Endogenous Endophthalmitis: Diagnosis and Treatment

UVEITIS OPHTHALMIC PEARLS

ndogenous endophthalmitis Pathogenesis 1 (EE) is an uncommon intraoc- The infectious agent travels via the Eular infection with potentially bloodstream and multiplies in the cho- devastating visual consequences. An roid, eventually infiltrating the retina endogenous source is responsible for and spreading into the vitreous.4 roughly 2% to 8% of all endophthal- A diagnosis of EE merits a systemic mitis.1 Prompt diagnosis and treatment workup for the source of infection, are essential to obtain the best visual although in 44% of cases no source is outcomes. The underlying infection found.2 EE has been most commonly should also be investigated and man- associated with liver abscesses, sinus aged, although it remains unidentified infections, endocarditis, meningitis, or in many cases. presence of indwelling catheters.

Etiology Diagnosis About half of reported EE cases are Presentation. Patient presentation YEAST INFECTION. Fundus photo of caused by bacteria and half by fungi.2 ranges from asymptomatic to symp- a white, fluffy chorioretinal infiltrate In North America and Europe, the toms typical of severe uveitis, including erupting into the vitreous. Vitreous fluid most frequently identified causative a red, painful eye with photophobia, grew Candida albicans. bacteria are Staphylococcus aureus and floaters, or reduced vision. Although EE Streptococcus pneumoniae, while in East is most often unilateral, up to a third of conditions, infectious and noninfec- Asia, Klebsiella pneumoniae is chiefly cases have bilateral involvement.5 tious, should be considered in formu- responsible.1 Among fungal etiologies, Ocular examination. Symptomat- lating the diagnosis. See “Differential Candida albicans (Fig. 1) is the most ic patients may have reduced visual Diagnosis” on the next page. common yeast, and Aspergillus (Fig. 2) acuity, conjunctival injection, corneal Diagnostic tests. Suspected EE is the most common mold.3 edema, hypopyon, anterior chamber should prompt a systemic workup for Major risk factors for EE are immu- cells, iritis, and vitritis. an occult infection; see Table 1 for tests nocompromised states (for example, A key diagnostic finding associated that might be useful, depending on pa- chronic corticosteroid use, malignancy, with an endogenous cause is the pres- tient presentation and history. Selected end-stage liver/renal disease, organ ence of a white infiltrate originating in tests from the table are discussed in transplant, diabetes mellitus), intra- the choroid and sometimes erupting greater detail below. venous drug use, indwelling catheter, into the vitreous cavity (Fig. 1). The Vitreous fluid biopsy. Vitreous fluid or dental procedures. In rare cases, fundus may be obscured because of obtained by means of vitrectomy has EE has also been reported in healthy vitreous haze or vitritis. If the posterior a higher diagnostic yield than vitreous individuals. Mean patient age was 63 segment cannot be visualized, B-scan fluid from needle biopsies, although years (range, 30-85 years) in a study of ultrasound can help identify vitritis or both are preferable to aqueous tap, 27 patients.2 The condition occurs very chorioretinal infiltrates. most likely because the sample is taken infrequently in children. Differential diagnosis. A number of closer to the infectious nidus.4 Blood cultures are positive in only a third of cases.5 Polymerase chain reac- BY FAITH BIRNBAUM, MD, AND GAURAV GUPTA, MD, MBA. EDITED BY tion (PCR) can identify both bacteria and 4 Rhode Island Eye Institute, Providence, R.I. Providence, Institute, Rhode Island Eye SHARON FEKRAT, MD, AND INGRID U. SCOTT, MD, MPH. fungi, even in culture-negative cases.

EYENET MAGAZINE • 33 Beta-glucan assay. In cases of sus- 2A 2B pected fungal EE, a serum beta-glucan assay can detect the presence of beta-D glucan found in the fungal walls of many species. The sensitivity and spec- ificity depend on the cutoff value and the commercial kit used; for example, a study in Japan using a threshold of 60 picograms/mL for invasive fungal infections showed a positive predictive value of 70% and a negative predictive value of 98%. These values are higher than those obtained with blood MOLD INFECTION. (2A) Findings in this eye with aspergillosis include vitritis, a dif- cultures.6 fuse chorioretinal lesion, subretinal/subhyaloid hypopyon, intraretinal hemorrhage, Imaging. Neuroimaging can evaluate and papillitis. (2B) 2 months after treatment, macular scar, preserved overlying reti- for an intraocular foreign body as well nal vessels, and temporal disc pallor were present. Final visual acuity was 20/400. as for intraorbital or intracranial sourc- es of infection. Wide-spectrum antibiotics, includ- consider administering intravenous Treatment ing fluoroquinolones, aminoglycosides, amphotericin-B (0.7-1.0 mg/kg daily), Treatment should be initiated as soon third-generation cephalosporins, and with or without flucytosine (100 mg/ as endophthalmitis is suspected, even clindamycin, may be considered. kg daily in 4 divided doses) until drug before a definitive diagnosis is made. In Systemic fluoroquinolones have sensitivity results are available. Alterna- our experience, this should start with good ocular penetration for most tively, oral voriconazole or fluconazole prompt intravitreal antibiotic adminis- bacteria, and it improves with repeat can be effective, although some isolates tration, combined with hospitalization, doses.7 In particular, the fourth-gener- of Candida are fluconazole resistant. infectious disease consultation, and ation fluoroquinolones (moxifloxacin, Echinocandins (e.g., caspofungin) do intravenous antibiotics. levofloxacin) have demonstrated excel- not adequately penetrate the eye. In determining the therapeutic lent penetration in animal and human For Aspergillus, voriconazole is approach, the potential causative studies.8,9 the drug of choice; it has adequate organism and the extent of ocular Ocular penetration of ciprofloxacin, involvement should direct the aggres- though not as good as the fourth-gen- siveness of therapy. If the ocular lesion eration drugs, can reach therapeutic is confined to the choroid, systemic levels with higher and multiple doses, Differential Diagnosis therapy with antibiotics or antifungals and it can supplement intravitreal and close observation may be adequate; injections to maintain therapeutic Noninfectious uveitis if the infection has spread beyond the concentrations.9,10 Idiopathic choroid into the vitreous, then more Aminoglycosides (gentamicin, Sarcoidosis aggressive intravitreal antibiotic thera- amikacin) reach intraocular therapeu- Behçet syndrome py, with or without pars plana vitrecto- tic levels for some pathogens, but not Sterile endophthalmitis from my, should be added to the regimen. reliably.10 recent intravitreal injection Although ceftazidime, a third-gen- (e.g., anti-VEFG or steroid) Systemic Therapy eration cephalosporin, is a favorable Sympathetic ophthalmia Bacterial. In choosing systemic anti choice in terms of its broad gram-neg- Juvenile idiopathic arthritis biotics, the clinician should keep in ative and Pseudomonas coverage, it has Vogt-Koyanagi-Harada mind both breadth of coverage and poor intraocular penetration.8 Rabbit disease intraocular penetration. Although in- studies have shown that in inflamed Infectious chorioretinitis traocular penetration of systemic drugs eyes, ceftazidime reaches the mean Herpes simplex virus is ordinarily limited by the blood-ret- inhibitory concentration threshold for Varicella-zoster virus ina barrier of the posterior segment Proteus, Haemophilus influenzae,and Epstein-Barr virus and the blood-aqueous barrier of the Neisseria but not for Pseudomonas or Cytomegalovirus anterior segment, inflammation may Acinetobacter when delivered through Malignancy make the blood-retina barrier more a systemic route only.8 Intraocular lymphoma permeable and allow better penetra- Intravenous vancomycin has limited Leukemic infiltrate tion. Regardless, patients being treated ocular penetration, even in inflamed Retinoblastoma with intravitreal antibiotics should also eyes with penetrating injury.8 Intraocular foreign body 7-9 receive systemic antibiotics. Fungal. The ophthalmologist should White dot syndromes PD et al. Ophthalmology . 1998;105(1):60. Weishaar

34 • JUNE 2016 intraocular penetration when used vancomycin (1.0 mg/0.1 mL) are the found that eyes treated with vitrecto- systemically and can be administered preferred intravitreal antibiotics for my and intravitreal antibiotics were intravitreally as well.11 Trough levels bacterial EE.1 Amikacin (0.4 mg/0.1 approximately 2 times more likely to between 2 and 5 µg/mL are the goal,11 mL) and clindamycin (1.0 mg/0.1 mL) have vision better than 20/200 and 3 as higher concentrations have been are alternatives for penicillin-allergic times less likely to require evisceration associated with neurotoxicity (visual patients. or enucleation when compared with and auditory hallucinations, confusion) For patients with fungal infection, in- intravitreal antibiotics alone.1 and hepatotoxicity, while lower concen- travitreal amphotericin-B (5-10 µg/0.1 Vitrectomy is generally advised in trations are associated with treatment mL) or, less frequently, voriconazole cases of moderate vitritis and retinal failure.12 Multiple factors influence (100 µg/0.1 mL) are options. infiltration. A decline in vision due to plasma concentrations, such as genetic Patients should be monitored daily inflammation, vitritis, corneal edema, polymorphisms and coadministered for response to treatment. If, after 2 to 3 or anterior segment inflammation medications.12 The optimal duration of days, there is worsening inflammation, further supports the use of immediate voriconazole therapy is not known, but declining vision, or increasing pain, vitrectomy. a common approach is to treat systemi- then repeated injections or vitrectomy cally for 4 to 6 weeks, depending on ob- may be necessary. Prognosis served ophthalmologic improvement. Outcomes of EE are variable and are Systemic voriconazole therapy should Vitrectomy generally dictated by the aggressiveness be managed by an infectious disease Vitrectomy may reduce the burden of of the causative organism. In general, physician experienced in its use. infectious organisms and inflammatory yeasts are associated with the best vi- mediators, but there is no consensus sual outcomes, bacteria with moderate Intravitreal Therapy about the indications. A systematic outcomes, and molds with the worst. Ceftazidime (2.25 mg/0.1 mL) and review of 342 cases of bacterial EE For example, 56% of patients with EE caused by Candida achieved a visual acuity of 20/200 or better,3 compared Table 1: Diagnostic Workup for Suspected EE with 41% who had bacterial EE1 and 33% who had EE caused by molds. Ocular fluid • Gram stain and culture (vitreous or aqueous) • Fungal stain and culture 1 Jackson TL et al. Surv Ophthalmol. 2014;59(6): • PCR (if indicated) for herpes simplex virus types 1 627-635. and 2, varicella-zoster virus, cytomegalovirus, Toxo- 2 Binder M et al. Medicine. 2003;82(2):97-105. plasma 3 Lingappan A et al. Am J Ophthalmol. 2012;153 (1):162-166. Blood tests • Bacterial culture 4 Zhang Y, Wang W. Retina. 2005;25(6):746-750. • Fungal culture 5 Vaziri K et al. Clin Ophthalmol. 2015;9:95-108. • Complete blood count with differential 6 Obayashi T et al. Clin Infect Dis. 2008;46(12): • Blood chemistries, including liver function tests 1864-1870. 7 Smith A et al. Drugs. 2001;61(6):747-761. • Tests for systemic infections/inflammation: HIV, 8 Ahmed S et al. J Ocul Pharmacol Ther. 2014;30 Toxoplasma IgM and IgG, hepatitis C virus, angio- (10):823-830. tensin-converting enzyme (for sarcoidosis), eryth- 9 García-Sáenz MC et al. J Cataract Refract Surg. rocyte sedimentation rate, rapid plasma reagin 2001;27(12):1969-1974. and fluorescent treponemal antibody absorption 10 Davis JL. Am J Ophthalmol. 1996;122(5):724- (for syphilis), Quantiferon-TB Gold, Lyme serology, 726. beta-D glucan assay (for fungal infection), galacto- 11 Riddell J et al. Clin Infect Dis. 2011;52(5):648- mannan assay (for aspergillosis) 653. Other laboratory tests • Urine culture 12 Dolton MJ, McLachlan AJ. Int J Antimicrob • Cerebrospinal fluid culture Agents. 2014;44(3):183-193. • Purified protein derivative (skin test) Dr. Birnbaum will be a resident in ophthalmolo- Imaging • B-scan ultrasound gy at Duke University, Durham, N.C.; at the time • Transesophageal echocardiogram of writing, she was a medical student at Alpert • Chest x-ray or, if high suspicion, chest computed Medical School, Brown University, Providence, tomography R.I. Dr. Gupta is clinical assistant professor of • Magnetic resonance imaging of brain and orbits surgery (ophthalmology) at Alpert Medical School, Brown University. Relevant financial • Ultrasound of right upper quadrant disclosures: None.

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