From the Divisions of Ophthalmology (NAS, RUD, CJS) and Infectious Disease (EKC), Maimonides Medical Center, Brooklyn, New York.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Norman A. Saffra, MD, Division of Ophthalmology, Maimonides Medical Center, 902 49th Street, Brooklyn, NY 11219. E-mail: firstname.lastname@example.org
Endogenous fungal endophthalmitis (EFE), a severe intraocular infection that can occur as a result of transient or persistent fungemia, is an uncommon entity. It typically occurs in patients with implanted prosthetic devices, intravascular catheters, neoplasms, diabetes mellitus, intravenous drug use, and immunodeficiency.1 Infection of the globe via the hematogenous route can have devastating visual effects.
The management of EFE is challenging because both local and systemic therapy are frequently needed.2 Although randomized studies have established a standard of care for acute postoperative endophthalmitis,3 the clinical variation and relative infrequency of EFE precludes the initiation of a prospective study to establish precise guidelines for its treatment.
We present an unusual case of EFE in a patient with an implanted prosthetic device in which the patient died due to the systemic complications of fungal infection, despite improvement in visual acuity. Although the literature provides guidance to the ophthalmologist for the management of endogenous bacterial endophthalmitis after cardiac surgery,4–6 there is no such guidance available regarding EFE.
A 74-year-old man with a history of emphysema and hypertension underwent a double coronary artery bypass graft with a bioprosthetic pericardial valve and transvenous dual chamber pacemaker. The postoperative course was complicated by a sternal wound infection due to methicillin-resistant Staphylococcus aureus (MRSA) and treated with levofloxacin and vancomycin. Cultures of blood, sputum, stool, and urine were negative. The patient was discharged on the 14th hospital day.
Four months postoperatively, the patient presented with blurred vision in the right eye of indeterminate duration. The patient was afebrile and hemodynamically stable, with visual acuity reduced to counting fingers at a 3-foot distance and significant vitritis. Three blood cultures were negative and trans-thoracic echocardiogram (TTE) did not identify any intracardiac vegetations. A presumptive diagnosis of endogenous bacterial endophthalmitis, related to the previous MRSA wound infection, was made. A trans-esophageal echocardiogram was not performed because it was thought to be redundant in light of the negative blood cultures and TTE results.
A therapeutic and diagnostic pars plana vitrectomy with intravitreal injections of 1 mg of vancomycin and 2.25 mg of ceftazidime was performed emergently. Five days later, intravitreal cultures grew Aspergillus fumigatus. Infectious disease and cardiology consultations were immediately obtained and therapy was modified to include repeat vitrectomy with an intravitreal injection of 5 mcg of amphotericin B, followed by 0.15% amphotericin B eye drops 4 times daily and 200 mg of oral itraconazole daily (because voriconazole was not yet available). Visual acuity improved after 1 week to 20/200.
Two weeks later, the patient presented to the hospital with diffuse weakness and dyspnea and was admitted to the intensive care unit in septic shock. He was treated empirically with intravenous vancomycin, imipenem/cilastatin, amphotericin B, and itraconazole. Blood cultures did not demonstrate any growth of organisms and a repeat TTE demonstrated a vegetation at the end of the pacemaker wire. The patient’s clinical situation precluded performance of a transesophageal echocardiogram at this time. Consultations from infectious disease and thoracic surgery concurred with a diagnosis of fungal endocarditis. Despite medical therapy, the patient’s condition worsened and he died on the 27th hospital day.
Although EFE is rare, its appearance raises concern in any patient with a history of thoracic surgery because up to 80% of non-immunosuppressed patients with Aspergillus fungal endophthalmitis have a history of intrathoracic surgery.1 EFE can arise from vegetations on pacemaker wires and prosthetic valves that were implanted up to 2 years previously.4–6 Hence, a high degree of clinical suspicion should be directed toward the cardiac implants of patients with EFE, especially because cultures and imaging are not completely reliable.
Although treatment guidelines are available for acute postoperative endophthalmitis, none exist for EFE. Treatment of EFE can be challenging, requiring a systemic antifungal medication of the azole class, and local therapy. Although voriconazole is the current systemic antifungal treatment of choice for Aspergillus,7 at the time of our patient’s presentation itraconazole was the only oral agent effective for the treatment of aspergillosis.
Voriconazole is available in oral and intravenous forms and can be started with an initial loading dose of 6 mg/kg intravenously for two doses, followed by 200 mg orally every 12 hours.8 After two doses, the mean vitreous concentration of voriconazole reaches 1.12 to 2.13 mg/mL, exceeding the minimum inhibitory concentration for 90% of a broad range of yeast and mold isolates.9 Its mechanism of action is inhibition of the fungal cytochrome P-450 pathway, which interferes with the synthesis of ergosterol, a necessary component of the fungal cytoplasmic membrane. Itraconazole, which works through a similar mechanism, is also available in oral and intravenous forms. It can be started with an initial loading dose of 200 mg orally three times per day for 3 days, followed by 400 mg per day. The intravenous solution is given at 200 mg every 12 hours for four doses for 2 days and then at 200 mg/day.10 Following an 80 mg/kg oral dose, the mean vitreous concentration of itraconazole has been shown to reach 0.22 mcg/mL.11 Regardless of itraconazole use, however, it is unlikely that different therapy would have impacted the outcome in this case because infected thoracic hardware was the nidus of the infection.
Pars plana vitrectomy has the highest potential of salvaging the patient’s vision by removing inflammatory debris, providing a specimen for culture, and enabling the administration of an additional intravitreal voriconazole.12 Vitreous culture can confirm a fungal etiology because its yield is 89% compared to the 33% yield of blood cultures in such patients.13 When frequent blood cultures repeatedly return negative, it suggests that the vitreous has been seeded from transient fungemia. However, the presence of vitritis does not necessarily suggest the presence of underlying endocarditis. In an earlier case series, although 15 of 26 patients with fungal endophthalmitis had cardiac involvement, none had endocarditis.14
Even if the probability of endocarditis is low, it is still recommended that a TTE always be performed in patients with prosthetic heart valves.15 In patients presenting with fungal endophthalmitis, a trans-esophageal echocardiogram should be performed even if the TTE, which is only 32% sensitive, does not show vegetations.16 Moreover, even with negative blood cultures and trans-esophageal echocardiogram, such patients should still be closely monitored because up to 15% of cases of infective endocarditis may be missed by trans-esophageal echocardiogram.16 A repeat trans-esophageal echocardiogram may be performed after 7 to 10 days if a high index of clinical suspicion remains.17 An earlier report in the literature described a patient with bilateral endophthalmitis who had an initially negative transesophageal echocardiogram who presented 3 weeks later with cardiopulmonary decompensation secondary to an aortic root abscess.18
Fungal infections of prosthetic valves or pacemakers are associated with a dire prognosis without surgical debridement or explantation of the hardware.19 As illustrated by this study, although local and systemic medical therapies were able to preserve the patient’s vision, these modalities were insufficient for the prevention of systemic morbidity and mortality. The management of EFE in patients with a history of thoracic surgery requires a high index of clinical suspicion for infective endocarditis and should be treated accordingly with both aggressive medical and surgical intervention.
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- Weishaar PD, Flynn HW Jr, Murray TG, et al. Endogenous aspergillus endophthalmitis: clinical features and treatment outcomes. Ophthalmology. 1998:105:57–65. doi:10.1016/S0161-6420(98)71225-3 [CrossRef]
- Endophthalmitis Vitrectomy Study Group. Results of the endophthalmitis vitrectomy study: a randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Arch Ophthalmol. 1995;113:1479–1496.
- Nahata SK, Saffra NA, Genovesi MH, et al. Endogenous endophthalmitis resulting from sternal wound infection after coronary artery bypass grafting. J Thorac Cardiovasc Surg. 1998;116:176–177.
- Arcieri ES, Jorge EF, de Abrea Ferreira L, et al. Bilateral endogenous endophthalmitis associated with infective endocarditis: case report. Braz J Infect Dis. 2001;5:356–359. doi:10.1590/S1413-86702001000600011 [CrossRef]
- Shmuely H, Kremer I, Sagie A, Pitlik S. Candida tropicalis multifocal endophthalmitis as the only initial manifestation of pacemaker endocarditis. Am J Ophthalmol. 1997;123:559–560.
- Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46:327–360. doi:10.1086/525258 [CrossRef]
- Hariprasad SM, Mieler WF, Holz ER, et al. Determination of vitreous, aqueous, and plasma concentration of orally administered voriconazole in humans. Arch Ophthalmol. 2004;122:42–47. doi:10.1001/archopht.122.1.42 [CrossRef]
- Hariprasad SM, Mieler WF, Lin TK, et al. Voriconazole in the treatment of fungal eye infections: a review of current literature. Br J Ophthalmol. 2008;92;871–878. doi:10.1136/bjo.2007.136515 [CrossRef]
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- Savani DV, Perfect JR, Cobo LM, Durack DT. Penetration of new azole compounds into the eye and efficacy in experimental Candida endophthalmitis. Antimicrob Agents Chemother. 1987;31:6–10.
- Rex JH, Stevens DA. Systemic antifungal agents. In: Mandell GL, Bennett JE, Dolan R, eds. Mandell, Douglas and Bennett’s Principles and Practice of Infectious Diseases, 7th ed. Maryland Heights, MO: Churchill Livingstone Elsevier; 2010:555–558.
- Binder MI, Chua J, Kaiser PK, et al. Endogenous endophthalmitis: an 18-year review of culture-positive cases at a tertiary care center. Medicine (Baltimore). 2003;82:97–105. doi:10.1097/00005792-200303000-00004 [CrossRef]
- 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. doi:10.1097/00005792-197401000-00002 [CrossRef]
- Edwards JE Jr, Foos RY, Montgomerie JZ, Guze LB. Diagnostic value of echocardiography in suspected endocarditis: an evaluation based on the pretest probability of disease. Circulation. 1996;93:730–736.
- Fowler VG, Durack DT. Infective endocarditis. Curr Opin Cardiol. 1994;9:389–400. doi:10.1097/00001573-199405000-00018 [CrossRef]
- Ansari A, Rigolin VH. Infective endocarditis: an update on the role of echocardiography. Curr Cardiol Rep. 2010;12:265–271. doi:10.1007/s11886-010-0107-8 [CrossRef]
- Park P, Khawly JA, Kearney DL, et al. Bilateral endogenous endophthalmitis secondary to endocarditis with negative transesophageal echocardiogram. Am J Ophthalmol. 2004;138:151–153. doi:10.1016/j.ajo.2004.02.013 [CrossRef]
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