Endophthalmitis is a potentially devastating ocular disease that may lead to permanent loss of vision. It is caused by bacteria in the majority of the cases. However, fungal endophthalmitis though rare has a poor prognosis and usually diagnosed late. The incidence of fungal endophthalmitis has increased in recent years, particularly in developing countries. ^1-3Unlike bacterial infections, we do not have much choice of medications in fungal infections. The fungus is slow-growing and we have limited choice of antifungalswhich act slowly. These are usually diagnosed late as patients are less symptomatic but have more signs. Moreover, fungal culture takes longer time and identification requires more expertise. Polymerase chain reaction (PCR) techniques can even detect dead remnants. Patients are usually treated as bacterial infections and would have received steroids before they are diagnosed to have fungal endophthalmitis. The prognosis of fungal endophthalmitis depends on the magnitude of intraocular involvement, the virulence of the organism, and the timing of treatment. Early diagnosis of fungal endophthalmitis is important in order to prevent irreversible damage to the retina and prevent visual loss.

Classification:

The fungus can be classified into yeasts, molds, and dimorphic. Yeasts include candida, cryptococcus, trichosporon, and rhodotorula. Molds can further be classified based on hyphae as aseptate (rhizopus and mucor) and sepate (aspergillus, fusarium, dermatophytes such as trichophyton and microspore). Dimorphic fungi include Histoplasma, Blastomyces, coccidiosis, and sporothrix.

Antifungal drugs can be classified based upon structure and their mechanism of action.

Fungal endophthalmitis can be classified into exogenous and endogenous types.

Exogenous Endophthalmitis

It occurs due to the direct inoculation of fungus following trauma or intraocular surgery. Source of pathogens is the ocular surface (e.g., in postoperative, keratitis-related, and bleb-related endophthalmitis) or the environment (e.g., in posttraumatic endophthalmitis). It usually occurs in immunocompetent patients. A study by Williamson et al have reported that the overall incidence of fungi was 2.9% in patients with healthy conjunctival flora. ⁴Fungal cultures comprised of Penicillium Sp., Aspergillus Sp., Rhodotorula Sp., Scopulariopsis Sp., and Candida Sp. in the majority of the cases. ⁴The incidence of fungal isolates increases in older age, prolonged steroid use, and patients with Sjogren's syndrome. ^4,5The frequency of endophthalmitis after cataract surgery and trauma ranges from 0.07% to 0.13% and 2.4 to 17%, respectively, as previously reported in the literature. ⁶In a retrospective study of 170 culture-positive postoperative endophthalmitis cases in India, 21.8% of cases were due to fungi.⁷The postoperative fungal endophthalmitis is usually seen due to use of contaminated intraocular irrigation solution, intraocular lenses, ventilation system, hospital construction activities or surgeries conducted in rural settings or eye camps. ⁸Fusarium and Aspergillus species are the most common causative organisms. ^(9,10) In the studies from India, Aspergillus species are found to be most common. ^2,3,7,8In a study by Chakrabarti et al, Aspergillus species were the most common (54.4%), followed by yeasts (24.6%) and melanized fungi (10.5%). ⁸Among Aspergilli, Aspergillus flavus was the most common (24.6%) whereas Candida tropicalis (8.8%) was most common in the yeast. Other rare agents included Fonsecaea pedrosoi, Fusarium solani, Paecilomyces lilacinus, Pseudallescheria boydii, Colletotrichum dematium, Cryptococcus neoformans, and Trichosporon cutaneum.

Endogenous Endophthalmitis

It arises from the hematogenous seeding of pathogens during fungemia. Most patients with endogenous fungal endophthalmitis have predisposing systemic risk factors, such as systemic debilitating disease, uncontrolled diabetes mellitus, intravenous drug use, recent hospitalization, parenteral nutrition, central venous catheter, malig­nancy, systemic surgeries especially abdominal surgery, an immunocompromised status due to HIV infection, neutropenia or prolonged steroid and immunosuppressant therapy for organ transplantation; liver disease, pulmonary disease or renal failure. ^11-14It has also been described in healthy patients after receiving presumably contaminated dextrose infusions. ^{15, 16}The most common causative organisms are Candida species. ^{8, 11, 17}In a study on endogenous endophthalmitis conducted in southern India, Pseudomonas was the most common organism (13.8%), followed by Candida (8.6%) and E. coli (6.9%). ¹⁸Children and adolescents can also get affected by fungal infections like Candida and Aspergillus. Neonatal Candida endogenous endophthalmitis has been reported secondary to neonatal sepsis. The incidenceof endogenous endophthalmitis in the pediatric age group is higher in India that could be due to general malnutrition which reduces the immunity, thus making children more prone to latent infections to become manifest.

Clinical features:

The patient usually presents with diminution in vision, pain, redness, and lid edema. Systemic symptoms such as fever or malaise are often present in patients with endogenous endophthalmitis.¹⁹On anterior segment examination, corneal edema, anterior chamber cellular reaction, posterior synechiae, fibrin or hypopyon is seen in most of the cases. Yellowish white nodular exudates are usually seen on the iris and lens surface. Hypopyon is nodular and organized. Fundus examination shows media haze due to vitreous exudates that often obscures the view of retinal vessels. It is important to differentiate between bacterial and fungal endophthalmitis. Bacterial endophthalmitis usually presents acutely, often within days of an inciting event such as cataract surgery or trauma. Fungal endophthalmitis typically has a subacute presentation with symptoms worsening over days to weeks. The symptoms are less severe in fungal endophthalmitis. The visual deterioration and pain are significantly lesser in fungal endophthalmitis. The patient presents with more signs. The intraocular inflammation in fungal endophthalmitis tends to be more localized and occurs in clumps while it is typically diffuse in bacterial endophthalmitis. The clinical picture may vary depending upon the etiologic agent. Fundus examination shows fluffy white focal areas of chorioretinal lesions with overlying vitritis or cotton balls may be suspended in the vitreous with “string of pearls” appearance in cases with Candida endophthalmitis. ¹⁰However in cases with Aspergillus endophthalmitis, a confluent yellowish infiltrate is often seen in the macular area, beginning in the choroid and subretinal space. It has an acute presentation and there can be associated retinal hemorrhages, retinal vascular occlusions, and full-thickness retinal necrosis. ²⁰Endophthalmitis should be differentiated from other similar looking conditions such as acute retinal necrosis, progressive outer retinal necrosis, degenerated cysticercus cyst ²¹, cytomegalovirus retinitis toxoplasmosis, Behcet’s disease, syphilis, intraocular tumors, and other masquerade syndromes. In a study by Maitray et al, they reported differences in endogenous endophthalmitis among children and adolescents from that in adults to include the relative lack of systemic features and lack of underlying systemic disorders as well as potential misdiagnosis as masquerade syndrome^.22Patient may present as panophthalmitis with marked lid edema, proptosis, and limitation of extraocular movements. Details of the anterior and posterior segments are not visible because of the prominent hypopyon. This rapidly developing infection invades the orbit leading to blindness, phthisis, or enucleation. Progression of a panophthalmitis may be life-threatening. Rishi et al has reported a study on endophthalmitis in eyes presenting with orbital signs (defined as ocular motility restriction and/or presence of "inverted perpendicular" sign on ultrasonography) and found out that orbital signs are independent risk factors for poor structural and visual outcomes in eyes with endophthalmitis. ²³

Management:

Ultrasonography:

It should be done to look for the extent of inflammation, vitreous membranes and opacities, presence and location of posterior vitreous detachment, presence of retinal detachment, choroidal detachment, or T sign, any choroidal abscess, any retained lens matter or intraocular foreign body and retinochoroidal thickening. It helps in monitoring response to treatment and rules out other masquerades like cysticercus cyst or intraocular tumors.

Aqueous tap/ Vitreous tap or biopsy:

After cleaning the eye and the periocular skin with 5% povidone-iodine and applying a wire speculum, a 30-gauge needle mounted on a 1 mL disposable syringe can be used for aspirating approximately 0.1-0.2 mL of aqueous humor. A vitreous sample may be obtained either by a needle tap or by vitreous biopsy. In a vitreous tap, a 27-gauge needle with 2 mL or 5 mL syringe is passed through pars plana and 0.2-0.3 mL of undiluted vitreous is removed avoiding forceful suction. Some vitreous aspirates are “dry taps” because of the difficulty in aspirating a gel. There is a possibility of vitreous traction and subsequent retinal detachment in non-vitrectomized eyes. Vitreous samples can be collected during planned therapeutic vitrectomy. The aspiration line can be connected to a 10 mL disposable syringe and gentle suction should be applied while the surgeon actuates the vitrectomy cutter. During this process, the infusion line should be kept blocked to avoid dilution of the vitreous sample. The vitreous samples collected during vitrectomy are known to yield higher culture-positive results than a needle biopsy of the vitreous. ⁽²⁴⁾ Aqueous aspirates usually have higher yields in endophthalmitis cases in which inflammation is greatest in the aqueous, such as cases secondary to keratitis. ²⁵The aqueousor vitreous sample is subjected to microbiological analysis. Samples can be sent for Gram stain, 10% KOH mount, Giemsa stain, and Ziehl-Neelsen stain to identify bacterial or fungal etiology. All samples should be inoculated on blood agar, chocolate agar, MacConkey agar, Sabouraud dextrose agar, thioglycolate medium, brain-heart infusion agar, and Lowenstein-Jensen agar. All samples must be inoculated in Sabaraud's dextrose agar media for at least six weeks at 25⁰C and 37⁰C respectively.³A positive culture is defined as the growth of the same organism on two or more solid phase media or confluent growth on one solid medium. Antimicrobial sensitivity patterns can be recorded using the Kirby-Bauer disc diffusion method. Cultures are positive in approximately 90% of vitrectomy samples, 50 to 70% of vitreous aspirates, and 40% of aqueous aspirates. ⁽²⁵⁾ Culture rates are lower in fungal endophthalmitis.

Molecular diagnostic techniques:

PCR testing of aqueous and vitreous samples can rapidly identify pathogens in endophthalmitis cases, including culture-negative cases. In fungal infections, even when cultures are positive, results usually take longer than a week because these organisms are difficult to identify and/or are slow-growing. Early diagnosis and rapid intervention are required for effective treatment of these ocular infections. Multicopy gene targets have been evaluated for increasing the sensitivity for the detection of fungal pathogens and universal fungal PCR primers have been developed for broadening the range of detectable fungi. ^26,27Ferrer et al have reported on rapid detection and identification of fungal pathogens by PCR and amplification of ITS2 and 5.8S ribosomal DNA and molecular typing. ²⁸Gandhi et al have evaluated the clinical utility of high-throughput sequencing approach-based analysis in identifying predominantly fungal genome in vitreous fluids after DNA extraction and amplification of ITS 2 region in patients with clinically infectious culture-negative endophthalmitis. ²⁹

Blood/Urine culture:

In cases of endogenous endophthalmitis, blood and urine cultures should be done. Blood cultures are often positive in these patients but may be negative in cases due to transient fungemia, such as those related to intravenous drug use, an indwelling central venous catheter, or an outpatient gastrointestinal procedure. Blood cultures are reported to be more likely positive than vitreous in a large series of endogenous endophthalmitis. ^19,30,31

Treatment:

The mainstay of treatment for postoperative fungal endophthalmitis is the intravitreal injection of antifungal agents [amphotericin (5 ug/0.1mL) or voriconazole (50 ug /0.1 mL)] and surgical debulking. Intravitreal injections can be repeated after 48 hours if a patient does not show improvement after the first injection or if there is any deterioration. Amphotericin B has been the drug of choice for a long time. It is a broad spectrum efficacious fungicidal drug. A combination of vitrectomy and antifungal agents appears to be the best therapy for fungal endophthalmitis.^14,19,31-35Vitrectomy debulks the infective tissue and may help in improving the diffusion of antifungal agents across the vitreous cavity, retina, and choroid.

The role of steroids in the treatment of fungal endophthalmitis is controversial. The size of fungal hyphae may preclude ingestion by the neutrophils, leading to the release of lysosomal enzymes and oxygen metabolites into the surrounding tissues. Steroids are often used to control the surrounding tissue destruction due to direct damage by fungal toxins and by host defense mechanisms. The use of steroids, as anti-inflammatory agents, in a case of fungal endophthalmitis has been reported in various studies.^36–40Adverse effects of steroids are reported mainly due to high intravitreal dosage and if they are not combined with an efficacious antifungal agent. ^41-43Systemic antifungals agents such as itraconazole 100 mg BD, voriconazole 200 mg BD or fluconazole 200 mg BD should be given in these cases. Liver function tests should be repeated at regular intervals to monitor hepatic toxicity. Topical antifungal agents should be added in case of corneal involvement. Natamycin has good efficacy against filamentous fungi but does not penetrate well into the cornea. Topical amphotericin B is commonly used in the management of fungal keratitis. Fungal endophthalmitis poorly responds to medication and early vitrectomy should be considered.

In all cases of endogenous endophthalmitis, intravenous anti­fungal agents are initially administered along with systemic antifungal agents. Post-traumatic endophthalmitis may be associated with an injury with vegetative matter and may require vitrectomy to debulk the fungal load and increase the penetration of antifungal drugs. Postoperative fungal endophthalmitis may require early vitrectomy along with the removal of the intraocular lens and capsular bag. Patients with significant vitritis and macula threatening lesions usually require vitrectomy along with intravitreal antifungal injections (amphotericin or voriconazole) in addition to systemic therapy. For systemic agents, fluconazole is recommended for fluconazole-susceptible Candida, voriconazole for fluconazole-resistant but voriconazole-susceptible isolates, and liposomal amphotericin, with or without 5-flucytosine, for azole-resistant strains. The advantage of voriconazole over fluconazole is that it has activity against Aspergillus species and fluconazole-resistant Candida species, such as Candida glabrata and Candida krusei. Low intraocular levels are attained with systemic administration of amphotericin B and it also carries the risk of infusion toxicity and nephrotoxicity. ⁴⁴Intravitreal amphotericin B can cause retinal toxicity and necrosis if given in high doses. Ganglion cell damage and retinal detachment are reported secondary to increased membrane permeability induced by amphotericin B. ⁴⁵Voriconazole may be safer than amphotericin B. It has excellent bioavailability, less toxic and immediately achieves high levels of the drug in the vitreous, whereas serum levels from systemic administration are gradually reaching a steady state. Clinical efficacy of systemic voriconazole has been reported in Aspergillus, Fusarium, and Candida endophthalmitis. The dose of intravenous fluconazole (12 mg/kg loading dose, then 6–12 mg/kg daily) or voriconazole (6 mg/kg every 12 hours (24 hours), then 4 mg/kg every 12 hours) can be used. Krishnan et al has reported the role of intravitreal voriconazole in the management of neonatal candidal endogenous endophthalmitis. ⁴⁶There is poor ocular penetration with newer antifungal agents such as posaconazole and echinocandins (micafungin, caspofungin, and anidulafungin). ^47-50Guest et al has reported a significant improvement in Aspergillus endophthalmitis in mice treated with isavuconazole, with a considerable reduction in both fungal burden and intraocular inflammation. ⁵¹

The nature of fungus is an important prognostic factor for visual outcomes. Aspergillus infection has been associated with a poor outcome with a higher chance of evisceration compared to Candida infection. Corneal involvement in addition to endophthalmitis and the presence of Aspergillus terreus were found to be poor prognostic markers.⁵²Prognosis of fungal endophthalmitis with concurrent retinal detachment is usually poor with severe visual impairment. Silicone oil has antimicrobial properties and found to be helpful for better anatomical and functional results in endophthalmitis.^53,54However, silicone oil might play a weaker role in antifungal therapy. ⁵⁵It has been found that nontoxic concentrations of intravitreal injections create toxicity in a silicone oil-filled eye. ⁵⁶Post cataractfungal endophthalmitisnearly always requiresremovalof the intraocular lens (IOL)in addition to antifungals and vitrectomy. Early debulking is important. The fungus may survive over the IOL surface and in the capsular bag and can cause recurrences. Vinekar et al. has described the role of combined IOL explantation with capsulectomy and re-vitrectomy in the management of recurrent postoperative fungal endophthalmitis after failed vitrectomy and antifungal therapy. ⁵⁷ Due to poor penetration of systemic and topical medications and recurrent need for vitrectomy to debulk the load of fungus, there is a high possibility of eye landing up in phthisis despite treatment. Patients and attendants should be counseled properly regarding the guarded prognosis at the earliest diagnosis of fungal endophthalmitis.

Conclusion:

Fungal endophthalmitis requires rapid diagnosis and treatment to save vision. Diagnosis is clinical, supported by a culture of aqueous or vitreous samples and also by blood cultures in patients with endogenous endophthalmitis. PCR can be done for the rapid detection of the fungal pathogen, especially in culture-negative cases. Combined treatment with intravitreal antifungal agents and vitrectomy offers good results.

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