreign material such as an intraocular lens, removal of an infected cornea if present), then systemic liposomal amphotericin could be used, but these cases are rare.

Endogenous endophthalmitis

●Perform a vitrectomy to decrease the fungal burden and to obtain a sample for stains and cultures (see "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis", section on 'Diagnosis'). In the rare case in which the retina specialist feels that they cannot safely perform a vitrectomy, or in patients too ill for eye surgery, a vitreous aspirate should be obtained for stains and cultures, although the diagnostic yield is lower than with vitrectomy.

●Surgically remove any foreign material (eg, intraocular lens).

●Administer 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). Repeat the intravitreal injection of voriconazole or amphotericin B after several days if no improvement has occurred. We recommend that the first injection be amphotericin B deoxycholate if the identity of the fungus is unknown, but we recommend voriconazole for subsequent injections if the fungus is one likely to be susceptible.

●Administer systemic antifungal therapy, optimized to the most likely fungal pathogen involved. This may be either a systemic amphotericin B formulation or voriconazole. The usual dosing of these agents is as follows:

•Liposomal amphotericin B – 5 mg/kg IV once daily; we favor this formulation of amphotericin B because it achieves higher concentrations in the central nervous system compared with other lipid formulations or amphotericin B deoxycholate; the blood-eye barrier is similar to the blood-brain barrier. (See "Candida infections of the central nervous system", section on 'Antifungal therapy'.)

•Voriconazole – 6 mg/kg IV every 12 hours for two doses, then 4 mg/kg IV every 12 hours. The IV formulation is recommended for at least the initial few days. Oral therapy at a dose of 200 mg twice daily on an empty stomach can be used following an initial response to the IV formulation. Higher doses may be required in obese patients. As noted above, it is important to measure serum concentrations of voriconazole four to seven days after initiating systemic therapy to ensure that adequate concentrations have been achieved to allow success and to avoid high levels that have been associated with adverse events. (See "Treatment and prevention of invasive aspergillosis", section on 'Voriconazole'.)

The treatment of invasive aspergillosis and fusariosis is discussed in detail separately. (See "Treatment and prevention of invasive aspergillosis" and "Treatment and prevention of Fusarium infection".)

Duration of therapy — The duration of systemic antifungal therapy for mold endophthalmitis depends upon the improvement of lesions as determined by serial ophthalmic examinations but also whether the infection was exogenous or endogenous. If exogenous, therapy is usually continued for at least one month (and sometimes several months) after resolution of all signs of active intraocular infection. For endogenous endophthalmitis, the duration of therapy is determined by the type, extent, and response to therapy of the systemic fungal infection being treated; treatment usually extends for several months.

PROGNOSIS — The visual prognosis in mold endophthalmitis has historically been poor, with at least two-thirds of eyes losing useful vision [21,47,48]. A large series of fungal endophthalmitis from India reported poor outcomes in the majority of patients with mold endophthalmitis, although systemic voriconazole was not part of the treatment regimen [7].Outcomes appear to be better when systemic voriconazole is included in the treatment regimen (for susceptible isolates) and for patients diagnosed early and treated aggressively. Exogenous and endogenous mold endophthalmitis cases have achieved very good visual outcomes with aggressive therapy [49,50]. A series from Texas reported excellent outcomes of five cases of mold endophthalmitis due to Fusarium, Scedosporium, or Glomerella species, with aggressive treatment, including systemic and intravitreal voriconazole [51]. The infection cleared in all eyes and four patients recovered excellent vision (20/20 in three, 20/50 in one); the remaining patient had poor baseline vision due to glaucoma and nearly recovered that vision.

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Endophthalmitis due to molds often results in loss of vision. It is rarely diagnosed in temperate climates, but it is common in tropical regions. Fusarium and Aspergillus spp account for most cases of mold endophthalmitis. (See 'Introduction' above.)

●Diagnosis – A sample of vitreous (and/or aqueous, if it is involved) should be obtained for stains and cultures prior to antifungal treatment. (See 'Approach to treatment' above and "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis", section on 'Diagnosis'.)

●Treatment – A combination of interventions are necessary including surgical removal of any foreign bodies, vitrectomy in most cases, and intraocular and systemic antifungal therapy. We use the following approach (see 'Approach to treatment' above):

•Surgery and intraocular antifungal therapy

-Removal of foreign bodies – All foreign bodies should be surgically removed. (See 'Approach to treatment' above.)

-Exogenous endophthalmitis involving the anterior segment only – For these patients, we recommend intracameral (into the aqueous) injection of either voriconazole (50 mcg in 0.1 mL sterile water) or amphotericin B deoxycholate (5 mcg in 0.1 mL sterile water) (Grade 1C). In such patients, we also recommend frequent administration (eg, hourly) of topical antifungal drops (Grade 1C). We prefer voriconazole (1% topical solution) rather than amphotericin B deoxycholate drops if the fungus is susceptible to voriconazole. Intravitreal voriconazole injection should also be considered even if there is no apparent vitreous involvement, since this involvement may be occult. (See 'Anterior segment involvement only' above.)

When exogenous mold endophthalmitis involving the aqueous arises from extension of keratomycosis, a corneal transplant may also be indicated to reduce the fungal burden and control the infection. The management of Fusarium keratitis is discussed in detail separately. (See 'Anterior segment involvement only' above and "Treatment and prevention of Fusarium infection", section on 'Keratitis'.)

-Exogenous or endogenous endophthalmitis involving the vitreous – For these individuals, we recommend a vitrectomy to debride the vitreous in nearly all cases (Grade 1C). A sample of vitreous should be sent for stains and cultures. An intravitreal injection of either amphotericin B deoxycholate or voriconazole (voriconazole if the fungus is susceptible) should be administered at the end of the procedure. If the ophthalmologist considers a vitrectomy too risky, or if the patient is too ill for eye surgery, a needle aspiration of the vitreous (for stains and cultures) followed by injection of either amphotericin B deoxycholate or voriconazole should be performed. The usual dose of intravitreal amphotericin B deoxycholate is 5 or 10 mcg in 0.1 mL sterile water, and the usual dose of intravitreal voriconazole is 100 mcg in 0.1 mL sterile water. (See 'Vitreous involvement' above.)

If the eye has not improved, we favor a repeat intravitreal injection of either voriconazole (for susceptible fungi) or amphotericin B deoxycholate after several days. Intravitreal voriconazole (100 mcg in 0.1 mL sterile water) is preferred over intravitreal amphotericin B deoxycholate (5 or 10 mcg in 0.1 mL sterile water) for fungi susceptible to voriconazole. Intravitreal injections may be repeated more than once for eyes that fail to improve despite maximal therapy (ie, vitrectomy, removal of foreign material, intravitreal and systemic antifungal therapy). (See 'Vitreous involvement' above.)

•Systemic antifungal therapy – We suggest systemic antifungals, depending on the source of endophthalmitis and the susceptibility of the mold to antifungal agents:

-Exogenous endophthalmitis – We recommend administering systemic voriconazole for molds that are found to be susceptible to this agent (Grade 1C). For the rare isolate that is resistant to voriconazole and when the infection progresses despite maximal surgical and intraocular therapy, we consider using intravenous liposomal amphotericin B. (See 'Exogenous mold endophthalmitis' above.)

-Endogenous endophthalmitis – These individuals all require systemic antifungal therapy with either liposomal amphotericin B or voriconazole, depending on the susceptibility of the mold. (See 'Endogenous endophthalmitis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Kieren A Marr, MD, who contributed to an earlier version of this topic review.