Presumed Candida endogenous fungal endophthalmitis: A case report and literature review

Optometry (2007) 78, 454-459

Presumed Candida endogenous fungal endophthalmitis: A case report and literature review Neeka G. Najmi, O.D.,a,b Huey-Fen Song, O.D.,a,b and Richard R. Ober, M.D.a,c a

Southern Arizona VA Health Care System, Tucson, Arizona; bSouthern California College of Optometry, Fullerton, California; and cThe University of Arizona, Tucson, Arizona. KEYWORDS Endogenous fungal endophthalmitis; Candida albicans; Candidemia; Candidiasis; Fluconazole; Amphotericin B

Abstract BACKGROUND: Endogenous fungal endophthalmitis (EFE) is a rare intraocular infection that has recently increased in incidence over the last few decades. The most common causative organism of endogenous endophthalmitis is Candida albicans. Treatment generally is initiated with an antifungal drug systemically and, depending on the ocular findings, may also include a vitrectomy with the injection of an intraocular antifungal agent. Specific predisposing factors may make a patient more at risk for development of an ocular infection. CASE REPORT: We present a case of presumed Candida endogenous endophthalmitis in an 83-year-old white man with a Candida albicans urinary tract infection and describe the general characteristics, treatment, and management of this condition. CONCLUSION: Endogenous fungal endophthalmitis is a potentially blinding condition that can signal an underlying systemic infection. Without a dilated fundus examination in the presence of ocular inflammation, the condition easily can be misdiagnosed. Fungal infection may lead to retinal and vitreal lesions that can be visually debilitating if left untreated. Prognosis for visual outcome is dependent on timely diagnosis and initiation of treatment. Optometry 2007;78:454-459

Endophthalmitis refers to intraocular inflammation, usually resulting from an infectious organism, which involves the vitreous and the anterior chamber of the eye. The infection can be categorized into the more common exogenous types, including postoperative and posttraumatic subgroups, and the less common endogenous type, indicating an underlying systemic etiology. Endogenous infections, in which the organism reaches the eye hematogenously, account for 2% to 15% of all types of endophthalmitis.1,2 Infections can be either bacterial or fungal. Of all exogenous causes, bacterial infections are more common than fungal.

Corresponding author: Neeka G. Najmi, O.D., Southern Arizona VA Health Care System, Optometry Section, 3601 South 6th Avenue, Tucson, Arizona 85723. E-mail: [email protected]

With the advent of antibiotics, the incidence of endogenous bacterial endophthalmitis has decreased and is now relatively rare. In contrast, the incidence of endogenous fungal endophthalmitis (EFE) has been on the rise in recent decades.3 During the first half of the century, EFE was rare. However, the incidence of EFE has risen and can be attributed to an increase in the number of intravenous drug users and patients with long-term indwelling catheters in hospitals as well as the increased use of chemotherapy, long-term systemic antibiotics, corticosteroids, and immunosuppressive therapy.4 The sharing of contaminated needles by intravenous (IV) drug users and longstanding indwelling catheters in patients getting hyperalimentation or hemodialysis treatment increases patient susceptibility to inoculation by fungal organisms. Immunosuppressive agents and

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corticosteroids decrease the host’s natural defense. Antibiotics cause a decrease in bacteria in the gastrointestinal tract, leading to an increase in normal floral growth of fungi in the tract.4 Debilitating diseases such as diabetes mellitus, malignancies, liver disease, renal disease, and alcoholism can also compromise immunity and increase patient risk for opportunistic infection.4 According to studies by Binder et al.,5 Jackson et al.,6 Schiedler et al.,2 and Leibovitch et al.1 the majority of patients with endogenous endophthalmitis, whether bacterial or fungal, had an associated debilitating disease or recent hospitalization. Although EFE is generally rare in immunocompetent patients without a history of IV drug use, no specific association has been made between candidal EFE and immunodeficiency.7,8 Historically, immunodeficiency, specifically referring to acquired immunodeficiency syndrome (AIDS), has been associated with increased fungal infections. However, Candida infections in particular are not common intraocular organisms in patients with AIDS. Immunodeficiency alone, in the absence of risk factors that increase the possibility of inoculation of fungi into the blood stream, is not sufficient for the development of EFE.9 Of all endogenous fungal invaders of the eye, Candida albicans is the most common cause of endophthalmitis.1,2,5 Other known but less common infective fungal organisms include Aspergillus species, Coccidioides immitis, Pseudallescheria boydii, Histoplasma capsulatum, Cryptococcus neoformans, Blastomyces dermatitidis, and Sporothrix schenckii.7,8 Ocular findings and treatment options between the varying fungal species are fairly similar. The most common symptoms and ocular findings of EFE include blurred vision, pain, photophobia, and conjunctival hyperemia.7,8 Other less common ocular findings may include episcleritis/scleritis, keratic precipitates, hypopyon, and optic nerve head edema.8 Most patients will present with a creamy-white abscess involving the choroid, retina, and vitreous. The majority of infected eyes have macular lesions, and 80% (determined by autopsy) have multiple lesions.4,10 Ocular findings of fungal infection can signal underlying systemic infection, and systemic fungal disease can predict EFE if left untreated.7 Bilateral disease is more common in fungal cases compared with bacterial infections. Because initial presentation of EFE can appear as an isolated anterior inflammation, 16% to 63% of cases go misdiagnosed as a benign uveitis, conjunctivitis, angle closure glaucoma, or cellulitis.1,2,5,11 Anterior segment findings generally follow posterior segment lesions. These diagnostic retinal and vitreal abscesses indicate progression of the disease process. Thus, it is essential that all patients with uveitis and other associated risk factors, such as a recent hospitalization, should be considered potential suspects for EFE. These patients should be followed up with dilated fundus examinations until fungal infection can be ruled out.

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Case report An 83-year-old white man was brought into the emergency room at the Southern Arizona VA Health Care System with mental status changes and a history of general weakness with a recent fall. Past history was significant for hypertension, arthritis, recurrent urinary tract infections, nephrolithiasis, and hydronephrosis. He had been treated with gatifloxacin for a bacterial urinary tract infection 3 months prior and had a history of right ureteral stent placement. He had no visual complaints on admission to the hospital. Results of laboratory testing, including a urinalysis, confirmed a positive culture for Candida albicans. The patient was immediately started on a 10-day course of oral fluconazole at 100 mg/d. Eleven days later, he complained of an overall reduction of vision associated with a painless, left red eye. He was treated with erythromycin ophthalmic ointment by the hospital staff and referred immediately to the eye clinic for further evaluation. On examination, the patient had best-corrected visual acuities of 20/25 in the right eye (O.D.) and 5/160 in the left eye (O.S.). Ocular findings were significant for left eye diffuse conjunctival injection, corneal endothelial striae, stromal edema, and mild corneal haze (see Figure 1). The anterior chamber had 3⫹ cell and flare. The right eye was quiet, and both eyes were pseudophakic. Left fundus examination found vitreous haze, mild optic nerve head swelling, and a preretinal yellow-white central macular abscess approximately 1 disc diameter in size (see Figure 2). Retinal vascular involvement or sheathing was not present. The right eye fundus was significant for mild mottling and drusen only. The diagnosis of presumed Candida EFE was made based on clinical observations and a positive urine culture. Despite negative blood cultures for C albicans, and after consultation with the infectious disease specialist, treatment was continued with oral fluconazole at an increased dose of 200 mg/d. Topical prednisolone acetate ophthalmic suspension 1% (5 times per day) and atropine 1% (twice per day) were

Figure 1

Anterior segment presentation in presumed Candida endogenous fungal endophthalmitis.

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Figure 2

Fundus photography shows a central macular yellow-white preretinal abscess or “fluff ball” extending into the vitreous chamber. Vitreous chamber haze resulted in reduced fundus views.

Figure 4

Fundus photography of postvitrectomy hypopigmented macular scar (magnified view of Figure 3)

Discussion prescribed for the anterior chamber inflammation. The patient was monitored closely over the next 3 days. Despite treatment with oral fluconazole, the ocular inflammation persisted and the patient’s vision worsened to 3/200 O.S. As a result, the retinal specialist performed a pars plana vitrectomy with biopsy and injection of amphotericin B, vancomycin, and amikacin the following day. To avoid risk of damage to the retina, removal of the abscess was not attempted because of firm attachment to the macula. Results of gram stain testing as well as vitreal and aqueous humor cultures were negative for any bacterial or fungal organisms. The patient was followed up closely, and, by the fifth postoperative week, the lesion was completely resolved with a remaining focal macular scar (see Figures 3 and 4). Fluconazole was administered orally for another 2 weeks to ensure no further recurrence. Four months after surgery, the patient’s condition had stabilized with a visual acuity of 5/200 O.S. The systemic infection resolved, and the fellow eye remained unaffected.

Figure 3 ular scar.

Fundus photography of postvitrectomy hypopigmented mac-

Candida albicans Fungi are the most common cause of endogenous endophthalmitis, and C albicans is the most frequently cultured organism.1,2,4,5,12,13 Candida is a common yeast found as normal flora in the respiratory, gastrointestinal, and female genital tracts and has low virulence for a healthy person. However, when the host’s natural immune system defense is breached, serious disease can result. The organism can invade the eye, skeleton, heart, and central nervous system. Of patients with systemic candidiasis (infection of 1 or more internal organs), anywhere from 5% to 78% have ocular involvement.14-16 Candida chorioretinitis is the most common fungal infection of the retina.17,18 Animal studies have found that Candida may have a greater propensity for the eye than do other species of fungi.17,18 Aside from having devastating visual results once the organism has invaded the eye, patients with known systemic candidemia (blood-borne infection), along with a debilitating disease, may have a mortality rate of up to 80%.19 Ocular presentation of the organism includes a creamywhite, well-circumscribed cottonlike lesion, resembling a “fluff ball,” involving the retina and choroid and extending into the vitreous cavity.3,8,20 The lesion usually is less than 1 mm in diameter, often localized in the posterior pole, and associated with overlying vitreous inflammatory cells. More than one half of patients will have vitreous involvement.4,10 Vascular sheathing of the retinal vessels may be present, and an associated iridocyclitis is common. Two thirds of patients have bilateral involvement of the fellow eye, and one half of patients have multiple lesions when first examined.4,7,10 Multiple yellow-white vitreous abscesses are classically referred to as a “string of pearls.”8 The abscess itself generally contains only a few organisms. It is, however, the surrounding inflammatory reaction that can be visually debilitating. If the infection remains localized in the retina and choroid, the infection is referred

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to as Candida chorioretinitis.3,20 If it extends into the vitreous as an abscess or fluff ball with vitreous haze, it is then referred to as Candida endophthalmitis.3,20 Because such fluff ball lesions are rare, a fully developed retinal 3-dimensional process extending into the vitreous cavity can be considered diagnostic of fungal endophthalmitis.3 In many cases, a dilated fundus examination showing such a lesion may be the first diagnostic sign of systemic candidiasis.21 The endogenous organism reaches the eye via the bloodstream. It initiates contact with the choroid, then proceeds to penetrate through Bruch’s membrane to form subretinal abscesses, soon spreading to the retina.7,8 As described by Tanaka et al.,22 this is considered the first stage of EFE, when the fungal infiltrate is limited to the retina. In the second stage, the fungal intruder can then migrate forward and bud into the vitreous cavity forming vitreous abscesses. The third stage includes an inflammatory reaction surrounding the abscess leading to a vitritis as well as an iridocyclitis. It is rare for the ciliary body or iris to become inflamed.7 The fourth stage occurs in advanced cases when the resulting fibrotic scar from the resolved abscess induces vitreoretinal traction, leading to a potential retinal detachment. According to Edwards et al.,3 78% of patients with autopsy-proven disseminated candidiasis had retinal involvement. Because Candida has such a high predilection for ocular tissue, it is suggested that all patients with candidiasis have repeated dilated fundus examinations weekly until resolution of the systemic infection.7 Once systemic treatment is initiated with an antifungal (e.g., fluconazole or amphotericin B), patients have a lower risk of developing serious ocular infections.7

Diagnosis Diagnosis of EFE often is difficult and limited to clinical findings. Cultured fungus from the vitreous confirms the diagnosis but is rare because the organism often is confined to the retina and abscess. Generally, only inflammatory cells are found in the vitreous itself. Blood and urine cultures may also confirm the diagnosis when the infection is known to be endogenous. However, because of the prolonged culture time, slow growing or fastidious fungal organisms are often undetected.20,23 Less than 50% of patients with autopsy-proven candidiasis showed positive blood cultures in retrospective studies.24 In 2003, Binder et al.5 showed that, aside from blood and eye specimen cultures, half of patients showed an additional systemic infection, most frequently a urinary tract infection. Overall, about 18% of EFE involving Candida appear to be associated with detectable retinal or vitreal lesions.3 Because the organism itself is not always isolated and cultured from the eye or other sources, many diagnoses of Candida EFE can be made based primarily on clinical observations.7,13-15,23,25 Although our patient presented with nega-

457 tive blood cultures for Candida albicans, a positive urine culture for the organism, presenting simultaneously with the distinct ocular features that characterize Candida endophthalmitis, was diagnostic for a blood-borne infection. Because the distinct ocular presentation of the fungal infection itself can be diagnostic, it is generally agreed to commence antifungal treatment immediately, regardless of diagnostic confirmation by culture.

Treatment and prognosis Fungal infections of the retina and choroid are among the most visually devastating of all ocular disorders. Early treatment, while the organism is limited to the choroid or retina, is more likely to result in better visual outcome.26 All cases of fungal endophthalmitis, regardless of species, must be treated promptly and appropriately to prevent severe infection and inflammation. Treatment generally is the same regardless of the causative organism. A complete failure to treat will ultimately result in blindness. Historically, intravenous administration of amphotericin B has been the drug of choice for the treatment of endogenous fungal infections.27 More recently, because of the side effects and systemic toxicity associated with IV amphotericin B, oral fluconazole (a second-generation azole compound) has gained popularity in the treatment of the disease.13,27-29 Systemically administered amphotericin B penetrates poorly into the vitreous, is associated with decreased renal function, and 80% of patients treated with it develop azotemia.7 Fluconazole, on the other hand, is tolerated well, has a longer half-life, has good intraocular and vitreous penetration, and has no reported ocular toxicity.27,30-33 The drug can also be found in measurable concentrations in the choroidal, retinal, and corneal tissues.27 Studies show little difference between the effectiveness of IV amphotericin B and fluconazole in treating EFE.29 Newer antifungal agents, such as voriconazole (a secondgeneration synthetic derivative of fluconazole) and caspofungin (an antifungal cell wall synthesis inhibitor), are currently being investigated and may be effective alternatives to the more popular fungal agents.30 When systemic Candida is detected by blood culture (candidemia), administration of either IV amphotericin B or oral fluconazole is recommended to prevent ocular infection. Patients who receive prompt systemic treatment have a much lower rate of the development of vitreal extension of any retinal infection that has already developed.20,34 In more recent years, early prophylactic treatment of confirmed systemic candidemia has proven to significantly decrease the prevalence of EFE.7 Results of rabbit studies suggest that administration of antifungal drugs in the early phase of the Candida endophthalmitis can inhibit the development of the infection, but in the late phases the drugs are ineffective.28 Fluconazole can kill Candida spores in the blood, but is not effective enough against the spores existing

458 outside vessels or inside granulomatous inflamed lesions, despite good penetration into ocular tissue.28 This suggests that, in our specific patient, the oral fluconazole administered may not have significantly contributed to the resolution of the granulomatous fluff ball as much as the intravitreal injection of amphotericin B. However, because two thirds of patients generally have bilateral involvement, it may have aided in preventing spread to the fellow eye. Fluconazole is thought to be less effective if treatment is delayed and more than a week of progression has already occurred.27 If ocular involvement progresses despite systemic treatment, surgical intervention is recommended. A vitrectomy with the injection of intravitreous amphotericin B may help prevent further visual loss. A vitrectomy is useful if the disease extends beyond the retina. Vitrectomy helps reduce the formation of epiretinal membranes and vitreoretinal traction after resolution of the lesion. It also allows for better diffusion of intravitreal-administered amphotericin B. It must be noted, however, that amphotericin B may be toxic to retinal tissue and may cause retinal necrosis if administered too close to the retina.35 Once healed, the vitreoretinal abscess will resolve, and a hypopigmented scar with well-demarcated borders will remain. Lesions that are confined to the retina may result in a translucent gliotic scar without pigmentary changes.36 With extensive vitreal involvement, fibrosis of the retina can occur, resulting in retinal traction and potentially leading to choroidal neovascularization and exudative retinal detachment.36 Hence, patients should be followed-up with care regardless of apparent resolution of fungal endophthalmitis. Prognosis and final visual outcome depend on the virulence of the organism, the extent of the ocular involvement, and the timing and mode of intervention. A delay in the initiation of treatment results in a prolonged resolution period of the fungal infection leading to potential epiretinal membrane and scar formation. In general, most patients do not regain useful vision.5

Conclusion EFE is a rare and potentially visually devastating intraocular infection that can be misdiagnosed easily in the absence of a dilated fundus examination. In patients with a definitive systemic Candida infection, or those with predisposing risk factors, weekly dilated fundus examinations are essential because of Candida’s high predilection for ocular tissue. Because prognosis for visual outcome is dependent on immediate treatment, oral antifungal drugs may be initiated based on clinical presentation alone, even in the absence of a confirmed diagnosis. In more severe cases, when posterior segment findings worsen despite systemic treatment, a vitrectomy with the injection of antifungal agents may be indicated.

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References 1. Leibovitch I, Lai T, Grant R, et al. Endogenous endophthalmitis: a 13-year review at a tertiary hospital in South Australia. Scand J Infect Dis 2005;37(3):184-9. 2. Schiedler V, Scott IU, Flynn HW, et al. Culture-proven endogenous endophthalmitis: clinical features and visual acuity outcomes. Am J Ophthalmol 2004;137:725-31. 3. Rodriguez-Adrian LJ, King RT, Tamayo-Derat LG, et al. Retinal lesions as clues to disseminated bacterial and candidal infections: frequency, natural history, and etiology. Medicine 2003;82:187-202. 4. Edwards JE Jr, Foos RY, Montgomerie JZ, et al. Ocular manifestations of Candida septicemia: review of seventy-six cases of hematogenous Candida endophthalmitis. Medicine (Baltimore) 1974;53:47-75. 5. Binder MT, Chua J, Kaiser PK, et al. Endogenous endophthalmitis: An 18-year review of culture-positive cases at a tertiary care center. Medicine 2003;82:97-105. 6. Jackson TL, Bykyn SJ, Graham EM, et al. Endogenous bacterial endophthalmitis: a 17-year prospective series and review of 267 reported cases. Surv Ophthalmol 2003;48:403-23. 7. Holland G. Endogenous fungal infection of the retina and choroid. In: Ryan SJ, ed. Retina, 4th ed. St. Louis: Mosby; 2005:1683-98. 8. Samiy N, D’Amico DJ. Endogenous fungal endophthalmitis. Int Ophthalmol Clin 1996;36(3):147-62. 9. Pepose JS, Holland GN, Nestor MS, et al. Acquired immunodeficiency syndrome: pathogenic mechanisms of ocular disease. Ophthalmology 1985;92:472-84. 10. Griffin JR, Petit TH, Fishman LS, et al. Blood-borne Candida endophthalmitis: a clinical and pathologic study of 21 cases. Arch Ophthalmol 1973;89:450-6. 11. Okada AA, Johnson RP, Liles WC, et al. Endogenous bacterial endophthalmitis: report of a 10-year retrospective study. Ophthalmology 1994;101:832-38. 12. Bouza E, Cobo-Soriano R, Rodriguez-Creixems M, et al. A prospective search for ocular lesions in hospitalized patients with significant bacteremia. Clin Infect Dis 2000;30:306-12. 13. Christmas N, Smiddy W. Vitrectomy and systemic fluconazole for treatment of endogenous fungal endophthalmitis. Ophthalmic Surg Lasers 1996;27:1012-8. 14. Brooks RG. Prospective study of Candida endophthalmitis in hospitalized patients with candidemia. Arch Intern Med 1989;149:2226-28. 15. Henderson DK, Edwards JEJ, Montgomerie JZ. Hematogenous Candida endophthalmitis in patients receiving parenteral hyperalimentation fluids. J Infect Dis 1981;143:655-61. 16. Parke DW II, Jones DB, Gentry LO. Endogenous endophthalmitis among patients with candidemia. Ophthalmol 1982;89:789-95. 17. Fujita NK, Henderson DK, Hockey LJ, et al. Comparative ocular pathogenicity of Cryptococcus neoformans, Candida glabrata, and Aspergillus fumigatus in the rabbit. Invest Ophthalmol Vis Sci 1982; 22:410-4. 18. Goldstein BG, Buettner H. Histoplasmic endophthalmitis: a clinicopathologic correlation. Arch Ophthalmol 1983;101:774-7. 19. Menezes AV, Sigesmund DA, Demajo WA, et al. Mortality of hospitalized patients with Candida endophthalmitis. Arch Intern Med 1994; 154:2093-7. 20. Donahue SP, Greven CM, Zuravless JJ, et al. Intraocular candidiasis in patients with candidemia: clinical implications derived from a prospective multicenter study. Ophthalmol 1994;101:1302-9. 21. Deutsch D, Adler S, Teller J, et al. Endogenous candidal endophthalmitis. Ann Ophthalmol 1989;21:260-8. 22. Tanaka M, Kobayashi Y, Takebayashi H, Kiyokawa M. Analysis of predisposing clinical and laboratory findings for the development of endogenous fungal endophthalmitis. Retina 2001;21:203-9. 23. Schulman JA, Peyman G, Fiscella R, et al. Toxicity of intravitreal injection of fluconazole in the rabbit. Can J Ophthalmol 1987;22: 304-6.

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24. Rodriguez LJ, Anaissie EJ, Rex JH. Pneumonia due to Candida species. In: Sarosi GA, Davies SF, eds. Fungal disease of the lung, ed 3. Philadelphia: Lippincott Williams & Wilkins; 2000:115-22. 25. Fishman LS, Griffin JR, Sapico FL, et al. Hematogenous Candida endophthalmitis—a complication of candidemia. N Engl J Med 1972; 286:675-81. 26. Breit SM, Hariprasad SM, Mieler WF, et al. Management of endogenous fungal endophthalmitis with voriconazole and caspofungin. Am J Ophthalmol 2005;139:135-40. 27. Perfect JR. Fluconazole therapy for experimental cryptococcosis and candidiasis in the rabbit. Rev Infect Dis 1990;12(3):S299-S301. 28. Isobe Y, Hatano H. Study of suppressive effect of intravenous fluconazole on endogenous Candida endophthalmitis in rabbits. Jpn J Ophthalmol 1992;36:23-7. 29. Kou H, Lin J, Chang K. Clinicopathological report of Candida granuloma from an endogenous candidal endophthalmitis. Chang Gund Med J 2001;24:460-3.

459 30. Debryne D, Rychelynck J. Pharmacokinetics of fluconazole. Clin Pharmacokinet 1993;24:10-27. 31. Mochizuki K, Yamashita Y, Torisaki T, et al. Intraocular penetration and effect on the retina of fluconazole. Lens Eye Tox Res 1992;9:537-46. 32. O’Day DM, Foulds G, Williams TE, et al. Ocular uptake of fluconazole following oral administration. Arch Ophthalmol 1990;108:1006-8. 33. Savani DV, Perfect JF, Cobo LM, et al. Penetration of new azole compounds into the eye and efficacy in experimental Candida endophthalmitis. Antimicrob Agents Chemother 1987;31:6-10. 34. Barza M. Editorial response: Treatment options for Candida endophthalmitis. Clin Infect Dis 1998;27:1134-6. 35. Axelrod AJ, Peyman GA, Apple DJ. Toxicity of intravitreal injection of amphotericin B. Am J Ophthalmol 1973;76:578-83. 36. Brod RD, Clarkson JG, Flynn HW, et al. Endogenous fungal endophthalmitis. In: Tasman W, Jaeger E, eds. Duane’s clinical ophthalmology. Philadelphia: Lippincott Co Inc; 1994:1-39.