Treatment of Fungal Endophthalmitis: Comparison
Please note this is a comparison between Version 1 by Diana-Maria Darabus and Version 3 by Jason Zhu.

 In recent, large case series of fungal endophthalmitis (FE) that were published by Asian authors, the most frequent etiologic agents for all types of FE are molds (usually Aspergillus species, while Fusarium is the prevalent etiology in keratitis-related FE). Candida was the organism found in most cases of endogenous FE. Lately, polymerase chain reaction (PCR) was increasingly used for the diagnosis of FE, allowing for very high diagnostic sensitivity, while the costs become more affordable with time. The most important shortcoming of PCR—the limited number of pathogens that can be simultaneously searched for—may be overcome by newer techniques, such as next-generation sequencing. There are even hopes of searching for genetic sequences that codify resistance to antifungals.

  • fungal endophthalmitis
  • Prognosis
  • Therapy

1. Introduction

Endophthalmitis is a serious ophthalmic condition, carrying the risk of permanent visual loss. Knowledge of its diagnosis and treatment is of essence for every ophthalmologist. In endophthalmitis the internal structures of the eye are invaded by replicating microorganisms, resulting in an inflammatory response [1]. The term endophthalmitis is usually reserved for bacterial or fungal infections, while inflammation of viral or parasitical cause is considered a form of uveitis. The causative organism may be directly inoculated into the eye (exogenous endophthalmitis, usually posttraumatic or post intraocular surgery) or may enter through hematogenous spread from distant foci (endogenous endophthalmitis). In fungal endophthalmitis (FE), the causative organism is either a mold or yeast.
The diagnosis and treatment of FE are challenging due to a series of particularities, especially the difficult, time consuming etiological diagnosis and the problems of antifungal therapy (availability, efficacy, potential toxicity). The relative rarity of the FE has led to the fact that there is no level 1 evidence to guide its management [2].

2. Therapy

2.1. Medical Therapy

Amphotericin B is a polyene that binds surface sterols in the cell membrane of fungi, creating pores that alter the permeability, causing leakage of intracellular material and subsequent fungal cell death [3][62]. Azoles (like voriconazole) act by depleting ergosterol, a bioregulator of membrane integrity [4][6].
In suspected fungal endophthalmitis, initial treatment may be with intravenous voriconazole, loading dose 400 mg BID for two doses, then intravenous 300 mg/day (or oral 200 mg BID) AND intravitreal voriconazole 100 µg/0.1 mL. Voriconazole has excellent susceptibility to Candida, Aspergillus and Fusarium [5][63]. Monitor aspartate-aminotransferase (ASAT) and alanine-aminotransferase (ALAT) weekly for the first month. There are strong recommendations for the monitoring of voriconazole serum-levels [6][64].
With the exception of purely chorioretinal fungal lesions (i.e., without vitritis), it is usually recommended to associate intravitreal therapy with the same antifungal used in intravenous or oral therapy, most frequently 100 µg/0.1 mL of voriconazole [5][63]. Another widely used intravitreal therapy is amphotericin B, 5–10 µg/0.1 mL. Intravitreal injections may be repeated after 72 h, depending on the clinical evolution [2]. Dave et al., reported that they have repeated intravitreal injections every 48 h for amphotericin B and every 24 h for voriconazole [7][24]. If the surgeon chooses to use silicone oil endotamponade at the conclusion of the vitrectomy, the dose of intravitreal anti-infection agents injected should be ¼-1/10 of the usual intravitreal dose [8][65].
The use of intravitreal corticosteroids in FE is controversial. An important concern is that corticosteroids may impair the efficacy of antifungals and interfere with the immunogenic response. A small retrospective study suggested that steroids may be beneficial in promoting faster clearance of inflammation in FE [9][66]. However, a review of the role of intravitreal corticosteroids in infectious endophthalmitis concluded that there is a lack of adequate experimental and human studies concerning steroids in FE [10][67]. Regarding oral steroids, we hadve found only one paper that advocated the use of oral prednisone, 1 mg/kg body weight in tapering doses [4][6]. When the laboratory results regarding antifungal susceptibility become available, the ophthalmologist may choose to change the therapy accordingly (however, we believe that a treatment that results in clinical improvement should not be changed based on laboratory findings). For susceptible Candida strains, fluconazole may be preferable to voriconazole because it is less hepatotoxic [5][63].
Fluconazole is preferred to voriconazole in children, because it is difficult to attain target voriconazole concentration and to monitor the serum levels. The loading dose is 12 mg/kg (intravenous or oral) fluconazole, followed by 6 mg/kg/day (or at 48 h for younger children) [11][68].
For azole-resistant Candida species, a combination of choice is intravenous amphotericin with oral flucytosine [12][58]. Liposomal amphotericin B may be less nephrotoxic and has higher vitreous penetration compared to amphotericin B deoxycholate [2]. Candida chorioretinitis without vitritis (which can occur in a setting of endogenous FE) can be treated with systemic therapy, without intravitreal injections [12][58]. Systemic treatment with echinocandins (micafungin, caspofungin, anidulafungin) may be effective in choroidal infiltrates with azole-resistant Candida, but are not effective in case of vitritis (due to low-moderate vitreous penetration) [13][4].
The Infectious Disease Society of America recommendations for the treatment of Aspergillus endophthalmitis are to combine oral or intravenous voriconazole with intravitreal voriconazole or intravitreal amphotericin B deoxycholate [14][69]. Azole-resistant species of Aspergillus may be treated with intravenous amphotericin B or intravenous anidulafungin. Itraconazole has a low minimum inhibitory concentration for Aspergillus, with better vitreous penetration than systemic amphotericin B (but the vitreous concentration remains a fraction of the serum level) [4][6].
For endophthalmitis caused by fungi other than Candida or Aspergillus there are very limited data regarding the immediate treatment, when the clinician has no information on the antifungals susceptibility. In Fusarium endophthalmitis there have been a few reports of successful treatment with systemic voriconazole (with or without amphotericin B) and intravitreal voriconazole [15][16][70,71].

2.1.1. Alternative Antifungal Therapies

For cases of endophthalmitis caused by fungi that are resistant to usual antifungals, Relhan et al., have proposed (based on limited knowledge of retinal toxicity in animal studies): intravitreal miconazole 25 µg/0.1 mL, intravitreal caspofungin 50 µg/0.1 mL or intravitreal micafungin 25 µg/0.1 mL [17][72]. There are a few reports of successful treatment of FE using intravitreal injections of caspofungin [18][19][20][21][73,74,75,76].
Guest et al., studied the use of isavuconazole in treating Aspergillus fumigatus endophthalmitis in an exogenous mouse model of the disease and concluded that it was as effective after oral administration as it was after intravitreal administration [22][77]. Isavuconazole is a second-generation broad-spectrum triazole, noninferior to voriconazole for invasive aspergillosis and suitable for stepdown therapy in cases of invasive candidiasis [23][78]. Recently, oral isavuconazole was reportedly used in a case of Candida endophthalmitis unresponsive to fluconazole [24][79].

2.1.2. Adverse Effects of Antifungal Treatment

Amphotericin B is nephrotoxic and may also be associated with variations of arterial pressure, fever or vomiting. However, liposomal amphotericin B has probably a lower rate of nephrotoxicity [2]. It should be used under the supervision of an internal medicine or infectious disease specialist [3][62].
Azole derivatives are hepatotoxic and should be use with caution in patients with pre-existing liver disease. Their risks include hepatic toxicity, cardia arrhythmias, fever and hypertension. Clinicians are advised to monitor aspartate-aminotransferase (ASAT) and alanine-aminotransferase (ALAT) weekly for the first month. There are strong recommendations for the monitoring of voriconazole serum-levels [6][64].
Caspofungin is a lipopeptide antifungal (from the echinocandins class). Risks associated include hepatotoxicity, Stevens-Johnson syndrome and toxic epidermal necrolysis [3][62].

2.2. Surgical Management

In the setting of acute postoperative endophthalmitis it can be difficult to immediately perform pars plana vitrectomy because of problems with operatory schedule. In those cases many ophthalmologists perform a vitreous needle tap and intravitreal injection, typically with antibiotics such as vancomycin and ceftazidime. However, most FE do not begin in an acute manner. Moreover, an inadvertent empirical antibiotic therapy does not preclude subsequent adequate identification of fungal etiological agents
There are no guidelines regarding the necessity and timing of pars plana vitrectomy in fungal endophthalmitis. There are several papers pleading for early and complete vitrectomy in bacterial endophthalmitis, and many surgeons have adopted theis view [25][26][27][80,81,82]. Pars plana vitrectomy has the advantages of drastically reducing the load of intraocular microorganisms, providing a large sample for the microbiology laboratory and promoting the diffusion of antimicrobial drugs in the vitreous cavity.
Typically, after positioning the trocars, with the infusion cannula still closed, the surgeon will place the tip of the vitrector behind the lens (or in the center of the vitreous cavity). An assistant carefully aspires in a syringe coupled at the aspiration line of the vitrector, while the surgeon may choose to active cutting function. After the first drops are aspirated, the surgeon withdraws the vitrector and the assistant continues to draw all the drops from the tubing into the syringe, while the infusion is turned on. This technique usually provides at least 0.2 mL of undiluted vitreous that should be immediately sent for culture seeding.
Removal of “sticky” hypopyon and repeated subsequent irrigation of anterior chamber permits the visualization of vitreous cavity. After careful, patient removal of vitreous and repeated lavage of floating debris, the retina may become visible and the surgeon may attempt to remove fungal colonies from the retinal surface (bearing in mind that inflamed retina is friable and easily teared).
In post-cataract surgery FE, especially in cases that present recurrence after a vitrectomy, it is advisable to remove the intraocular lens and the capsular bag. Vinekar et al., have suggested that fungal spores sequestered in the capsular bag are responsible for the recurrences [28][83]. Relimpio-Lopez et al., pleaded for extreme surgical maneuvers that may help to salvage a globe with FE: “hot” penetrating keratoplasty (for perforated, infected cornea), iridectomy of infiltrated iris regions, endodiathermy or endophotocoagulation of chorioretinitis foci [29][84]. In a series of patients with posttraumatic FE, lensectomy was performed in all cases, together with pars plana vitrectomy [30][25].
A recent review of several series of patients with endogenous FE found that vitrectomy was performed in 24.2% to 56.9% of eyes [31][9]. In a retrospective cohort of 44 eyes with endogenous Candida endophthalmitis, Sallam et al., found that performing an early vitrectomy reduced significantly the risk of retinal detachment [32][85].
A more recent paper by Behera et al., studied the outcomes obtained in 66 consecutive patients with FE, divided in two groups based on the timing of vitrectomy. The patients in one group were subject to immediate vitrectomy, the others received a delayed diagnostic vitrectomy (after an average of 18 days). Both groups also received intravitreal antifungals. The researcheuthors concluded that the visual acuity improved significantly in the immediate vitrectomy group [33][86]. However, William et al., found that 42% of eyes with endogenous FE developed a retinal detachment. There was no association between the duration of symptoms and the development of retinal detachment [34][87].
In one retrospective study, nearly significant difference in final visual acuity (p = 0.06) was found in eyes that received intravitreal antifungals at the moment of the first vitrectomy, compared to those who received intravitreal antibiotics initially [30][25]. However, most ophthalmologists prefer to treat endophthalmitis with intravitreal antibiotics while awaiting microbiological diagnosis (simply because bacterial endophthalmitis is more prevalent that FE).

3. Prognosis

The visual prognosis in fungal endophthalmitis is poor, and exogenous FE has a worse prognosis than endogenous FE [2]. In a large retrospective series of 388 eyes with culture-positive endophthalmitis that were eviscerated, 35.3% were caused by fungi, suggesting a worse prognosis of FE relative to endophthalmitis of all causes [35][88]. The eyes with Aspergillus endophthalmitis present in a larger proportion with visual acuities inferior to hand movement (compared to eyes with other fungal etiologies) and this trend is maintained also when measuring the visual acuities at the end of the follow-up [36][3].
In a cohort of 342 patients with postoperative FE, 5.8% of eyes were eventually eviscerated and 13.7% of eyes had finally lost the light perception, while 30.1% of eyes gained a visual acuity ≥ 20/400 [36][3]. Sen et al., reported that 35.3% obtained a visual acuity of 6/60 or better, corneal involvement in addition to endophthalmitis and the presence of Aspergillus terreus being poor prognostic markers [37][89].
From 260 eyes with post-traumatic FE, 6.9% had no light perception at the end of the follow-up and 5% were eviscerated, but 31.1% had a final visual acuity of 20/400 or better [36][3]. Similar outcomes were found by Zhuang et al., in a cohort of patients from eastern China diagnosed with post-traumatic FE: 5.7% of eyes were finally enucleated, while 34.3% achieved a visual acuity ≥ 20/400 [30][25].
In the cohort of fungal endogenous endophthalmitis cases (128 patients), only one eye was eviscerated (0.8%). In 17.9% the final visual acuity was no light perception and in 10.9% of eyes it was ≥20/400. All patients were treated with vitreous surgery and at least one intravitreal injection of antifungals [36][3]. In a review of several series of endogenous FE cases (where primary vitrectomies were performed in 24.2% to 56.9% of eyes), intravitreal antifungals were administered in 54% to 100% of eyes and were repeated in 33% to 50%. All researcheuthors have reported high rates of anatomical success (75% to 100%). However, functional success (defined as final visual acuity ≥ 20/400) was reported in only 33% (in mold infections) to 56% of eyes (in yeast infections). Patients with mold infections had worse visual acuities, both at the presentation and during the follow-up [31][9].
In a smaller series of patients with FE from North China, of which almost half were diagnosed with Fusarium endophthalmitis, 56.4% obtained final visual acuity of 20/400 or better [38][27].
In a retrospective study of eyes with Aspergillus endophtalmitis, 34% eyes obtained a final visual acuity ≥ counting fingers (21.9% final VA ≥ 20/400). The factors associated with better visual outcomes were: presenting vision greater than hand motions, absence of corneal infiltrate, early vitrectomy and the use of intravitreal voriconazole (as compared to intravitreal amphotericin B) [7][24].
Video Production Service