Int Ophthalmol (2014) 34:945–950 DOI 10.1007/s10792-013-9880-x
CASE REPORT
Third case of Candida dubliniensis endogenous endophthalmitis in North America: case report and review of the literature Elizabeth Rosenberger • Dima A. Youssef • Sara Safdar • Cristoforo R. Larzo • James Myers
Received: 9 August 2013 / Accepted: 31 October 2013 / Published online: 14 November 2013 Ó Springer Science+Business Media Dordrecht 2013
Abstract There are two previous reports of Candida dubliniensis endophthalmitis in North America. Here, we report a third case of C. dubliniensis endogenous endophthalmitis in a 31-year-old male patient who complained of left-sided decreased visual acuity. He had an associated mitral and tricuspid valve endocarditis, in the setting of intravenous drug use. Blood and sputum cultures were positive for C. dubliniensis. Fundoscopic examination was consistent with a fungal endophthalmitis. He was treated with fluconazole followed by intravenous liposomal amphotericin B for 6 weeks. C. dubliniensis is an important but rare cause of endophthalmitis in intravenous drug abusers. Keywords Candida dubliniensis Endophthalmitis Endocarditis Visual acuity Intravenous drug use
E. Rosenberger James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA D. A. Youssef (&) S. Safdar J. Myers Division of Infectious Diseases, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, P.O. Box 70622, VAMC Bldg. 1, Dogwood Ave., Johnson City, TN 37614, USA e-mail: [email protected] C. R. Larzo Southeastern Retina Associates, 100 Med Tech Parkway, Suite 140, Johnson City, TN 37604, USA
Case report A 31-year-old intravenous drug user known to have hepatitis C presented to the Emergency Department with an altered mental status, and left-sided hemiplegia. He had recently finished a 6-week course of antibiotic therapy for methicillin-sensitive staphylococcus aureus (MSSA) tricuspid and mitral valve infective endocarditis. His examination revealed a temperature of 100.7 °F, with an associated tachycardia, and tachypnea. The patient’s blood pressure was 103/61 mmHg; he had bilateral crackles on lung examination, and a systolic ejection murmur over the mitral valve area. He was obtunded, but followed simple commands. He was noted to be hemiplegic on the left side with a left facial droop, and left-sided tongue deviation. He had grossly normal extraocular movements, and his motor power on the right upper and lower extremity was 4/5. The patient had left-sided upper and lower extremity flaccidity, and a motor power of 0/5. Laboratory studies revealed a white blood count of 9,000 cells/mm3 (87 % neutrophils), with hemoglobin of 8.8 g/dl, and a platelet count of 216,000. Magnetic resonance imaging of the head revealed a subacute right middle cerebral artery territory infarction, as well as many other punctate bilateral supra and infratentorial infarctions, compatible with an embolic process. There was also an intraparenchymal hemorrhage at the posterior superior right frontal lobe with moderate surrounding vasogenic edema.
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His blood and sputum cultures grew Candida dubliniensis that was identified using CHROMagar Candida [1]. A subsequent transesophageal echocardiogram showed a moderate to severe mitral valve regurgitation, and a severe tricuspid regurgitation. He had mitral valve vegetation measuring 1.490.49 cm, and a tricuspid valve vegetation measuring 2.991.82cm. These measurements were larger than the previously recorded values when he suffered MSSA infective endocarditis. He was complaining of decreased left-sided visual acuity. Ophthalmological examination revealed right and left eye acuity of 20/30 and 20/400, respectively. His intraocular pressures were normal at 10 and 6 in the right and left eyes, respectively. The right eye anterior segment was normal, but the left eye anterior segment showed corneal endothelial keratic precipitates and posterior synechiae at 3 o’clock. His left vitreous had a 2? (moderate) vitritis. The fundus photograph from this date shows no view due to the scarred down pupil and vitritis in the left eye. The right eye examination showed no signs of infiltrate (Fig. 1). There was no diagnostic ophthalmic intervention undertaken at this time due to his known diagnosis of C. dubliniensis fungemia. The C. dubliniensis isolate had a minimal inhibitory concentration (MIC) of \0.12 compared to fluconazole and 0.5 compared to amphotericin B. Table 1 shows the different yeast MICs tested for this Candida isolate. The patient was started on oral fluconazole 800 mg daily (8 mg/kg oral daily), but he developed a torsade de pointes and ventricular fibrillation 18 days
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after starting fluconazole. He was switched to liposomal amphotericin B. He later underwent mitral valve and tricuspid valve replacement, with placement of an epicardial right ventricular pacemaker lead. He finished a 6-week course of fluconazole and liposomal amphotericin B. He returned three months later for follow-up and was noted to have improved vision in his left eye. The visual acuity had improved to 20/25. He had developed a trace cataract in the interim, and had a slight residual pigmented scaring on his anterior lens surface. His anterior chamber inflammation had resolved. The view of his fundus had improved greatly, and the posterior fundus photograph showed an essentially normal examination with a large resultant vitreous opacity (Figs. 2, 3).
Discussion There have been only two previously reported cases of C. dubliniensis endophthalmitis in North America, highlighting the rarity of this diagnosis. In contrast to those previous reports, our patient demonstrated a documented fungemia associated with an endocarditis. Endogenous endophthalmitis is a sight-threatening infection that requires prompt treatment [2]. Most patients with endogenous endophthalmitis have one or more systemic risk factors including immunosuppression, indwelling catheters, endocarditis, intravenous drug abuse, or recent invasive surgery [3–5]. Endogenous endophthalmitis comprises *5–7 % of all endophthalmitis cases.
Table 1 Antimicrobial susceptibility—yeast Yeast
Fig. 1 The right eye was unaffected and showed normal fundus exam
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MIC
Anidulafungin
0.06 S
Micafungin
0.016 S
Caspofungin
0.06 S
5-Fluorocytosine Posaconazole
B0.06 S 0.03 S
Voriconazole
B0.008 S
Itraconazole
0.03 S
Fluconazole
B0.12 S
Amphotericin B
0.5 Nonea
a
Interpretive guidelines are not available
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Fig. 2 There is now a clear view to the fundus showing a large vitreous opacity only
Fig. 3 There is now a clear view to the fundus showing a large vitreous opacity only
A recent review of 21 patients with endogenous endophthalmitis revealed a predominance of fungal isolates with C. albicans as the most common organism, accounting for 33 % of all cases [3].
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Endogenous Candida endophthalmitis is caused by hematogenous spread and varies in presentation from an isolated chorioretinitis to a chorioretinitis with extension into the vitreous [2, 6]. The chorioretinitis is often asymptomatic, leading to a delay in diagnosis. Without treatment, this will progress to include vitritis and a subsequent decrease in visual acuity [6]. Other symptoms may include ocular pain, floaters, or photophobia [3]. Candida dubliniensis is a relatively novel Candida subspecies but it is a close relative of C. albicans. It was first isolated in Dublin (Ireland) in 1995 from human immunodeficiency virus (HIV)-infected patients with oral candidiasis [7]. It is not limited to Ireland but exists throughout the world, and is not exclusively associated with HIV patients. It was found to be associated with a variety of infections ranging from a simple mucocutaneous candidiasis to more serious, invasive infections. It is often less virulent than C. albicans, likely due to the fact that C. dubliniensis triggers a stronger early neutrophil response than C. albicans [8, 9]. In addition, C. albicans has an expansion of virulence-related gene families [10]. Candida dubliniensis is a dimorphic yeast consisting of spherical blastospores. It is usually germ tubepositive and produces abundant chylamydospores. It is often difficult to discriminate between C. dubliniensis and the closely related species C. albicans; however, there are certain points of differentiation. C. dubliniensis grows at 30 and 37 °C but not at 42 °C. This helps distinguish it from C. albicans which grows well at 42 °C [7]. Furthermore, this yeast does not assimilate xylose or a-methyl-D-glucoside [11, 12], and is usually dark green in color on CHROMagar Candida medium following 48 h of growth at 37 °C [7, 9, 12]. Definitive identification is usually determined using genotypic-based molecular techniques, such as rapid real-time multiplex polymerase chain reaction (PCR) [13–15]. According to a recent review, C. dubliniensis is primarily associated with oropharyngeal carriage or infection in HIV-infected patients, but is rarely present as normal oral flora in an otherwise healthy individual. The first reports of fungemia from C. dubliniensis were in patients with leukemia, HIV, or end-stage liver disease. The most common risk factors are intravenous drug abuse, HIV infection, bone marrow and solid organ transplantation, and neutropenia resulting from
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chemotherapy [16, 17]. It is also a reported cause of catheter-related fungemia. The exact incidence of C. dubliniensis candidemia is not known, mostly due to phenotypic similarities to C. albicans [18]; however, Sullivan et al. [9] reported that C. dubliniensis constituted 2.2 % of yeast-positive blood cultures. The first case of C. dubliniensis endogenous endophthalmitis was reported in 2008 in a 38-yearold immunocompetent male maintenance worker, who presented with a 2-month history of pain, redness and a gradual decrease in vision in his right eye. His slitlamp examination showed an injected conjunctiva, hypopyon, fluffy white nodules on the iris and a poor view of the posterior pole. An ultrasound showed vitreous opacity but no retinal detachment. Initial management of this patient included aspirations for culture, synechiolysis, pars plana lensectomy, vitrectomy, vitreous culture and intravitreal injections of vancomycin and ceftazidime. The anterior chamber and the vitreous cultures later grew C. dubliniensis, so he received intravitreal injections of amphotericin B, topical amphotericin B, and systemic voriconazole [19]. The second reported case of C. dubliniensis endophthalmitis, also in a healthy immunocompetent male, was published in 2012. This case was initially thought to represent the first case of C. dubliniensis endophthlamitis in North America, but a letter to the editor sent by Wiwanitkit revealed that the first case was indeed the one discussed above, rendering the case by Espinosa-Heidmann et al. second on the list [20]. This case concerned a 27-year-old white male with a history of intravenous drug use as his only risk factor, and onychomycosis as the suspected source of infection [16]. There was another reported case from Spain of a 41-year-old HIV-positive male who was positive for hepatitis B and C antibody and had a history of intravenous drug abuse [16]. Therefore, our case report represents the third reported case of C. dubliniensis endophthalmitis in North America, and the fourth reported case in the world. Our patient was noted to be positive for hepatitis C antibody but without evidence of chronic liver disease, and with a setting of recurrent endocarditis due to intravenous drug use. Most likely this was the portal of entry for Candida into his bloodstream. Diagnosis of endophthalmitis is often difficult. The differential diagnoses often include uveitis, other
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infectious causes of chorioretinitis, malignancy, and autoimmune causes. Prompt diagnosis and treatment is important for a good visual outcome, emphasizing the importance of a high index of suspicion for fungal endophthalmitis in those patients with ocular symptoms and fungemia, or possessing risk factors for fungemia [16]. The first symptom of endophthalmitis is usually a painless decrease in vision [6]. Earlier diagnosis may be possible if visual acuity is routinely tested in patients with these risk factors. Candida endophthalmitis is often incorrectly diagnosed as uveitis, with rates approaching 50 %, emphasizing the importance of a high index of suspicion [3]. Candida endophthalmitis should be considered in patients who have persistent uveitis, even without the usual risk factors for fungemia, as it can result from fungal infections at distant sites [21]. Diagnosis is usually by culture of the vitreous at the time of diagnostic vitrectomy [6]. The vast majority of C. dubliniensis isolates identified are susceptible to all of the commonly used antifungal drugs [9]. Fluconazole resistance has been reported for C. dubliniensis [22, 23], but the vast majority of isolates tested to date are susceptible to commonly used antifungal drugs, including azoles and amphotericin B [24]. Current Infectious Diseases Society of America guidelines for the treatment of fungal endophthalmitis recommend the use of deoxycholic amphotericin B or fluconazole. Alternative options would be liposomal amphotericin B, voriconazole or an echinocandin. The duration of therapy is at least 4–6 weeks as determined by repeated examinations to verify resolution. Patients with severe endophthalmitis or vitreitis should undergo surgical intervention [25]. The two main factors associated with a poor visual outcome are centrally located fungal lesions, and an initial poor visual acuity on presentation [26]. Prevention of endophthalmitis may be possible with early use of azoles. Our patient had infective endocarditis with C. dubliniensis that was most likely the source of his endophthalmitis. It should be noted that septic intracranial emboli due to C. dubliniensis endocarditis is also a rare entity. The first reported case of C. dubliniensis infective endocarditis was reported in Dublin, in a 30-year-old intravenous drug user with hepatitis C. He had metastatic septic emboli to his brain, kidneys and spleen. The C. dubliniensis isolate was confirmed by the use of a rapid and novel real-
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time PCR assay based on the internal transcribed spacer 2 variable region of the rRNA operon [27]. Another case of recurrent infective endocarditis has been reported in an HIV-negative patient [28]. This leads us to consider our patient as likely representing another rare case of endocarditis with this yeast.
Conclusion Candida dubliniensis endogenous endophthalmitis is a rare but important entity in intravenous drug users. It can be differentiated phenotypically from C. albicans. Visual outcomes depend on the prompt diagnosis and initiation of appropriate therapy. Clinicians need to consider C. dubliniensis as another cause of candida endophthalmitis. Early fundoscopic examination is important to establish this diagnosis in the setting of fungemia, even in the absence of endocarditis.
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14. Acknowledgments The authors have no financial disclosures to declare and no conflicts of interest to report. All authors contributed to the writing of the manuscript. 15.
References 1. Odds FC, Bernaerts R (1994) CHROMagar Candida, a new differential isolation medium for presumptive identification of clinically important Candida species. J Clin Microbiol 32:1923–1929 2. Riddell J, Comer GM, Kauffman CA (2011) Treatment of endogenous fungal endophthalmitis: focus on new antifungal agents. Clin Infect Dis 52:648–653 3. Schiedler V, Scott IU, Flynn HW Jr, Davis JL, Benz MS, Miller D (2004) Culture-proven endogenous endophthalmitis: clinical features and visual acuity outcomes. Am J Ophthalmol 137:725–731 4. Binder MI, Chua J, Kaiser PK et al (2003) Endogenous endophthalmitis. An 18-year review of culture-positive cases at a tertiary care center. Medicine 82:97–105 5. Essman TF, Flynn HW Jr, Smiddy WE et al (1997) Treatment outcomes in a 10-year study of endogenous fungal endophthalmitis. Ophthalmic Surg Lasers 28:185–194 6. Mandell GL (2009) Mandell, Douglas, and Bennett’s Principles and practice of infectious diseases, 7th edn. Churchill Livingstone, Philadelphia 7. Sullivan DJ, Westerneng TJ, Haynes KA, Bennett DE, Coleman DC (1995) Candida dubliniensis sp. nov.: phenotypic and molecular characterization of a novel species associated with oral candidosis in HIV-infected individuals. Microbiology 141:1507–1521 8. Svobodova E, Staib P, Losse J, Hennicke F, Barz D, Jozsi M (2012) Differential interaction of the two related fungal
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species Candida albicans and Candida dubliniensis with human neutrophils. J Immunol 189:2502–2511 Sullivan DJ, Moran GP, Pinjon E, Al-Mosaid A, Stokes C, Vaughan C, Coleman DC (2004) Comparison of the epidemiology, drug resistance mechanisms, and virulence of Candida dubliniensis and Candida albicans. FEMS Yeast Res 4:369–376 Moran GP, Coleman DC, Sullivan DJ (2012) Candida albicans versus Candida dubliniensis: why is C. albicans more pathogenic? Int J Microbiol 2012:205921 Gales AC, Pfaller MA, Houston AK, Joly S, Sullivan DJ, Coleman DC, Soll DR (1999) Identification of Candida dubliniensis based on temperature and utilization of xylose and a-methyl-D-glucoside as determined with the API 20C Aux and Vitek YBC systems. J Clin Microbiol 37:3804–3808 Pincus DH, Coleman DC, Pruitt WR, Padhye AA, Salkin IF, Geimer M, Bassel A, Sullivan DJ, Clarke M, Hearn V (1999) Rapid identification of Candida dubliniensis with commercial yeast identification systems. J Clin Microbiol 37:3533–3539 Biswas SK, Yokoyama K, Wang L, Nishimura K, Miyaji M (2001) Identification of Candida dubliniensis based on the specific amplification of mitochondrial cytochrome b gene. Nippon Ishinkin Gakkai Zasshi 42:95–98 Donnelly SM, Sullivan DJ, Shanley DB, Coleman DC (1999) Phylogenetic analysis and rapid identification of Candida dubliniensis based on analysis of ACT1 intron and exon sequences. Microbiology 145:1871–1882 Kanbe T, Horii T, Arishima T, Ozeki M, Kikuchi A (2002) PCR-based identification of pathogenic Candida species using primer mixes specific to Candida DNA topoisomerase II genes. Yeast 19:973–989 Espinosa-Heidmann DG, McMillan BD, Lasala PR, Stanley J, Larzo CR (2012) Candida dubliniensis endophthalmitis: first case in North America. Int Ophthalmol 32:41–45 Pelegrin L, Mesquida M, Adan A, Cervera C, Bosch-Mestres J, Esteban-Redondo C, Juiz-Gonzalez P, Llorec V, Miro JM (2011) Candida dubliniensis endophthalmitis in a HIVinfected intravenous drug abuser. Mycoses 54:e856–e858 Loreto ES, Scheid LA, Nogueira CW, Zeni G, Santurio JM, Alves SH (2010) Candida dubliniensis: epidemiology and phenotypic methods for identification. Mycopathologia 169:431–433 First Case Report of Candida Dubliniensis endogenous endophthalmitis. R.W. Sedeek, M. Shah1, R. Gentile, C.M. Samson. Ophthalmology, New York Eye and Ear Infirmary, New York, NY; Ophthalmology, New York Medical 365College, New York, NY. http://files.abstractsonline. com/SUPT/163/1808/SessionPDF/156.pdf. Accessed 29 Oct 2012. http://www.nyee.edu/pdf/2008-research-dayroster.pdf Wiwanitkit S, Wiwanitkit V (2013) The first case of Candida dubliniensis endophthalmitis in North America. Int Ophthalmol 33:3 Chavan R, Mustafa MZ, Narendran N, Tarin S, Yang Y (2012) A case of Candida albicans endophthalmitis with no predisposing risk factors and a distant source of infection. Case Rep Ophthalmol 3:277–282 Moran GP, Sullivan DJ, Henman MC, McCreary CE, Harrington BJ, Shanley DB, Coleman DC (1997) Antifungal drug susceptibilities of oral Candida dubliniensis isolates
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950 from human immunodeficiency virus (HIV)-infected and non-HIV-infected subjects and generation of stable fluconazole-resistant derivatives in vitro. Antimicrob Agents Chemother 41:617–623 23. Ruhnke M, Schmidt-Westhausen A, Morschhauser J (2000) Development of simultaneous resistance to fluconazole in Candida albicans and Candida dubliniensis in a patient with AIDS. J Antimicrob Chemother 46:291–295 24. Pfaller MA, Messer SA, Gee S, Joly S, Pujol C, Sullivan DJ, Coleman DC, Soll DR (1999) In vitro susceptibilities of Candida dubliniensis isolates tested against the new triazole and echinocandin antifungal agents. J Clin Microbiol 37:870–872 25. Pappas PG, Kauffman CA, Andes D, Benjamin DK Jr, Calandra TF, Edwards JE Jr et al (2009) Clinical practice
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Int Ophthalmol (2014) 34:945–950 guidelines for the management of candidiasis: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 48:503–535 26. Sallam A, Taylor SR, Khan A, McCluskey P, Lynn WA, Manku K, Pacheco PA, Lightman S (2012) Factors determining visual outcome in endogenous Candida endophthalmitis. Retina 32:1129–1134 27. Carr MJ, Clarke S, O’Connell F, Sullivan DJ, Coleman DC, O’Connell B (2005) First reported case of endocarditis caused by Candida dubliniensis. J Clin Microbiol 43:3023–3026 28. Tran C, Cometta A, Letovanec I, Jaton K, Wenger A, Ruchat P, Jaussi A (2007) Candida dubliniensis in recurrent polymicrobial tricuspid endocarditis. Echocardiography 24:756–759
CASE REPORT
Third case of Candida dubliniensis endogenous endophthalmitis in North America: case report and review of the literature Elizabeth Rosenberger • Dima A. Youssef • Sara Safdar • Cristoforo R. Larzo • James Myers
Received: 9 August 2013 / Accepted: 31 October 2013 / Published online: 14 November 2013 Ó Springer Science+Business Media Dordrecht 2013
Abstract There are two previous reports of Candida dubliniensis endophthalmitis in North America. Here, we report a third case of C. dubliniensis endogenous endophthalmitis in a 31-year-old male patient who complained of left-sided decreased visual acuity. He had an associated mitral and tricuspid valve endocarditis, in the setting of intravenous drug use. Blood and sputum cultures were positive for C. dubliniensis. Fundoscopic examination was consistent with a fungal endophthalmitis. He was treated with fluconazole followed by intravenous liposomal amphotericin B for 6 weeks. C. dubliniensis is an important but rare cause of endophthalmitis in intravenous drug abusers. Keywords Candida dubliniensis Endophthalmitis Endocarditis Visual acuity Intravenous drug use
E. Rosenberger James H. Quillen College of Medicine, East Tennessee State University, Johnson City, TN, USA D. A. Youssef (&) S. Safdar J. Myers Division of Infectious Diseases, Department of Internal Medicine, James H. Quillen College of Medicine, East Tennessee State University, P.O. Box 70622, VAMC Bldg. 1, Dogwood Ave., Johnson City, TN 37614, USA e-mail: [email protected] C. R. Larzo Southeastern Retina Associates, 100 Med Tech Parkway, Suite 140, Johnson City, TN 37604, USA
Case report A 31-year-old intravenous drug user known to have hepatitis C presented to the Emergency Department with an altered mental status, and left-sided hemiplegia. He had recently finished a 6-week course of antibiotic therapy for methicillin-sensitive staphylococcus aureus (MSSA) tricuspid and mitral valve infective endocarditis. His examination revealed a temperature of 100.7 °F, with an associated tachycardia, and tachypnea. The patient’s blood pressure was 103/61 mmHg; he had bilateral crackles on lung examination, and a systolic ejection murmur over the mitral valve area. He was obtunded, but followed simple commands. He was noted to be hemiplegic on the left side with a left facial droop, and left-sided tongue deviation. He had grossly normal extraocular movements, and his motor power on the right upper and lower extremity was 4/5. The patient had left-sided upper and lower extremity flaccidity, and a motor power of 0/5. Laboratory studies revealed a white blood count of 9,000 cells/mm3 (87 % neutrophils), with hemoglobin of 8.8 g/dl, and a platelet count of 216,000. Magnetic resonance imaging of the head revealed a subacute right middle cerebral artery territory infarction, as well as many other punctate bilateral supra and infratentorial infarctions, compatible with an embolic process. There was also an intraparenchymal hemorrhage at the posterior superior right frontal lobe with moderate surrounding vasogenic edema.
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His blood and sputum cultures grew Candida dubliniensis that was identified using CHROMagar Candida [1]. A subsequent transesophageal echocardiogram showed a moderate to severe mitral valve regurgitation, and a severe tricuspid regurgitation. He had mitral valve vegetation measuring 1.490.49 cm, and a tricuspid valve vegetation measuring 2.991.82cm. These measurements were larger than the previously recorded values when he suffered MSSA infective endocarditis. He was complaining of decreased left-sided visual acuity. Ophthalmological examination revealed right and left eye acuity of 20/30 and 20/400, respectively. His intraocular pressures were normal at 10 and 6 in the right and left eyes, respectively. The right eye anterior segment was normal, but the left eye anterior segment showed corneal endothelial keratic precipitates and posterior synechiae at 3 o’clock. His left vitreous had a 2? (moderate) vitritis. The fundus photograph from this date shows no view due to the scarred down pupil and vitritis in the left eye. The right eye examination showed no signs of infiltrate (Fig. 1). There was no diagnostic ophthalmic intervention undertaken at this time due to his known diagnosis of C. dubliniensis fungemia. The C. dubliniensis isolate had a minimal inhibitory concentration (MIC) of \0.12 compared to fluconazole and 0.5 compared to amphotericin B. Table 1 shows the different yeast MICs tested for this Candida isolate. The patient was started on oral fluconazole 800 mg daily (8 mg/kg oral daily), but he developed a torsade de pointes and ventricular fibrillation 18 days
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after starting fluconazole. He was switched to liposomal amphotericin B. He later underwent mitral valve and tricuspid valve replacement, with placement of an epicardial right ventricular pacemaker lead. He finished a 6-week course of fluconazole and liposomal amphotericin B. He returned three months later for follow-up and was noted to have improved vision in his left eye. The visual acuity had improved to 20/25. He had developed a trace cataract in the interim, and had a slight residual pigmented scaring on his anterior lens surface. His anterior chamber inflammation had resolved. The view of his fundus had improved greatly, and the posterior fundus photograph showed an essentially normal examination with a large resultant vitreous opacity (Figs. 2, 3).
Discussion There have been only two previously reported cases of C. dubliniensis endophthalmitis in North America, highlighting the rarity of this diagnosis. In contrast to those previous reports, our patient demonstrated a documented fungemia associated with an endocarditis. Endogenous endophthalmitis is a sight-threatening infection that requires prompt treatment [2]. Most patients with endogenous endophthalmitis have one or more systemic risk factors including immunosuppression, indwelling catheters, endocarditis, intravenous drug abuse, or recent invasive surgery [3–5]. Endogenous endophthalmitis comprises *5–7 % of all endophthalmitis cases.
Table 1 Antimicrobial susceptibility—yeast Yeast
Fig. 1 The right eye was unaffected and showed normal fundus exam
123
MIC
Anidulafungin
0.06 S
Micafungin
0.016 S
Caspofungin
0.06 S
5-Fluorocytosine Posaconazole
B0.06 S 0.03 S
Voriconazole
B0.008 S
Itraconazole
0.03 S
Fluconazole
B0.12 S
Amphotericin B
0.5 Nonea
a
Interpretive guidelines are not available
Int Ophthalmol (2014) 34:945–950
Fig. 2 There is now a clear view to the fundus showing a large vitreous opacity only
Fig. 3 There is now a clear view to the fundus showing a large vitreous opacity only
A recent review of 21 patients with endogenous endophthalmitis revealed a predominance of fungal isolates with C. albicans as the most common organism, accounting for 33 % of all cases [3].
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Endogenous Candida endophthalmitis is caused by hematogenous spread and varies in presentation from an isolated chorioretinitis to a chorioretinitis with extension into the vitreous [2, 6]. The chorioretinitis is often asymptomatic, leading to a delay in diagnosis. Without treatment, this will progress to include vitritis and a subsequent decrease in visual acuity [6]. Other symptoms may include ocular pain, floaters, or photophobia [3]. Candida dubliniensis is a relatively novel Candida subspecies but it is a close relative of C. albicans. It was first isolated in Dublin (Ireland) in 1995 from human immunodeficiency virus (HIV)-infected patients with oral candidiasis [7]. It is not limited to Ireland but exists throughout the world, and is not exclusively associated with HIV patients. It was found to be associated with a variety of infections ranging from a simple mucocutaneous candidiasis to more serious, invasive infections. It is often less virulent than C. albicans, likely due to the fact that C. dubliniensis triggers a stronger early neutrophil response than C. albicans [8, 9]. In addition, C. albicans has an expansion of virulence-related gene families [10]. Candida dubliniensis is a dimorphic yeast consisting of spherical blastospores. It is usually germ tubepositive and produces abundant chylamydospores. It is often difficult to discriminate between C. dubliniensis and the closely related species C. albicans; however, there are certain points of differentiation. C. dubliniensis grows at 30 and 37 °C but not at 42 °C. This helps distinguish it from C. albicans which grows well at 42 °C [7]. Furthermore, this yeast does not assimilate xylose or a-methyl-D-glucoside [11, 12], and is usually dark green in color on CHROMagar Candida medium following 48 h of growth at 37 °C [7, 9, 12]. Definitive identification is usually determined using genotypic-based molecular techniques, such as rapid real-time multiplex polymerase chain reaction (PCR) [13–15]. According to a recent review, C. dubliniensis is primarily associated with oropharyngeal carriage or infection in HIV-infected patients, but is rarely present as normal oral flora in an otherwise healthy individual. The first reports of fungemia from C. dubliniensis were in patients with leukemia, HIV, or end-stage liver disease. The most common risk factors are intravenous drug abuse, HIV infection, bone marrow and solid organ transplantation, and neutropenia resulting from
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chemotherapy [16, 17]. It is also a reported cause of catheter-related fungemia. The exact incidence of C. dubliniensis candidemia is not known, mostly due to phenotypic similarities to C. albicans [18]; however, Sullivan et al. [9] reported that C. dubliniensis constituted 2.2 % of yeast-positive blood cultures. The first case of C. dubliniensis endogenous endophthalmitis was reported in 2008 in a 38-yearold immunocompetent male maintenance worker, who presented with a 2-month history of pain, redness and a gradual decrease in vision in his right eye. His slitlamp examination showed an injected conjunctiva, hypopyon, fluffy white nodules on the iris and a poor view of the posterior pole. An ultrasound showed vitreous opacity but no retinal detachment. Initial management of this patient included aspirations for culture, synechiolysis, pars plana lensectomy, vitrectomy, vitreous culture and intravitreal injections of vancomycin and ceftazidime. The anterior chamber and the vitreous cultures later grew C. dubliniensis, so he received intravitreal injections of amphotericin B, topical amphotericin B, and systemic voriconazole [19]. The second reported case of C. dubliniensis endophthalmitis, also in a healthy immunocompetent male, was published in 2012. This case was initially thought to represent the first case of C. dubliniensis endophthlamitis in North America, but a letter to the editor sent by Wiwanitkit revealed that the first case was indeed the one discussed above, rendering the case by Espinosa-Heidmann et al. second on the list [20]. This case concerned a 27-year-old white male with a history of intravenous drug use as his only risk factor, and onychomycosis as the suspected source of infection [16]. There was another reported case from Spain of a 41-year-old HIV-positive male who was positive for hepatitis B and C antibody and had a history of intravenous drug abuse [16]. Therefore, our case report represents the third reported case of C. dubliniensis endophthalmitis in North America, and the fourth reported case in the world. Our patient was noted to be positive for hepatitis C antibody but without evidence of chronic liver disease, and with a setting of recurrent endocarditis due to intravenous drug use. Most likely this was the portal of entry for Candida into his bloodstream. Diagnosis of endophthalmitis is often difficult. The differential diagnoses often include uveitis, other
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infectious causes of chorioretinitis, malignancy, and autoimmune causes. Prompt diagnosis and treatment is important for a good visual outcome, emphasizing the importance of a high index of suspicion for fungal endophthalmitis in those patients with ocular symptoms and fungemia, or possessing risk factors for fungemia [16]. The first symptom of endophthalmitis is usually a painless decrease in vision [6]. Earlier diagnosis may be possible if visual acuity is routinely tested in patients with these risk factors. Candida endophthalmitis is often incorrectly diagnosed as uveitis, with rates approaching 50 %, emphasizing the importance of a high index of suspicion [3]. Candida endophthalmitis should be considered in patients who have persistent uveitis, even without the usual risk factors for fungemia, as it can result from fungal infections at distant sites [21]. Diagnosis is usually by culture of the vitreous at the time of diagnostic vitrectomy [6]. The vast majority of C. dubliniensis isolates identified are susceptible to all of the commonly used antifungal drugs [9]. Fluconazole resistance has been reported for C. dubliniensis [22, 23], but the vast majority of isolates tested to date are susceptible to commonly used antifungal drugs, including azoles and amphotericin B [24]. Current Infectious Diseases Society of America guidelines for the treatment of fungal endophthalmitis recommend the use of deoxycholic amphotericin B or fluconazole. Alternative options would be liposomal amphotericin B, voriconazole or an echinocandin. The duration of therapy is at least 4–6 weeks as determined by repeated examinations to verify resolution. Patients with severe endophthalmitis or vitreitis should undergo surgical intervention [25]. The two main factors associated with a poor visual outcome are centrally located fungal lesions, and an initial poor visual acuity on presentation [26]. Prevention of endophthalmitis may be possible with early use of azoles. Our patient had infective endocarditis with C. dubliniensis that was most likely the source of his endophthalmitis. It should be noted that septic intracranial emboli due to C. dubliniensis endocarditis is also a rare entity. The first reported case of C. dubliniensis infective endocarditis was reported in Dublin, in a 30-year-old intravenous drug user with hepatitis C. He had metastatic septic emboli to his brain, kidneys and spleen. The C. dubliniensis isolate was confirmed by the use of a rapid and novel real-
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time PCR assay based on the internal transcribed spacer 2 variable region of the rRNA operon [27]. Another case of recurrent infective endocarditis has been reported in an HIV-negative patient [28]. This leads us to consider our patient as likely representing another rare case of endocarditis with this yeast.
Conclusion Candida dubliniensis endogenous endophthalmitis is a rare but important entity in intravenous drug users. It can be differentiated phenotypically from C. albicans. Visual outcomes depend on the prompt diagnosis and initiation of appropriate therapy. Clinicians need to consider C. dubliniensis as another cause of candida endophthalmitis. Early fundoscopic examination is important to establish this diagnosis in the setting of fungemia, even in the absence of endocarditis.
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14. Acknowledgments The authors have no financial disclosures to declare and no conflicts of interest to report. All authors contributed to the writing of the manuscript. 15.
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