Voriconazole for Candida Endophthalmitis

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1 SANJEEWA S. WICKREMASINGHE, FRCOOPHTH, FRANZCO, 1 SUKHPAL S. SANDHU, MD, FRCOPHTH, 1 LUCY BUSIJA, PHD, 1 JONATHAN LIM, BMEDSCI, MBBS, 1 DEVINDER S. CHAUHAN, MD, FRCOPHTH, FRANZCO, 2 ROBYN H. GUYMER, PHD, FRANZCO 1 1 Department of Medical Retina, Centre for Eye Research Australia, University of Melbourne, Royal Victorian Eye, East Melbourne, Melbourne, Australia; 2 Eastern Retinal Service, Victoria, Australia Ophthalmology Volume 119, Number 11, November 2012 References 1. Lim J, Wickremasinghe SS, Xie J, et al. Delay to treatment and visual outcomes in patients treated with anti-vascular endothelial growth factor for age-related macular degeneration. Am J Ophthalmol 2012;153: Lux A, Llacer H, Heussen FM, Joussen AM. Non-responders to bevacizumab (Avastin) therapy of choroidal neovascular lesions. Br J Ophthalmol 2007;91: Teper SJ, Nowinska A, Pilat J, et al. Involvement of genetic factors in the response to a variable-dosing ranibizumab treatment regimen for age-related macular degeneration. Mol Vis 2010;16: Holz FG, Amoaku W, Donate J, et al. Safety and efficacy of a flexible dosing regimen of ranibizumab in neovascular age-related macular degeneration: the SUSTAIN study. Ophthalmology 2011;118: Fleckenstein M, Charbel Issa P, Helb HM, et al. High-resolution spectral domain-oct imaging in geographic atrophy associated with age-related macular degeneration. Invest Ophthalmol Vis Sci 2008;49: Financial Disclosures: This project was funded by National Health and Medical Research Council (NHMRC) project grant The Centre for Eye Research Australia (CERA) receives Operational Infrastructure Support from the Victorian Government. Voriconazole for Candida Endophthalmitis Dear Editor: Endogenous fungal endophthalmitis is a serious sight-threatening complication of systemic fungemia. Infectious Diseases Society of America (IDSA) guidelines for the management of endogenous Candida endophthalmitis recommend intravenous amphotericin-b and oral flucytosine, possibly with vitrectomy. 1,2 Recently, there have been reports of using intravitreal voriconazole injection as a treatment option in fungal endophthalmitis, including Aspergillus, Fusarium, Scedosporium, and Candida. To the best of our knowledge, the following is the first reported case of combined multiple voriconazole injection and systemic medication in a patient with bilateral endogenous Candida endophthalmitis. We searched PubMed, MEDLINE, and Google Scholar in March 2012 for key words including bilateral endogenous fungal endophthalmitis, Candida endophthalmitis, drug-resistant fungal endophthalmitis, and multiple intravitreal voriconazole injection (all languages without dates restriction), which showed no prior reports of bilateral Candida endophthalmitis successfully treated with multiple intravitreal voriconazole injections combined with systemic medication. A 69-year-old man with diabetic mellitus, was referred to our emergency room due to pain and blurring vision in both eyes for 2 weeks. He had undergone right percutaneous nephrolithotomy 1 month ago at another hospital, complicated with subsequent Candida urosepsis. Urine culture showed Candida albicans. Then days later, he undergone cholecystectomy due to cholecystitis, but further blood culture revealed Candida albicans. Following this, intravenous fluconazole was prescribed for 9 days. Fundus examination revealed multifocal yellow-white lesions with fluffy borders, severe vitritis with string-of-pearls signs in both eyes, compatible with the diagnosis of Candida endophthalmitis (Fig 1A B; available at Visual acuity was counting fingers only in both eyes. There was anterior chamber flare and cells. Optical coherence tomography (OCT) showed multiple chorioretinal lesions with marked retinal thickening, protrusion, and poor macular contour (Fig 2A B; available at In addition to systemic therapy with amphotericin-b and flucytosine, the patient was treated with intravitreal voriconazole injection (100 g/0.1 ml) immediately, again at the time of vitrectomy in both eyes 3 days later after systemic condition stabilized, and further weekly intravitreal injection. After 6 weeks of treatment, retinal lesions showed regression, and visual acuity improved from counting fingers to 1/60 in right eye and 6/60 in left eye. Fundus examination (Fig 3A B available at and OCT (Fig 4A B; available at 4 months after treatment demonstrated significant improvement of the endophthalmitis with resolution of candida chorioretinitis and subretinal chorioretinal scarring. Later cultures of blood, urine, and vitreous were negative for fungus growth. Latest ocular examination reported stable visual acuity. Voriconazole, a promising broad-spectrum triazole agent, solves difficult cases as failure in first-line treatment or drug-resistant fungus. For vision-threatening macular involvement, intravitreal voriconazole injection is an effective way for rapid achievement of therapeutic concentration with minimal systemic side effect. Instead of single injection, the current case was treated with multiple injections during the treatment course. In a study regarding the clearance profile of intravitreal voriconazole, injecting 35 g/0.1 ml into vitreous cavity of rabbit yielded a fast decline of concentration, with half-life of 2.5 hours and rapid decay within 24 hours after injection. 3 The authors suggest that supplementation of intraocular voriconazole to maintain therapeutic levels might be required. 3 An in vitro safety study claimed that concentrations 250 g/ml of voriconazole had no influence neither on human retinal pigmented epithelium nor on optic nerve head astrocytes cell proliferation and cell viability. 4 In our case, the estimated concentration after injecting voriconazole 100 g/0.1 ml into vitreous cavity (which became 2.5 g/ml in a 4 ml-volume vitreous cavity) doesn t exceed the safety range. 2414

2 Several reasons support the necessity of adjunctive multiple intravitreal voriconazole injections in current case. First, it was a bilateral, severe multifocal candida endophthalmitis with macular involvement. Visual acuity was only counting fingers. Second, our patient had received prior systemic fluconazole treatment, but Candida still spread hematogenously to choroid and retina. It indicates a fluconazoleresistant Candida spp. Third, diagnosis was delayed for 2 weeks. It is important to deliver an effective antifungal agent as voriconazole into the vitreous cavity as soon as possible, and maintain its concentration by repeated injections. Our patient was successfully cured with adjunctive multiple voriconazole injections. There are several factors influencing the final visual outcome in our case. Early vitrectomy is associated with decreased incidence of developing retinal detachment. Poor initial visual acuity and centrally located lesions are risks of final visual loss. 5 Timing of initiating treatment is another factor. The earlier the intervention, the better outcome it may produce. Finally, after the inflammatory process in choroid and retina, the chorioretinal scar and reactive epiretinal membrane at the fovea may further decrease final visual acuity. In summary, multiple intravitreal voriconazole injection is not only a safe and effective therapy for fluconazole-resistant bilateral endogenous Candida endophthalmitis, but also an immediate way to achieve intraocular therapeutic concentration. By way of this promising regimen, satisfactory disease control and visual improvement were achieved in current case. YU-FAN CHANG, MD, 1,2 CHANG-SUE YANG, MD, MHA, 1,2,3 FENQ-LIH LEE, MD, 1,2 SHUI-MEI LEE, MD 1,2 1 School of Medicine, National Yang-Ming University; 2 Department of Ophthalmology, Taipei Veterans General Hospital; 3 Department of Ophthalmology, Taipei Medical University, Taipei, Taiwan, Republic of China. References Letters to the Editor 1. Pappas PG, Kauffman CA, Andes D, et al. Clinical practice guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;48: Riddell JT, Comer GM, Kauffman CA. Treatment of endogenous fungal endophthalmitis: focus on new antifungal agents. Clin Infect Dis 2011;52: Shen YC, Wang MY, Wang CY, et al. Clearance of intravitreal voriconazole. Invest Ophthalmol Vis Sci 2007;48: Kernt M, Neubauer AS, De Kaspar HM, Kampik A. Intravitreal voriconazole: in vitro safety-profile for fungal endophthalmitis. Retina 2009;29: Sallam A, Taylor SR, Khan A, et al. Factors determining visual outcome in endogenous Candida endophthalmitis. Retina 2012;32: General Correspondence Surgeon Cataract Volume and Endophthalmitis Dear Editor: In an effort to study a relatively uncommon disease endophthalmitis after cataract surgery Keay et al 1 have evaluated a Medicare dataset of unprecedented size, and have identified several risk factors for the development of this preventable infection. One important risk factor identified in the study relates to surgeon volume. The investigators found that the endophthalmitis rate for the highest volume surgeons was 4-fold lower than that of the lowest volume surgeons. Because this study is derived from administrative data, the authors acknowledge that they were unable to measure the effect of specific practice patterns (e.g., the use prophylactic antibiotics) that may influence the development of endophthalmitis. However, there is indirect evidence that may help to explain this important finding of the current study. In correspondence after the publication of an American Society of Cataract and Refractive Surgery (ASCRS) survey regarding the use of antibiotics to prevent endophthalmitis, 2 Chang reported that the routine use of prophylactic intracameral antibiotics correlated in a linear fashion with surgeon volume, even prior to the publication of the European Society of Cataract and Refractive Surgeons prospective study on endophthalmitis prevention. 3 Specifically, whereas only 16% of low-volume surgeons ( 100 cases/year) reported using intracameral antibiotics for endophthalmitis prophylaxis, 45% of high-volume surgeons ( 500 cases/year) reported using intracameral antibiotics in the ASCRS survey. Although other factors could explain the observation of relatively low rates of endophthalmitis among the highest volume surgeons, this information suggests that the highest volume surgeons have been using different strategies for endophthalmitis prophylaxis, strategies that some had espoused even before the European Society of Cataract and Refractive Surgeons randomized, prospective trial. 4,5 AYMAN NASERI, MD Department of Ophthalmology, University of California, San Francisco, California References 1. Keay L, Gower EW, Cassard SD, et al. Postcataract surgery endophthalmitis in the United States. Analysis of the complete 2003 to 2004 Medicare Database of Cataract Surgeries Ophthalmology 2012;119: Naseri A, Lietman T. Results of the 2007 ASCRS survey. J Cataract Refract Surg 2008;34: ESCRS Endophthalmitis Study Group. Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors. J Cataract Refract Surg 2007;33: Gimbel HV, Sun R. Prophylactic intracameral vancomycin and CME [letter]. Ophthalmology 2000;107: Arshinoff SA, Strube YNJ, Yagev R. Simultaneous bilateral cataract surgery. J Cataract Refract Surg 2003;29:

3 Ophthalmology Volume 119, Number 11, November 2012 Figure 1. Fundus examination in acute phase showed multiple chorioretinitis foci with fluffy margin and dot hemorrhage at the macula in (A) right eye and (B) left eye e1

4 Letters to the Editor Figure 2. Optical coherence tomography (OCT) showed multiple chorioretinal lesions with marked retinal thickening, protrusion, and disorganized macular contour in (A) right eye and (B) left eye e2

5 Ophthalmology Volume 119, Number 11, November 2012 Figure 3. Fundus examination at 4-month follow-up showed the resolution of previous chorioretinitis with (both A and B) chorioretinal scarring formation, and (A) epiretinal membrane e3

6 Letters to the Editor Figure 4. Optical coherence tomography (OCT) examination at 4-month followed-up showed the subretinal chorioretinal scarring and epiretinal membrane formation in (A) the right eye, and recovered macular contour in (B) the left eye e4

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