- , - - Aspergillus . These patients maypatients These 11 Candida , a mold (Table). In endog In (Table). mold a , , a yeast, followed by by followed yeast, a , The most common organism organism common most The The symptoms of fungal endo fungal of symptoms The Candida Aspergillus cataract after infections enous com most the trauma, or surgery is isolated organism mon penetrating trauma, and intraocularand trauma, penetrating mayfungi the cases, these In surgery. theof structures anterior the involve andvitreous the affecting before eye segment. posterior infection endogenous causes that is followed by followed CLINICAL PRESENTATION shareand diverse are phthalmitis uveitis.of types other with similarities the endophthalmitis, fungal mild In and subtle be may features clinical challenginga for making nonspecific, withpatients of series a In diagnosis. endophthalmitis,fungal endogenous wasmisdiagnosis of rate initial the 50%. as high as - -

8 - - 2,7,8 9,10 ASHVINI K. REDDY, MD MD ASHVINI K. REDDY, and AT A GLANCE Ocular signs of fungal endophthalmitis include anterior segment inflammationsegment include anterior signs of fungal endophthalmitis Ocular in the management of fungal role of pars plana vitrectomy The with hypopyon, keratic precipitates, and conjunctival injection. and hypopyon, keratic precipitates, with large controlled studies. to a lack of endophthalmitis is under debate due Fungal endophthalmitis can be classified as either exogenous (infection endophthalmitis Fungal following trauma, surgery, or direct spread from fungal keratitis) or from fungal or direct spread surgery, following trauma, with associated endogenous (infection through hematogenous spread nerve). the optic central nervous system via fungemia or through the

 Risk factors for exogenous endo exogenous for factors Risk Due to increased opioid abuse inabuse opioid increased to Due s s s ing membrane and vitreous. Tanakavitreous. and membrane ing anatomicfour-stage a developed al et highera which in system classification poorera with correlated was stage awith as well as acuity, visual final of presentation the between delay anddiagnosis the and symptoms initial therapy. of initiation keratitis,fungal include phthalmitis dialysis, malignancy, diabetes mellitus, mellitus, diabetes malignancy, dialysis, postpartum or pregnancy alcoholism, use. drug intravenous and state, Unitedthe of regions Eastern the fun endogenous of rate the States, withassociated endophthalmitis gal grown. has abuse drug intravenous originateto thought is infection The eyethe entering organisms fungal from choroid.vascularized highly a through toprior occurs seeding Chorioretinal limit internal the of involvement the immunosuppressive therapy, HIV therapy, immunosuppressive hemo surgery, abdominal infection, ------

3,4 Challenges in the diagnosis and management of fungal endophthalmitis. diagnosis and management of fungal Challenges in the MD, BY ALICE Y. ZHANG, In this article,this In 2 In endogenousIn 1

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ungal endophthalmitis is a rarea is endophthalmitis ungal can that uveitis infectious of cause inflam intraocular severe to lead blindness.irreversible and mation classifiedbe can infections These As noted above, endogenous fungal endogenous above, noted As Due to the rarity of fungal endo fungal of rarity the to Due the hematogenous spread of fungal of spread hematogenous the Predisposing eye. the into organisms indwell include infection for factors periph catheters, intravenous ing prolonged hyperalimentation, eral therapy, corticosteroid or antibiotic Among candidemia patients, thepatients, candidemia Among fungalendogenous of prevalence 3%between ranges endophthalmitis 45%. and from results usually endophthalmitis the rise due to the increased use ofuse increased the to due rise the immunosuppres and chemotherapy ofprevalence the medications, sive bemay endophthalmitis endogenous positivewith patients as decreasing, treated commonly are cultures blood antifungals. systemic with early RISKS FACTORS AND PATHOGENESIS RISKS FACTORS AND PATHOGENESIS isprevalence exact its phthalmitis, prevalencethe Although unknown. on be to thought is candidemia of either through hematogenous spread hematogenous through either com less or, fungemia with associated sys nervous central the from monly, nerve. optic the via tem managementand diagnosis review we endophthalmitis. fungal for strategies as either exogenous or endogenous. In endogenous. or exogenous either as organismsfungal infections, exogenous externalan or surface ocular the from eyethe into introduced are source spreaddirect or surgery, trauma, after keratitis. fungal from eyethe access fungi the infections,

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Aspergillus endophthalmitis can TABLE. ORGANISMS THAT CAUSE INFECTION generally be associated with retinal or choroidal vascular occlusion and exu- Candida Aspergillus dative retinal detachment, leading to a Type of fungus Yeast Mold poorer prognosis than Candida endo- More commonly found Endogenous fungal endophthalmitis Exogenous fungal endophthalmitis phthalmitis.4,13,14 TESTING AND DIAGNOSIS The diagnosis of fungal endo- First-line treatment Amphotericin B or fluconazole Voriconazole phthalmitis relies on gram staining and aqueous or vitreous culture. This can be challenging, as fungal organ- isms are difficult to culture and have present with decreased vision, photo- material in a “string of pearls” configura- long incubation periods. In a patient phobia, eye pain, and floaters. tion, retinal hemorrhage, and vascular with a clinically suspected endoge- Compared with bacterial endo- sheathing (Figure). nous fungal infection, a blood culture phthalmitis, the onset of symptoms In later phases, a vitreous band may should be obtained. If the culture is in fungal endophthalmitis is typically develop with the formation of an negative, diagnostic vitrectomy may more indolent and the degree of pain epiretinal membrane, causing retinal be performed. If there is a corneal less severe. Ocular signs of fungal endo- detachment. In exogenous cases spread infiltrate, corneal scrapings and cul- phthalmitis include anterior segment from fungal keratitis, a white corneal tures may aid in diagnosis. Before a inflammation with hypopyon, keratic infiltrate may be found with satellite definitive fungal endophthalmitis precipitates, and conjunctival injec- lesions. Fungal endophthalmitis may diagnosis is established, the use of tion. In the posterior segment, fungal present with a white plaque on the broad-spectrum intravitreal antibiot- endophthalmitis may present with foci surface of an intraocular lens and mild ics may be required in post-cataract of chorioretinal yellow-white lesions, vitritis, similar to delayed-onset post– surgery or post-trauma cases. vitreous inflammation and haze, fungal cataract surgery endophthalmitis.12 Fungal cultures from ocular fluid can be positive in 40% of vitreous samples, but the rate can increase to 70% with histopathology.15,16 Vitrectomy has the highest yield of all intraocular speci- mens. The highest yield fungal culture is from a vitrectomy sample (92%), compared with vitreous paracente- sis (44%) and aqueous paracentesis (25%).17 As results of cultures may take several days and false negatives are possible, patients should be treated empirically with antifungal medica- tions and may require concurrent broad-spectrum antibiotics. The differential diagnosis of endophthalmitis is wide, including infectious causes of posterior uveitis (eg, syphilis, tuberculosis, and toxo- plasmosis), acute retinal necrosis, intraocular lymphoma, tumor necrosis with inflammation, Vogt- Koyanagi-Harada disease, sympathet- ic ophthalmia, and sarcoidosis. It is important to have a low threshold of Figure. Fungal chorioretinal lesion adjacent to the optic nerve with associated disc edema, intraretinal suspicion for fungal endophthalmitis, hemorrhages, and macular edema. as steroidal treatments for uveitis

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can worsen a fungal infection. amphotericin B is considered safe in detection of fungal organisms from Depending on the clinical pre- pregnancy (category B), whereas vori- cultured fluid may aid in earlier diag- sentation, it may be appropriate to conazole is associated with a risk of nosis and improve prognosis. n initiate a workup with a quantiferon- fetal malformation in animal studies 18 1. Chee YE, Eliott D. The role of vitrectomy in the management of fungal tuberculosis gold test, treponemal (category D). endophthalmitis. Semin Ophthalmol. 2017;32(1):29-35. tests, toxoplasmosis titers, polymerase The role of pars plana vitrectomy 2. Samiy N, D’Amico DJ. Endogenous fungal endophthalmitis. Int Ophthalmol Clin. 1996;36(3):147-162. chain reaction analysis of aqueous (PPV) in the management of fungal 3. Donahue SP, Hein E, Sinatra RB. Ocular involvement in children with fluid, and chest x-ray to rule out other endophthalmitis is under debate candidemia. Am J Ophthalmol. 2003;135(6):886-887. 4. Ryan SJ. Retina. 5th ed. London: Saunders/Elsevier; 2013. infectious causes. Because an immu- due to a lack of large controlled 5. Brooks RG. Prospective study of Candida endophthalmitis in hospitalized nocompromised state is a risk factor, studies. PPV can decrease the infec- patients with candidemia. Arch Intern Med. 1989;149(10):2226-2228. 6. Scherer WJ, Lee K. Implications of early systemic therapy on the incidence of testing for concurrent HIV infection tious burden by removing fungi endogenous fungal endophthalmitis. Ophthalmology. 1997;104(10):1593-1598. should be considered in the absence from the vitreous, while also clear- 7. Kresloff MS, Castellarin AA, Zarbin MA. Endophthalmitis. Surv Ophthalmol. 1998;43(3):193-224. of other systemic illness. ing opacities, improving vision, and 8. Tirpack AR, Duker JS, Baumal CR. An outbreak of endogenous fungal improving the diffusion of antifungal endophthalmitis among intravenous drug abusers in New England. JAMA 1 Ophthalmol. 2017;135(6):534-540. CLINICAL MANAGEMENT AND agents into the vitreous cavity. 9. Takebayashi H, Mizota A, Tanaka M. Relation between stage of endogenous VITRECTOMY In persistent cases of fungal endo- fungal endophthalmitis and prognosis. Graefes Arch Clin Exp Ophthalmol. 2006;244(7):816-820. A systemic evaluation by an inter- phthalmitis after cataract surgery, 10. Tanaka M, Kobayashi Y, Takebayashi H, Kiyokawa M, Qiu H. Analysis of pre- nist or infectious disease specialist the intraocular lens may have to be disposing clinical and laboratory findings for the development of endogenous fungal endophthalmitis. A retrospective 12-year study of 79 eyes of 46 may be necessary. There are two removed at the time of PPV or dur- patients. Retina. 2001;21(3):203-209. main classes of antifungal agents ing a second surgery. Serous, trac- 11. Schiedler V, Scott IU, Flynn HW Jr, Davis JL, Benz MS, Miller D. Culture- proven endogenous endophthalmitis: clinical features and visual acuity used to treat fungal endophthalmitis: tional, and rhegmatogenous retinal outcomes. Am J Ophthalmol. 2004;137(4):725-731. polyenes and azoles. Other antifun- detachments can be associated with 12. Gregori NZ, Flynn HW Jr, Miller D, et al. Clinical features, management strategies, and visual acuity outcomes of Candida endophthalmitis following gal therapies such as echinocandins fungal endophthalmitis, and these cataract surgery. Ophthalmic Surg Lasers Imaging. 2007;38(5):378-385. have poor ocular penetration and can lead to poor visual outcomes. 13. Jampol LM, Dyckman S, Maniates V, Tso M, Daily M, O’Grady R. Retinal and choroidal infarction from Aspergillus: clinical diagnosis and clinicopathologic generally are not used to treat fungal Although it is controversial, some correlations. Trans Am Ophthalmol Soc. 1988;86:422-440. endophthalmitis. Chorioretinitis may retina specialists recommend early 14. Chakrabarti A, Shivaprakash MR, Singh R, et al. Fungal endophthalmitis: fourteen years’ experience from a center in India. Retina. 2008;28(10):1400-1407. be treated with systemic antifungal vitrectomy in which the posterior 15. Binder MI, Chua J, Kaiser PK, Procop GW, Isada CM. Endogenous drugs, but their vitreous penetration hyaloid is lifted to decrease the risk endophthalmitis: an 18-year review of culture-positive cases at a tertiary care center. Medicine (Baltimore). 2003;82(2):97-105. may vary. Therefore, intravitreal treat- of future membrane formation and 16. Liu K, Fang F, Li H. Reliability of vitreous histological detection of ment may be required in cases of retinal detachment.1,20 pathogenic fungi in the diagnosis of fungal endophthalmitis. Eye (Lond). 2015;29(3):424-427. severe intravitreal inflammation. Depending on the location of 17. Lingappan A, Wykoff CC, Albini TA, et al. Endogenous fungal endo- Amphotericin B, a polyene, has fungal lesions and the virulence of phthalmitis: causative organisms, management strategies, and visual acuity outcomes. Am J Ophthalmol. 2012;153(1):162-166. the advantage of broad-spectrum the infectious organisms, the prog- 18. Cottreau JM, Barr VO. A review of antiviral and antifungal use and safety coverage, but it has limited intraocu- nosis for fungal endophthalmitis during pregnancy. Pharmacotherapy. 2016;36(6):668-678. 19. Silva RA, Sridhar J, Miller D, Wykoff CC, Flynn HW Jr. Exogenous fungal en- lar penetration and carries a risk of is generally poor. A delay between dophthalmitis: an analysis of isolates and susceptibilities to antifungal agents infusion-related toxicity and neph- diagnosis and treatment, a traumatic over a 20-year period (1990-2010). Am J Ophthalmol. 2015;159(2):257-264. 18 20. Christmas NJ, Smiddy WE. Vitrectomy and systemic fluconazole for rotoxicity. As such, the preferred cause of the endophthalmitis, and treatment of endogenous fungal endophthalmitis. Ophthalmic Surg Lasers. drug delivery option for this agent the isolation of Aspergillus species 1996;27(12):1012-1018. 21. Pflugfelder SC, Flynn HW Jr, Zwickey TA, et al. Exogenous fungal endo- is intravitreal injection, but this has are each associated with an unfavor- phthalmitis. Ophthalmology. 1988;95(1):19-30. been associated with retinal toxic- able outcome. Eventual evisceration ity and necrosis. Among the azoles, or enucleation occurs in 24% to 78% both fluconazole and voriconazole of cases.19,21 ASHVINI K. REDDY, MD have good oral bioavailability and n Assistant Professor of Ophthalmology in the intraocular penetration.19 Systemic POTENTIALLY DEVASTATING Division of Ocular Immunology, Johns Hopkins voriconazole is associated with hepa- Fungal endophthalmitis is a rare University, Wilmer Eye Institute, Baltimore, Maryland totoxicity and skin rash, so intravitreal but potentially devastating infection. n [email protected] n administration may be preferred.19 It is important to have a low thresh- Financial disclosure: None acknowledged The recommended first-line treat- old of suspicion for fungal infection to ALICE Y. ZHANG, MD ment for Candida endophthalmitis is prevent delay in the onset of appro- n Vitreoretinal Surgeon, Department of amphotericin B or fluconazole, where- priate therapies. PPV may play an Ophthalmology, University of North Carolina- as voriconazole is recommended for important role in the diagnosis and Chapel Hill, Chapel Hill, North Carolina 19 Aspergillus endophthalmitis. treatment of fungal endophthalmitis. n [email protected] It is important to note that Further developments to improve the n Financial disclosure: None acknowledged

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