ORIGINAL CLINICAL STUDY
Endogenous Endophthalmitis: A 10-Year Retrospective Study at a Tertiary Hospital in South India Dhanashree Ratra, FRCS (Edin), Kumar Saurabh, MS, Debmalya Das, DNB, Kasinathan Nachiappan, FRCS, Amit Nagpal, MS, Ekta Rishi, MS, Pramod Bhende, MS, Tarun Sharma, FRCSEd, and Lingam Gopal, FRCSEd
Purpose: The aim of this study was to review the clinical profile including predisposing systemic conditions, microorganisms responsible, clinical presentation, and outcomes of endogenous endophthalmitis (EE) in South India. Design: This study is a retrospective, noncomparative case series. Methods: This study presents a retrospective analysis of records of patients with EE in a 10-year period. Results: A total of 61 eyes of 58 patients were included in the study. Preceding systemic illness or surgery was noted in 31 patients (53.4%). No predisposing condition was found in 27 patients (46.5%). All eyes had severe diffuse EE. Culture positivity was seen in 34 of 58 patients (58.6%). Gram-positive organisms were isolated in 9 cases (15.5%), and Gram-negative organisms were isolated in 20 cases (34.5%). Pseudomonas aeruginosa (13.8%) was the most common isolate. Eleven eyes (18%) were managed medically with intravenous and intravitreal antibiotics, and 38 eyes (62.3%) also underwent vitrectomy. Eight eyes (13.1%) required repeat vitrectomy, and 12 eyes (19.7%) were eviscerated. The mean follow-up was 16.2 T 13.9 months. Final visual acuity of 20/200 or better was seen in 29.5% eyes. A favorable outcome was noted in culture-positive patients (P = 0.03) and in patients with no predisposing causes. Conclusions: This study provides information about the clinical and microbiologic profile of EE. Aggressive medical and surgical treatment can result in favorable outcomes. Key Words: endogenous endophthalmitis, adult, Pseudomonas, vitrectomy, India, diabetes mellitus (Asia Pac J Ophthalmol 2015;4: 286Y292)
In addition, the associated septicemia may be life threatening with a mortality rate of 5% to 15%.1 The associated systemic factors include chronic debilitating and immune suppressive diseases [diabetes, renal failure, malignancy, acquired immune deficiency syndrome (AIDS), organ transplantation], long-term indwelling catheters, intravenous drug abuse, endocarditis, urinary tract infections, recent major surgeries, and dental procedures. Systemic disease may be obvious or subtle. In 1 review, only 57% of patients with bacterial EE had systemic symptoms.2 These cases add to the diagnostic and therapeutic challenge. The management encompasses treatment of the eye disease as well as a search for the source of infection. Large case series have reported variation in the causative pathogen based on geographic location.1,3Y5 Gram-positive bacteria were more common in Western countries, whereas Gramnegative organisms were more prevalent in East Asian countries. In the bacterial etiology, their susceptibility was seen to differ greatly by region within the country as well.6 This emphasizes the need for reporting EE from different geographic areas. Knowledge of these changing patterns may help in choosing the initial empirical treatment when culture reports are awaited or are negative. Studies from India have mainly concentrated on postsurgical or posttraumatic endophthalmitis with inclusion of only a few cases of EE.5Y9 The present study was performed to determine the clinical profile of EE in South India. It was aimed at identifying the predisposing systemic disease conditions, the microorganisms responsible, clinical presentations, and outcomes of EE in this part of the country.
MATERIALS AND METHODS
E
ndogenous endophthalmitis (EE) is a rare but potentially blinding intraocular infection. In contrast to exogenous endophthalmitis where the microorganism gains entry into the eye from the external environment after intraocular surgery or an injury, the source of infection in EE is via the blood stream. Endogenous endophthalmitis is much less common than exogenous endophthalmitis and is estimated to account for 2% to 6% of all endophthalmitis cases.1 The visual prognosis in such cases is often poor, leading to blindness, atrophy of the globe, or evisceration.
From the Bhagawan Mahavir Department of Vitreoretinal Diseases, Sankara Nethralaya Medical Research Foundation, Chennai, India. Received for publication November 2, 2014; accepted April 9, 2015. The authors have no funding or conflicts of interest to declare. Reprints: Dhanashree Ratra, MS, DNB, FRCS (Edin), C-MER (Shenzhen) Dennis Lam Eye Hospital, 1-2/F Shengtang Building, Futian, Shenzhen, China. E-mail: [email protected]. Copyright * 2015 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000120
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This is a retrospective analysis of case records of 61 eyes of 58 patients with EE treated at our center in a 10-year period from January 2000 to December 2009. The study was approved by the institutional review board. The data obtained from the medical records included demographic details such as age, sex, and area of residence. The patients’ medical history was scrutinized in detail to ascertain predisposing factors. A history of diabetes mellitus, malignancy, chronic illnesses, therapy with immunosuppressive medicines, recent surgery, infection, or blood transfusion was noted. Patients with recent intraocular surgery (within the previous 5 years), intraocular trauma (within the previous year), or any other external source of infection were excluded from the study. Records with ambiguous information or inadequate follow-up were excluded. The eye affected and the best-corrected visual acuity (BCVA) for each eye were noted from the records. Slit-lamp examination findings pertaining to the status of the cornea, anterior chamber, hypopyon, iris, and lens changes were noted. On indirect ophthalmoscopy, the grade of visibility and vitreous involvement was recorded. In the status of the retina, any retinal or choroidal changes were noted in cases where visualization
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was possible. In cases with media opacities, ultrasonography was done to exclude retinal detachment and to determine the status of vitreous inflammation. Various specimens were collected for culture. Aqueous tap was the first step in the microbiological analysis. It was done in the outpatient department at the first visit. Patients were comfortably seated in a reclining chair, and indirect ophthalmoscope was used as the light source. After cleaning the eye and the periocular skin with 5% povidone iodine and applying a wire speculum, a 30-gauge needle mounted on a 1-mL disposable syringe was used for aspirating approximately 0.1 mL of aqueous humor. Vitreous samples were always collected during planned therapeutic vitrectomy. A vitrectomy cutter was used to obtain a vitreous sample. The aspiration line was connected to a 10-mL disposable syringe, and the assistant was asked to apply gentle suction while the surgeon actuated the vitrectomy cutter. During this process, the infusion line was kept blocked to avoid dilution of the vitreous sample. A separate vitreous tap was not done for eyes that did not undergo vitrectomy. In patients undergoing evisceration, the eviscerated specimen was subjected to microbiological and histopathological analysis. In all cases of EE, blood and urine samples were collected for culture. Other specimens were sometimes collected based on the original site of infection. Various case-specific investigations were done, which included complete blood counts, chest x-ray, abdominal ultrasonography, and so on. The samples were studied with Gram stain, 10% wet potassium hydroxide mount, Giemsa stain, and Ziehl-Neelsen stain to identify bacterial or fungal etiology. Samples were directly inoculated on blood agar, chocolate agar, Sabouraud dextrose agar, thioglycolate medium, brain-heart infusion agar, and Lowenstein-Jensen agar. Polymerase chain reaction (PCR) tests were done on the aqueous and vitreous samples in all cases. A positive culture was defined as growth of the same organism on 2 or more solid phase media or confluent growth on 1 solid medium. Antimicrobial sensitivity patterns were recorded using the Kirby-Bauer disc diffusion method. All patients were started on intravenous cefotaxime 1 g thrice a day and intravenous gentamicin 80 mg 2 times a day. Intravitreal antibiotics were chosen based on the culture or PCR report. Initial therapy before culture reports or in cases with negative culture and PCR results was done with intravitreal vancomycin (1 mg/0.1 mL) and ceftazidime (2.25 mg/0.1 mL). Intravitreal steroids were added if the clinician was sure of having ruled out a fungal infection. The treatment was modified based on susceptibility reports and clinical response. Cases with fungal isolates were treated with antifungal agents based on susceptibility and patient affordability. Fluconazole (100 mg twice daily) or voriconazole (200 mg loading dose followed by 100 mg daily) were used as oral antifungals. Intravitreal voriconazole (50 Kg) or amphotericin B (5 Kg) was administered until clinical improvement. Liver function tests were monitored during the antifungal treatment. A favorable anatomical outcome was defined as an attached retina with clear vitreous cavity at the final follow-up. In addition, a favorable functional outcome was defined as a final visual acuity of 20/200 or better. Modalities of treatment and follow-up data were recorded at 1 month, 3 months, 6 months, 1 year, and yearly thereafter. At each visit, the visual acuity and retinal status were noted. The results were analyzed using the W2 test.
RESULTS Of a total of 58 patients with EE, 36 (62.1%) were male and 22 (37.9%) were female. The age of the patients ranged * 2015 Asia Pacific Academy of Ophthalmology
Endogenous Endophthalmitis in South India
from 18 to 73 years (mean, 34.6 T 14.9 years). The disease was bilateral in 3 (5.2%) and unilateral in 55 (94.8%) patients. Of the total 61 eyes, the right eye (35, 57.4%) was more commonly involved than the left eye (26, 42.6%). Endogenous endophthalmitis was preceded by an episode of systemic illness in 22 patients (37.9%). Nine (15.5%) had a history of undergoing systemic surgery before the onset of EE. No systemic predisposing disease condition was noted for 27 patients (46.5%). Table 1 lists the various systemic causes. Except for 1 patient (1.7%) who was AIDS positive, all were apparently immunocompetent. Among the 61 eyes with EE, 8 eyes (13.1%) had no light perception at the time of presentation, and 38 (62.3%) had only light perception. Ten (16.4%) eyes had BCVA of less than hand movements to 20/200, and only 5 eyes (8.19%) had a relatively good BCVA of 20/200 to less than 20/60. None of the eyes had better than or equal to 20/60. Reduced vision (60, 98.4%), redness (47, 77%), and pain (42, 68.8%) were the 3 most common presenting symptoms. Other symptoms included watering and discharge in 13 eyes (21.3%) and swelling of the eye, floaters, and intolerance to light in 2 eyes (3.3%) each. All eyes had severe diffuse endophthalmitis involving the posterior segment. Diffuse vitreous exudates were seen in 47 eyes (77%). In 14 eyes (22.9%), a cataractous lens precluded a view of the vitreous cavity; however, ultrasound examination revealed vitreous involvement in these eyes too. Retina could be visualized in 13 eyes (21.3%) only, and in 3 (4.9%) of them, it was detached. None had panophthalmitis. A positive culture from either ocular or other body fluids was obtained in 34 patients (58.6%). Vitreous was positive in 16 patients (27.6%) and aqueous in 11 patients (18.9%). Other samples with positive cultures were blood (2, 3.4%), sputum (1, 1.7%), and urine (4, 6.9%). In 3 cases (5.2%), microorganisms were isolated from the eviscerated material. The microorganisms identified have been enumerated in Table 2. Of these 34 culture-positive cases, 29 (85.3%) had bacterial and
TABLE 1. Systemic Ailments in EE (N = 58)* None 27 (46.5%) Medical conditions* 22 (37.9%) Diabetes mellitus 14 (24.1%) Enteric fever 3 (5.2%) Chronic renal failure 2 (3.4%) Urinary tract infection 2 (3.4%) Pulmonary tuberculosis 2 (3.4%) Septicemia 2 (3.4%) Meningitis, diarrhea, AIDS, hepatitis B, 1 each (1.7%) gastroparesis, liver cirrhosis, fungal infection of toes, mitral regurgitation Surgical conditions 9 (15.5%) Abdominal surgery 6 (10.3%) Appendectomy 2 (3.4%) Total gastrectomy, cesarean delivery, laparotomy 1 each (1.7%) and intestinal reanastomosis, pouch excision Genitourinary surgery 2 (3.4%) Urinary lithotripsy, surgical termination 1 each (1.7%) of pregnancy Head and neck surgery 1 (1.7%) Tooth extraction 1 (1.7%) *Some patients had more than 1 systemic condition.
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TABLE 2. Causative Microorganisms Identified in Patients With EE (N = 58)
P. aeruginosa E. coli C. albicans S. epidermidis S. aureus C. freundii E. faecalis M. tuberculosis* S. viridans Candida tropicalis Candida parapsilosis Alcaligenes faecalis Acinetobacter calcoaceticus Aeromonas specie K. pneumoniae Klebsiella oxytoca P. acnes* Total
Total
Aqueous
Vitreous
8 (13.8%) 4 (6.9%) 3 (5.2%) 3 (5.2%) 3 (5.2%) 3 (5.2%) 2 (3.4%) 2 (3.4%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 37 (63.8%)
3 (5.2%) 1 (1.7%)
5 (8.6%)
1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%)
Eviscerated Material
Blood
Urine
Sputum
3 (5.1%) 3 2 1 2 1
(5.2%) (3.4%) (1.7%) (3.4%) (1.7%)
1 (1.7%) 1 (1.7%) 1 (1.7%)
1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 11 (18.9%)
16 (27.6%)
3 (5.2%)
2 (3.4%)
4 (6.8%)
1 (1.7%)
*Identified on PCR.
5 (14.7%) had fungal isolates. Among bacterial isolates, 9 (26.5%) were Gram positive and 20 (58.8%) were Gram negative. An antimicrobial sensitivity record of the isolated microorganisms was available for 25 patients (43.1%) (Table 3). All isolates of Pseudomonas aeruginosa were sensitive to ciprofloxacin. Similarly, all staphylococci were sensitive to vancomycin, and all Escherichia coli isolates were sensitive to amikacin. All of the 24 patients (41.4%) with negative culture were under intravenous antibiotic treatment for 1 week or more before attending our hospital. Three cases revealed microorganisms on PCR (Mycobacterium tuberculosis in 2 cases and Propionibacterium acnes in 1 case). Overall, 11 eyes (18%) were managed medically with intravenous and intravitreal antibiotics. Vitrectomy was required in 38 eyes (62.3%) at the initial phase of management. Twelve eyes (19.7%) needed evisceration. During further follow-up, 8 eyes (13.11%) needed repeat vitrectomy within 2 weeks due to the persistence of intraocular infection. The mean follow-up period was 16.2 T 13.9 months (range, 6 months to 6 years). At the final follow-up, 33 eyes (54%) had attached retina with clear vitreous cavity, 5 eyes (8.2%) had
inoperable retinal detachment, and 11 (18%) had phthisis bulbi. Twenty eyes (32.8%) had lost light perception, whereas 12 eyes (19.7%) had light perception only. The final BCVA was hand movement to less than 20/200 in 11 eyes (18%) and 20/200 to less than 20/60 in 7 eyes (11.5%). Only 11 eyes (18%) had final BCVA in the range of 20/60 to 20/20. Among the eyes with no light perception (n = 20), P. aeruginosa (4, 20%) and E. coli (2, 10%) were the most common isolates, whereas 8 (40%) such eyes were culture and PCR negative. In the remaining eyes, Enterococcus faecalis, Streptococcus viridans, Staphylococcus aureus, Aeromonas, Klebsiella pneumoniae, and Citrobacter freundii were isolated in 1 case (5%) each. Favorable anatomical outcome defined as an attached retina at the final follow-up was noted in 18 (64.3%) of 28 eyes among apparently healthy individuals with no known predisposing condition. In individuals with predisposing medical conditions, favorable anatomical outcome was noted in 10 (45.4%) of 22 eyes (P = 0.18). Similarly, 5 (45.4%) of 11 eyes of individuals with predisposing surgical conditions had favorable anatomical outcomes (P = 0.06). Favorable functional outcome defined as final visual acuity of 20/200 or better was noted
TABLE 3. In Vitro Antimicrobial Sensitivity of the Microorganisms Isolated From EE Cases (n = 25)* Organism P. aeruginosa E. coli S. epidermidis S. aureus† C. freundii‡ E. faecalis
Ciprofloxacin 100% (8/8) 0% (0/4) 100% (3/3) Not done 66.6% (2/3) 0% (0/2)
Amikacin
Gentamicin Cefotaxime Ceftazidime Vancomycin Chloramphenicol Azithromycin
100% (8/8) 37.5% (3/8) 37.5% (3/8) 25% (2/8) 100% (4/4) 75% (3/4) 25% (1/4) 25% (1/4) Not done 100% (3/3) 100% (3/3) 66.6% (2/3) Not done Not done 66.6% (2/3) 0% (0/3) 66.6% (2/3) 66.6% (2/3) 66.6% (2/3) 66.6% (2/3) Not done 50% (1/2) 100% (2/2) 0% (0/2)
0% (0/8) Not done 100% (3/3) 100% (3/3) Not done 100% (2/2)
0% (0/8) 75% (3/4) Not done Not done 0% (0/3) Not done
0% (0/8) Not done Not done Not done 0% (0/3) Not done
*Two isolates of C. albicans were sensitive to fluconazole, amphotericin B, and voriconazole and were resistant to natamycin. †All isolates of S. aureus were sensitive to methicillin. ‡One isolate of C. freundii was resistant to all antibiotics; it was tested for imipenem, azithromycin, cotrimoxazole, and chloramphenicol.
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* 2015 Asia Pacific Academy of Ophthalmology
Phthisis PL Intravitreal antibiotics None None CF M 38 OD 9
8
CF indicates counting fingers close to face; CNVM, choroidal neovascular membrane; HM, hand movement close to face; F indicates female; M, male; NPL, no perception of light; OD, right eye; OS, left eye; PL, light perception only; VA, visual acuity.
None 20/80 Intravitreal antibiotics Aqueous P. aeruginosa CF M 52
NPL F 54 OS
Total gastrectomy for neuroendocrine malignancy Laparotomy and intestinal reanastomosis Intestinal pouch excision 7
OD
None NPL
CF 20/80 NPL HM PL NPL PL NPL
C. albicans Vitreous Vitrectomy + intravitreal voriconazole C. albicans Vitreous Vitrectomy + intravitreal voriconazole None None None C. parapsilosis Vitreous Vitrectomy + intravitreal voriconazole None None Vitrectomy + intravitreal antibiotics None None Vitrectomy + intravitreal antibiotics None None Vitrectomy + intravitreal antibiotics C. freundii Eviscerated Evisceration material None None Intravitreal antibiotics PL PL NPL CF CF CF PL NPL F F F M F F F F 34 34 30 31 48 48 29 30 OD OS OD OD OD OS OD OD Lithotripsy for renal calculi Lithotripsy for renal calculi Appendectomy Appendectomy Tooth extraction Tooth extraction Surgical termination of pregnancy Cesarean delivery 1 1 2 3 4 4 5 6
Organism Eye Age, y Sex Initial VA
TABLE 4. Characteristics of Patients With EE After Systemic Surgery (9 Patients, 11 Eyes)
DISCUSSION Although EE is responsible for only 2% to 6% of the total cases of endophthalmitis, its management poses a greater challenge because of the occult nature of the infection or complicating systemic disease conditions.2,10,11 Presence of EE in apparently healthy individuals may herald systemic sepsis.1 Hence the management of EE incorporates not only the control and treatment of the eye infection but also the search and eradication of the systemic sepsis. The absence of antecedent events such as surgery or trauma may delay the identification of EE in an inflamed eye in a systemically ill person.12 Early diagnosis and treatment are imperative for salvaging useful vision. The fact that etiology and features of EE may vary from 1 region of the globe to another puts further emphasis on reporting from different geographic areas.1,3Y6 Similar to other studies, our study too had a male preponderance with unilateral involvement.3,11,13,14 The right eye was more commonly involved than the left eye. Theoretically, the infectious load present in the blood stream should reach equally to both eyes, making bilateral EE more common. However, a predilection for right eye involvement has been reported by many.3,11,13 Greenwald et al15 attributed it to more proximal and direct blood flow to the carotid artery on the right side. Predisposing systemic disease conditions were noted in around half (31 patients, 53.4%) of our patients. Diabetes mellitus was the most common medical condition associated (14 patients, 24.1%), whereas abdominal surgery was the most common surgical predisposing condition (6 patients, 10.3%). The rest of the patients (27, 46.5%) did not have any predisposing systemic conditions. Leibovitch et al3 from Australia (13 cases), Zhang and Liu13 from China (19 cases), and Keswani et al14 from India (14 cases) found at least 1 predisposing systemic condition in all their patients. The occurrence ranges from 73% to 92.6% in various reports,1,4,11 whereas Okada et al2 and Jackson and colleagues1 in the reviewed literature found predisposing systemic conditions in only 56% (149 of 267) of the cases. A transient bacteremia that causes minimal systemic symptoms and clears quickly may go unnoticed by the patient. There is a high risk of misdiagnosis in such a situation where obvious predisposing conditions are absent. The common misdiagnoses are noninfectious uveitis and acute angle closure glaucoma.1
Source
Intervention
Final VA
Remarks
in 42.8% (12 of 28 eyes) of apparently healthy individuals, 18.2% (4 of 22 eyes) of patients with predisposing medical conditions, and 18.2% (2 of 11 eyes) of patients with predisposing surgical conditions (P = 0.28 and 0.14, respectively). Favorable anatomical outcome was noted in 65.7% (23 of 35) of the culture-positive eyes in contrast to 38.5% (10 of 26) of the culture-negative eyes. This difference was statistically significant (P = 0.03). A favorable functional outcome was noted in 37.1% (13 of 35) of the culture-positive eyes and 9.2% (5 of 26) of the culture-negative eyes (P = 0.12). Tables 4 and 5 give a clinical summary of patients with predisposing disease conditions, the organisms isolated, and their final outcomes. Candida albicans was isolated from both eyes of a patient who underwent lithotripsy for renal stones. One of these eyes developed choroidal neovascular membrane, which was treated with 3 injections of ranibizumab. Vision improved to 20/60 at final follow-up. One patient developed C. freundii EE 1 month after a lower segment cesarean delivery. This eye had scleral necrosis and thinning. We also noted an iris abscess in 1 eye of an 18-year-old patient with P. aeruginosa EE. However, he did not have any predisposing systemic conditions.
Endogenous Endophthalmitis in South India
Macular scar CNVM treated with ranibizumab Phthisis None Total corneal opacity Phthisis Macular scar None
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OS
OD OD OD OD OS OD OS OS
OS OD OS
OD
OD OD OD OD OS OD OS
OS OD
Eye
62
38 34 19 50 50 50 39 69
22 25 19
44
35 36 45 61 55 68 73
38 58
Age, y
F
M M M M M M F M
F F M
M
M F M M F M M
F F
Sex
NPL
20/120 PL CF NPL 20/120 PL PL PL
20/200 20/200 NPL
PL
PL PL PL PL PL PL NPL
20/20 NPL
Initial VA
None
C. tropicalis None P. acnes* Aeromonas None K. pneumoniae None None
E. coli None None
M. tuberculosis*
S. epidermidis P. aeruginosa K. oxytoca None E. faecalis S. aureus None
P. aeruginosa E. coli
Organism
None
Aqueous None Vitreous Eviscerated material None Sputum None None
Urine None None
Aqueous
Aqueous Vitreous Urine None Vitreous Eviscerated material None
Vitreous Aqueous
Source
Evisceration
Vitrectomy + intravitreal voriconazole Intravitreal antibiotics Vitrectomy Evisceration Intravitreal antibiotics Intravitreal antibiotics Vitrectomy + intravitreal antibiotics Vitrectomy + intravitreal antibiotics
Intravitreal antibiotics Intravitreal antibiotics Evisceration
Vitrectomy + intravitreal antibiotics
Intravitreal antibiotics Vitrectomy + intravitreal antibiotics Vitrectomy + intravitreal antibiotics Evisceration Vitrectomy + intravitreal antibiotics Evisceration Evisceration
Vitrectomy + intravitreal antibiotics Intravitreal antibiotics
Intervention
NPL
CF PL CF NPL 20/80 NPL CF 20/120
20/60 CF NPL
CF
PL 20/120 CF NPL NPL NPL NPL
NPL NPL
Final VA
Phthisis
BSK None None None None Phthisis None None
None None Juvenile diabetic
None
None None Corneal opacity None Phthisis None None
None None
Remarks
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*Detected on PCR. BSK indicates band shaped keratopathy; CF, counting fingers close to face; CNVM, choroidal neovascular membrane; F, female; HM, hand movement close to face; M, male; NPL, no perception of light; OD, right eye; OS, left eye; PL, light perception only.
Diabetes mellitus Diabetes mellitus, gastroparesis, urinary tract infection, septicemia Diabetes mellitus Diabetes mellitus Diabetes mellitus Diabetes mellitus, enteric fever Diabetes mellitus, septicemia Diabetes mellitus Diabetes mellitus, mitral regurgitation Diabetes mellitus, fungal infection of toes Enteric fever Enteric fever Diabetes mellitus, chronic renal failure Meningitis AIDS, pulmonary tuberculosis Gastroenteritis Urinary tract infection Pulmonary tuberculosis Hepatitis B, liver cirrhosis Diabetes mellitus Diabetes mellitus, chronic renal failure Diabetes mellitus
Medical Condition
Asia-Pacific Journal of Ophthalmology
22
14 15 16 17 18 19 20 21
11 12 13
10
3 4 5 6 7 8 9
1 2
Patient
TABLE 5. Characteristics of Patients With EE With Predisposing Medical Conditions (22 Patients, 22 Eyes)
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The importance of microbiological tests cannot be overemphasized. Obtaining cultures establishes the infectious etiology and allows for the therapy to be individually tailored. It also shows us the changing patterns and sensitivities of the microorganisms. In large series of EE,1,2,4 blood cultures were more likely to be positive than vitreous. In our series, however, the ocular fluid samples tended to give positive culture results more than blood (58.6% vs 3.4%). This is because all the patients with suspected EE immediately underwent an aqueous tap in the outpatient department before any intravitreal therapy. The vitreous samples were collected during vitrectomy, which is known to yield higher culture-positive results than a needle biopsy of the vitreous.11 In addition, for most of the patients, systemic antibiotic treatment was started before referral to our tertiary center. A low microbial inoculum such as in prior antibiotic therapy or fastidious organisms may yield negative results. Some bacteria such as Staphylococcus epidermidis may sterilize spontaneously during the course of the infection.16 A faulty technique of collecting samples may also give negative results. Greenwald et al15 recommended ocular fluid cultures only when the organism cannot be isolated from a nonocular source. Considering the high number of patients with no apparent source of infection and negative blood cultures in our study, we propose ocular fluid sampling and culture as a routine in all cases of EE. This would also avoid a delay in instituting appropriate antibiotic therapy, which can occur in sequential sampling and culture of various specimens before the ocular fluids. Although a wide range of microorganisms have been shown to metastasize to the eye, there are differences in their distribution pattern depending on geography, time, age of the patient, predisposing conditions, and source of sepsis. Grampositive organisms such as S. aureus, Streptococcus pneumoniae, and other streptococcal species are the most common causes of EE in the West, whereas in the East, K. pneumoniae and E. coli are more common.1,3,4 The incidence of Bacillus cereus endophthalmitis has increased since the 1970s because of the increase in the number of intravenous drug abusers.1 There was a reduction in the number of adult cases caused by Neisseria meningitidis, but it remains an important cause of infection in children. A distinct association was noted between Klebsiella liver abscess and Klebsiella EE among the East Asian population. A literature review by Jackson et al1 found that almost two thirds of patients with Klebsiella EE had a liver abscess and half of them were also diabetic. There are no large case series of EE reported from any part of India, barring a few isolated reports of uncommon organisms.7Y9 In a 10-year retrospective study of culture-proven cases of exogenous and EE from the southern part of India by Ramakrishnan et al,17 EE comprised 2.6% of the cases. The most common cause for EE was Gram-positive cocci (63.6%, 7 of 11), of which S. pneumoniae (27.3%, 3 of 11) and S. aureus (18.2%, 2 of 11) were predominant. Gram-negative bacilli were responsible for 36.4% (4 of 11) of the EE, including P. aeruginosa (18.2%, 2 of 11), E. coli (9%, 1 of 11), and K. pneumoniae (9%, 1 of 11). In another study in South India by Bharathi et al6 among 9 cases of culture-proven EE, 7 isolates were Gram negative (P. aeruginosa, 2; Haemophilus influenzae, 2; Haemophilus parainfluenzae, 1; N. meningitidis, 1; K. pneumoniae, 1) and only 2 isolates were Gram positive (S. aureus and S. pneumoniae). A similar trend was seen by Anand et al,18 albeit in postoperative endophthalmitis from southern India. They found Gram-negative organisms in 41.7% (71 of 135) of the isolates, with P. aeruginosa the majority at 17.1% (29 of 135). In our series of EE, we also found Pseudomonas as the most common organism (13.8%, 8 of 58), followed by * 2015 Asia Pacific Academy of Ophthalmology
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Candida (8.6%, 5 of 58) and E. coli (6.9%, 4 of 58). Chen et al19 have reported a large series of endophthalmitis caused by P. aeruginosa, among which 12.5% (9 of 72) were endogenous. The ubiquitous distribution of the organism along with certain characteristics such as the ability to survive for long periods in aqueous solutions, the ability to invade any tissue, and the resistance to phagocytosis and host immune defenses are factors that make Pseudomonas a likely organism for EE. The role of intravitreal antibiotics and vitrectomy has been debated. Greenwald et al15 classified EE based on tissue involvement and strongly recommended withholding intraocular antibiotics in favor of more conservative therapy. They also found no compelling evidence that vitrectomy improved the outcome. In fact, no eye in their series of posterior diffuse EE recovered useful vision, regardless of management. The study by Lim et al20 from Korea noted that though vitrectomy did not have significant visual benefits, it did avoid the need for evisceration. In a recent review of published cases, Jackson et al21 also commented that intravitreal dexamethasone and vitrectomy were associated with a higher chance of retaining useful vision. In our study, we found that there was a definite improvement in ocular signs and visual acuity after vitrectomy and intravitreal antibiotics. The classification by Greenwald et al15 was not useful for us because all eyes in our series had severe diffuse posterior involvement. About two thirds (62.3%) of the patients in our study underwent vitrectomy, and a further 18% were managed with intravitreal and intravenous antibiotics. Nearly 30% of our patients (18 of 61 eyes) regained useful vision of 20/200 or better. Therefore, considering the constraints of a retrospective review of an uncommon condition, our data suggest that a combined aggressive medical and surgical treatment approach can result in preservation of useful vision even in severe EE. A favorable outcome was noted in patients with no known predisposing factors where the host defenses were not compromised and the infection was well contained. In addition, favorable outcomes were noted in culture-positive patients as opposed to culturenegative ones. A positive culture and sensitivity would enable the selection of proper antibiotics, leading to a better outcome. This is in contrast to Sharma et al5 who found superior visual acuity in culture-negative patients. These patients in their series may have had a sterile infection or low virulent bacterial infection. In our study, at the end of available follow-up, 20 eyes (32.8%) were lost. Most of these eyes had infection with P. aeruginosa and E. coli, which are known to be more devastating.18,19 We noted an iris abscess in 1 eye of an 18-year-old patient with P. aeruginosa EE, who did not have any predisposing condition. Ramonas and Freilich22 have reported S. aureus iris abscesses in a patient with bacterial endocarditis. Cumurcu et al23 have reported S. aureus iris abscess with gluteal abscess. Our patient may be the first reported case of an iris abscess in P. aeruginosa EE. Furthermore, 1 of our 3 patients with C. freundii EE had scleral necrosis and thinning. Chen et al24 have studied 6 cases of Citrobacter endophthalmitis and found corneal thinning and perforation in 1 of them. They have stated that endotoxins and proteases were responsible for the extensive damage to the ocular surface tissue. The present study was a hospital-based and record-based study and does not include the longevity data that would have further enhanced the understanding of the long-term effects and outcomes of EE. Our study has presented a clinical profile of EE in southern India. Gram-negative infection leading to a visually devastating result is common in this region. The fact that almost half of the patients were apparently healthy may warrant a more aggressive approach for the diagnosis of suspected EE. The www.apjo.org
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present study is also the first report of P. aeruginosa as the most common cause of culture-positive EE. These findings might be of use in the management of EE in this part of globe and add to the existing information about this rare but potentially devastating ocular disease. ACKNOWLEDGMENTS The authors acknowledge the help of Dr H.N. Madhavan, Dr K. Lily Therese from L & T Microbiology Research Centre, 18, College Road, Chennai. REFERENCES 1. Jackson TL, Eykyn SJ, Graham EM, et al. Endogenous bacterial endophthalmitis: a 17-year prospective series and review of 267 reported cases. Surv Ophthalmol. 2003;48:403Y423.
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10. Shrader SK, Band JD, Lauter CB, et al. The clinical spectrum of endophthalmitis: incidence, predisposing factors, and features influencing outcome. J Infect Dis. 1990;162:115Y120. 11. Zhang YQ, Wang WJ. Treatment outcomes after pars plana vitrectomy for endogenous endophthalmitis. Retina. 2005;25:746Y750. 12. Chee SP, Jap A. Endogenous endophthalmitis. Curr Opin Ophthalmol. 2001;12:464Y470. 13. Zhang H, Liu Z. Endogenous endophthalmitis: a 10-year review of culture-positive cases in northern China. Ocul Immunol Inflamm. 2010;18:133Y138. 14. Keswani T, Ahuja V, Changulani M. Evaluation of outcomes of various treatment methods for endogenous endophthalmitis. Indian J Med Sci. 2006;60:454Y460. 15. Greenwald MJ, Wohl LG, Sell CH. Metastatic bacterial endophthalmitis: a contemporary reappraisal. Surv Ophthalmol. 1986;31:81Y101.
2. Okada AA, Johnson RP, Liles WC, et al. Endogenous bacterial endophthalmitis. Report of a ten-year retrospective study. Ophthalmology. 1994;101:832Y838.
16. Meredith TA, Trabelsi A, Miller MJ, et al. Spontaneous sterilization in experimental Staphylococcus epidermidis endophthalmitis. Invest Ophthalmol Vis Sci. 1990;31:181Y186.
3. Leibovitch I, Lai T, Raymond G, et al. Endogenous endophthalmitis: a 13-year review at a tertiary hospital in South Australia. Scand J Infect Dis. 2005;37:184Y189.
17. Ramakrishnan R, Bharathi MJ, Shivkumar C, et al. Microbiological profile of culture-proven cases of exogenous and endogenous endophthalmitis: a 10-year retrospective study. Eye (Lond). 2009;23:945Y956.
4. Wong JS, Chan TK, Lee HM, et al. Endogenous bacterial endophthalmitis: an East Asian experience and a reappraisal of a severe ocular affliction. Ophthalmology. 2000;107:1483Y1491.
18. Anand AR, Therese KL, Madhavan HN. Spectrum of etiological agents of postoperative endophthalmitis and antibiotic susceptibility of bacterial isolates. Indian J Ophthalmol. 2000;48:123Y128.
5. Sharma S, Padhi TR, Basu S, et al. Endophthalmitis patients seen in a tertiary eye care centre in Odisha: a clinico-microbiological analysis. India J Med Res. 2014;139:91Y98.
19. Chen KJ, Sun MH, Lai CC, et al. Endophthalmitis caused by Pseudomonas aeruginosa in Taiwan. Retina. 2011;31:1193Y1198.
6. Bharathi MJ, Ramakrishnan R, Shivkumar C, et al. Etiology and antibacterial susceptibility pattern of community-acquired bacterial ocular infections in a tertiary eye care hospital in South India. Indian J Ophthalmol. 2010;58:497Y507.
20. Lim HW, Shin JW, Cho HY, et al. Endogenous endophthalmitis in the Korean population: a six-year retrospective study. Retina. 2014;34:592Y602. 21. Jackson TL, Paraskevopoulos T, Georgalas I. Systematic review of 342 cases of endogenous bacterial endophthalmitis. Surv Ophthalmol. 2014;59:627Y635.
7. Kar S, Basu S, Sharma S, et al. Endogenous endophthalmitis caused by bacteria with unusual morphology in direct microscopic examination of the vitreous. Indian J Ophthalmol. 2011;59:329Y331.
22. Ramonas KM, Freilich BD. Iris abscess as an unusual presentation of endogenous endophthalmitis in a patient with bacterial endocarditis. Am J Ophthalmol. 2003;135:228Y229.
8. Dave VP, Majji AB, Pappuru RR. A rare case of Aspergillus terreus endogenous endophthalmitis in a patient of acute lymphoid leukemia with good clinical outcome. Eye (Lond). 2011;25:1094Y1096.
23. Cumurcu T, Demirel S, Doganay S. Iris abscess as an unusual presentation of endogenous endophthalmitis after intramuscular injection. Ocul Immunol Inflamm. 2010;18:190Y191.
9. Sambhav K, Mathai A, Reddy AK, et al. Endogenous endophthalmitis caused by Enterococcus casseliflavus. J Med Microbiol. 2011;60:670Y672.
24. Chen KJ, Sun MH, Hwang YS, et al. Endophthalmitis caused by Citrobacter species. Ocul Immunol Inflamm. 2008;16:147Y153.
We know what we are, but know not what we may be. V William Shakespeare
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Endogenous Endophthalmitis: A 10-Year Retrospective Study at a Tertiary Hospital in South India Dhanashree Ratra, FRCS (Edin), Kumar Saurabh, MS, Debmalya Das, DNB, Kasinathan Nachiappan, FRCS, Amit Nagpal, MS, Ekta Rishi, MS, Pramod Bhende, MS, Tarun Sharma, FRCSEd, and Lingam Gopal, FRCSEd
Purpose: The aim of this study was to review the clinical profile including predisposing systemic conditions, microorganisms responsible, clinical presentation, and outcomes of endogenous endophthalmitis (EE) in South India. Design: This study is a retrospective, noncomparative case series. Methods: This study presents a retrospective analysis of records of patients with EE in a 10-year period. Results: A total of 61 eyes of 58 patients were included in the study. Preceding systemic illness or surgery was noted in 31 patients (53.4%). No predisposing condition was found in 27 patients (46.5%). All eyes had severe diffuse EE. Culture positivity was seen in 34 of 58 patients (58.6%). Gram-positive organisms were isolated in 9 cases (15.5%), and Gram-negative organisms were isolated in 20 cases (34.5%). Pseudomonas aeruginosa (13.8%) was the most common isolate. Eleven eyes (18%) were managed medically with intravenous and intravitreal antibiotics, and 38 eyes (62.3%) also underwent vitrectomy. Eight eyes (13.1%) required repeat vitrectomy, and 12 eyes (19.7%) were eviscerated. The mean follow-up was 16.2 T 13.9 months. Final visual acuity of 20/200 or better was seen in 29.5% eyes. A favorable outcome was noted in culture-positive patients (P = 0.03) and in patients with no predisposing causes. Conclusions: This study provides information about the clinical and microbiologic profile of EE. Aggressive medical and surgical treatment can result in favorable outcomes. Key Words: endogenous endophthalmitis, adult, Pseudomonas, vitrectomy, India, diabetes mellitus (Asia Pac J Ophthalmol 2015;4: 286Y292)
In addition, the associated septicemia may be life threatening with a mortality rate of 5% to 15%.1 The associated systemic factors include chronic debilitating and immune suppressive diseases [diabetes, renal failure, malignancy, acquired immune deficiency syndrome (AIDS), organ transplantation], long-term indwelling catheters, intravenous drug abuse, endocarditis, urinary tract infections, recent major surgeries, and dental procedures. Systemic disease may be obvious or subtle. In 1 review, only 57% of patients with bacterial EE had systemic symptoms.2 These cases add to the diagnostic and therapeutic challenge. The management encompasses treatment of the eye disease as well as a search for the source of infection. Large case series have reported variation in the causative pathogen based on geographic location.1,3Y5 Gram-positive bacteria were more common in Western countries, whereas Gramnegative organisms were more prevalent in East Asian countries. In the bacterial etiology, their susceptibility was seen to differ greatly by region within the country as well.6 This emphasizes the need for reporting EE from different geographic areas. Knowledge of these changing patterns may help in choosing the initial empirical treatment when culture reports are awaited or are negative. Studies from India have mainly concentrated on postsurgical or posttraumatic endophthalmitis with inclusion of only a few cases of EE.5Y9 The present study was performed to determine the clinical profile of EE in South India. It was aimed at identifying the predisposing systemic disease conditions, the microorganisms responsible, clinical presentations, and outcomes of EE in this part of the country.
MATERIALS AND METHODS
E
ndogenous endophthalmitis (EE) is a rare but potentially blinding intraocular infection. In contrast to exogenous endophthalmitis where the microorganism gains entry into the eye from the external environment after intraocular surgery or an injury, the source of infection in EE is via the blood stream. Endogenous endophthalmitis is much less common than exogenous endophthalmitis and is estimated to account for 2% to 6% of all endophthalmitis cases.1 The visual prognosis in such cases is often poor, leading to blindness, atrophy of the globe, or evisceration.
From the Bhagawan Mahavir Department of Vitreoretinal Diseases, Sankara Nethralaya Medical Research Foundation, Chennai, India. Received for publication November 2, 2014; accepted April 9, 2015. The authors have no funding or conflicts of interest to declare. Reprints: Dhanashree Ratra, MS, DNB, FRCS (Edin), C-MER (Shenzhen) Dennis Lam Eye Hospital, 1-2/F Shengtang Building, Futian, Shenzhen, China. E-mail: [email protected]. Copyright * 2015 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0000000000000120
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This is a retrospective analysis of case records of 61 eyes of 58 patients with EE treated at our center in a 10-year period from January 2000 to December 2009. The study was approved by the institutional review board. The data obtained from the medical records included demographic details such as age, sex, and area of residence. The patients’ medical history was scrutinized in detail to ascertain predisposing factors. A history of diabetes mellitus, malignancy, chronic illnesses, therapy with immunosuppressive medicines, recent surgery, infection, or blood transfusion was noted. Patients with recent intraocular surgery (within the previous 5 years), intraocular trauma (within the previous year), or any other external source of infection were excluded from the study. Records with ambiguous information or inadequate follow-up were excluded. The eye affected and the best-corrected visual acuity (BCVA) for each eye were noted from the records. Slit-lamp examination findings pertaining to the status of the cornea, anterior chamber, hypopyon, iris, and lens changes were noted. On indirect ophthalmoscopy, the grade of visibility and vitreous involvement was recorded. In the status of the retina, any retinal or choroidal changes were noted in cases where visualization
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was possible. In cases with media opacities, ultrasonography was done to exclude retinal detachment and to determine the status of vitreous inflammation. Various specimens were collected for culture. Aqueous tap was the first step in the microbiological analysis. It was done in the outpatient department at the first visit. Patients were comfortably seated in a reclining chair, and indirect ophthalmoscope was used as the light source. After cleaning the eye and the periocular skin with 5% povidone iodine and applying a wire speculum, a 30-gauge needle mounted on a 1-mL disposable syringe was used for aspirating approximately 0.1 mL of aqueous humor. Vitreous samples were always collected during planned therapeutic vitrectomy. A vitrectomy cutter was used to obtain a vitreous sample. The aspiration line was connected to a 10-mL disposable syringe, and the assistant was asked to apply gentle suction while the surgeon actuated the vitrectomy cutter. During this process, the infusion line was kept blocked to avoid dilution of the vitreous sample. A separate vitreous tap was not done for eyes that did not undergo vitrectomy. In patients undergoing evisceration, the eviscerated specimen was subjected to microbiological and histopathological analysis. In all cases of EE, blood and urine samples were collected for culture. Other specimens were sometimes collected based on the original site of infection. Various case-specific investigations were done, which included complete blood counts, chest x-ray, abdominal ultrasonography, and so on. The samples were studied with Gram stain, 10% wet potassium hydroxide mount, Giemsa stain, and Ziehl-Neelsen stain to identify bacterial or fungal etiology. Samples were directly inoculated on blood agar, chocolate agar, Sabouraud dextrose agar, thioglycolate medium, brain-heart infusion agar, and Lowenstein-Jensen agar. Polymerase chain reaction (PCR) tests were done on the aqueous and vitreous samples in all cases. A positive culture was defined as growth of the same organism on 2 or more solid phase media or confluent growth on 1 solid medium. Antimicrobial sensitivity patterns were recorded using the Kirby-Bauer disc diffusion method. All patients were started on intravenous cefotaxime 1 g thrice a day and intravenous gentamicin 80 mg 2 times a day. Intravitreal antibiotics were chosen based on the culture or PCR report. Initial therapy before culture reports or in cases with negative culture and PCR results was done with intravitreal vancomycin (1 mg/0.1 mL) and ceftazidime (2.25 mg/0.1 mL). Intravitreal steroids were added if the clinician was sure of having ruled out a fungal infection. The treatment was modified based on susceptibility reports and clinical response. Cases with fungal isolates were treated with antifungal agents based on susceptibility and patient affordability. Fluconazole (100 mg twice daily) or voriconazole (200 mg loading dose followed by 100 mg daily) were used as oral antifungals. Intravitreal voriconazole (50 Kg) or amphotericin B (5 Kg) was administered until clinical improvement. Liver function tests were monitored during the antifungal treatment. A favorable anatomical outcome was defined as an attached retina with clear vitreous cavity at the final follow-up. In addition, a favorable functional outcome was defined as a final visual acuity of 20/200 or better. Modalities of treatment and follow-up data were recorded at 1 month, 3 months, 6 months, 1 year, and yearly thereafter. At each visit, the visual acuity and retinal status were noted. The results were analyzed using the W2 test.
RESULTS Of a total of 58 patients with EE, 36 (62.1%) were male and 22 (37.9%) were female. The age of the patients ranged * 2015 Asia Pacific Academy of Ophthalmology
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from 18 to 73 years (mean, 34.6 T 14.9 years). The disease was bilateral in 3 (5.2%) and unilateral in 55 (94.8%) patients. Of the total 61 eyes, the right eye (35, 57.4%) was more commonly involved than the left eye (26, 42.6%). Endogenous endophthalmitis was preceded by an episode of systemic illness in 22 patients (37.9%). Nine (15.5%) had a history of undergoing systemic surgery before the onset of EE. No systemic predisposing disease condition was noted for 27 patients (46.5%). Table 1 lists the various systemic causes. Except for 1 patient (1.7%) who was AIDS positive, all were apparently immunocompetent. Among the 61 eyes with EE, 8 eyes (13.1%) had no light perception at the time of presentation, and 38 (62.3%) had only light perception. Ten (16.4%) eyes had BCVA of less than hand movements to 20/200, and only 5 eyes (8.19%) had a relatively good BCVA of 20/200 to less than 20/60. None of the eyes had better than or equal to 20/60. Reduced vision (60, 98.4%), redness (47, 77%), and pain (42, 68.8%) were the 3 most common presenting symptoms. Other symptoms included watering and discharge in 13 eyes (21.3%) and swelling of the eye, floaters, and intolerance to light in 2 eyes (3.3%) each. All eyes had severe diffuse endophthalmitis involving the posterior segment. Diffuse vitreous exudates were seen in 47 eyes (77%). In 14 eyes (22.9%), a cataractous lens precluded a view of the vitreous cavity; however, ultrasound examination revealed vitreous involvement in these eyes too. Retina could be visualized in 13 eyes (21.3%) only, and in 3 (4.9%) of them, it was detached. None had panophthalmitis. A positive culture from either ocular or other body fluids was obtained in 34 patients (58.6%). Vitreous was positive in 16 patients (27.6%) and aqueous in 11 patients (18.9%). Other samples with positive cultures were blood (2, 3.4%), sputum (1, 1.7%), and urine (4, 6.9%). In 3 cases (5.2%), microorganisms were isolated from the eviscerated material. The microorganisms identified have been enumerated in Table 2. Of these 34 culture-positive cases, 29 (85.3%) had bacterial and
TABLE 1. Systemic Ailments in EE (N = 58)* None 27 (46.5%) Medical conditions* 22 (37.9%) Diabetes mellitus 14 (24.1%) Enteric fever 3 (5.2%) Chronic renal failure 2 (3.4%) Urinary tract infection 2 (3.4%) Pulmonary tuberculosis 2 (3.4%) Septicemia 2 (3.4%) Meningitis, diarrhea, AIDS, hepatitis B, 1 each (1.7%) gastroparesis, liver cirrhosis, fungal infection of toes, mitral regurgitation Surgical conditions 9 (15.5%) Abdominal surgery 6 (10.3%) Appendectomy 2 (3.4%) Total gastrectomy, cesarean delivery, laparotomy 1 each (1.7%) and intestinal reanastomosis, pouch excision Genitourinary surgery 2 (3.4%) Urinary lithotripsy, surgical termination 1 each (1.7%) of pregnancy Head and neck surgery 1 (1.7%) Tooth extraction 1 (1.7%) *Some patients had more than 1 systemic condition.
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TABLE 2. Causative Microorganisms Identified in Patients With EE (N = 58)
P. aeruginosa E. coli C. albicans S. epidermidis S. aureus C. freundii E. faecalis M. tuberculosis* S. viridans Candida tropicalis Candida parapsilosis Alcaligenes faecalis Acinetobacter calcoaceticus Aeromonas specie K. pneumoniae Klebsiella oxytoca P. acnes* Total
Total
Aqueous
Vitreous
8 (13.8%) 4 (6.9%) 3 (5.2%) 3 (5.2%) 3 (5.2%) 3 (5.2%) 2 (3.4%) 2 (3.4%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 37 (63.8%)
3 (5.2%) 1 (1.7%)
5 (8.6%)
1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%)
Eviscerated Material
Blood
Urine
Sputum
3 (5.1%) 3 2 1 2 1
(5.2%) (3.4%) (1.7%) (3.4%) (1.7%)
1 (1.7%) 1 (1.7%) 1 (1.7%)
1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 1 (1.7%) 11 (18.9%)
16 (27.6%)
3 (5.2%)
2 (3.4%)
4 (6.8%)
1 (1.7%)
*Identified on PCR.
5 (14.7%) had fungal isolates. Among bacterial isolates, 9 (26.5%) were Gram positive and 20 (58.8%) were Gram negative. An antimicrobial sensitivity record of the isolated microorganisms was available for 25 patients (43.1%) (Table 3). All isolates of Pseudomonas aeruginosa were sensitive to ciprofloxacin. Similarly, all staphylococci were sensitive to vancomycin, and all Escherichia coli isolates were sensitive to amikacin. All of the 24 patients (41.4%) with negative culture were under intravenous antibiotic treatment for 1 week or more before attending our hospital. Three cases revealed microorganisms on PCR (Mycobacterium tuberculosis in 2 cases and Propionibacterium acnes in 1 case). Overall, 11 eyes (18%) were managed medically with intravenous and intravitreal antibiotics. Vitrectomy was required in 38 eyes (62.3%) at the initial phase of management. Twelve eyes (19.7%) needed evisceration. During further follow-up, 8 eyes (13.11%) needed repeat vitrectomy within 2 weeks due to the persistence of intraocular infection. The mean follow-up period was 16.2 T 13.9 months (range, 6 months to 6 years). At the final follow-up, 33 eyes (54%) had attached retina with clear vitreous cavity, 5 eyes (8.2%) had
inoperable retinal detachment, and 11 (18%) had phthisis bulbi. Twenty eyes (32.8%) had lost light perception, whereas 12 eyes (19.7%) had light perception only. The final BCVA was hand movement to less than 20/200 in 11 eyes (18%) and 20/200 to less than 20/60 in 7 eyes (11.5%). Only 11 eyes (18%) had final BCVA in the range of 20/60 to 20/20. Among the eyes with no light perception (n = 20), P. aeruginosa (4, 20%) and E. coli (2, 10%) were the most common isolates, whereas 8 (40%) such eyes were culture and PCR negative. In the remaining eyes, Enterococcus faecalis, Streptococcus viridans, Staphylococcus aureus, Aeromonas, Klebsiella pneumoniae, and Citrobacter freundii were isolated in 1 case (5%) each. Favorable anatomical outcome defined as an attached retina at the final follow-up was noted in 18 (64.3%) of 28 eyes among apparently healthy individuals with no known predisposing condition. In individuals with predisposing medical conditions, favorable anatomical outcome was noted in 10 (45.4%) of 22 eyes (P = 0.18). Similarly, 5 (45.4%) of 11 eyes of individuals with predisposing surgical conditions had favorable anatomical outcomes (P = 0.06). Favorable functional outcome defined as final visual acuity of 20/200 or better was noted
TABLE 3. In Vitro Antimicrobial Sensitivity of the Microorganisms Isolated From EE Cases (n = 25)* Organism P. aeruginosa E. coli S. epidermidis S. aureus† C. freundii‡ E. faecalis
Ciprofloxacin 100% (8/8) 0% (0/4) 100% (3/3) Not done 66.6% (2/3) 0% (0/2)
Amikacin
Gentamicin Cefotaxime Ceftazidime Vancomycin Chloramphenicol Azithromycin
100% (8/8) 37.5% (3/8) 37.5% (3/8) 25% (2/8) 100% (4/4) 75% (3/4) 25% (1/4) 25% (1/4) Not done 100% (3/3) 100% (3/3) 66.6% (2/3) Not done Not done 66.6% (2/3) 0% (0/3) 66.6% (2/3) 66.6% (2/3) 66.6% (2/3) 66.6% (2/3) Not done 50% (1/2) 100% (2/2) 0% (0/2)
0% (0/8) Not done 100% (3/3) 100% (3/3) Not done 100% (2/2)
0% (0/8) 75% (3/4) Not done Not done 0% (0/3) Not done
0% (0/8) Not done Not done Not done 0% (0/3) Not done
*Two isolates of C. albicans were sensitive to fluconazole, amphotericin B, and voriconazole and were resistant to natamycin. †All isolates of S. aureus were sensitive to methicillin. ‡One isolate of C. freundii was resistant to all antibiotics; it was tested for imipenem, azithromycin, cotrimoxazole, and chloramphenicol.
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Phthisis PL Intravitreal antibiotics None None CF M 38 OD 9
8
CF indicates counting fingers close to face; CNVM, choroidal neovascular membrane; HM, hand movement close to face; F indicates female; M, male; NPL, no perception of light; OD, right eye; OS, left eye; PL, light perception only; VA, visual acuity.
None 20/80 Intravitreal antibiotics Aqueous P. aeruginosa CF M 52
NPL F 54 OS
Total gastrectomy for neuroendocrine malignancy Laparotomy and intestinal reanastomosis Intestinal pouch excision 7
OD
None NPL
CF 20/80 NPL HM PL NPL PL NPL
C. albicans Vitreous Vitrectomy + intravitreal voriconazole C. albicans Vitreous Vitrectomy + intravitreal voriconazole None None None C. parapsilosis Vitreous Vitrectomy + intravitreal voriconazole None None Vitrectomy + intravitreal antibiotics None None Vitrectomy + intravitreal antibiotics None None Vitrectomy + intravitreal antibiotics C. freundii Eviscerated Evisceration material None None Intravitreal antibiotics PL PL NPL CF CF CF PL NPL F F F M F F F F 34 34 30 31 48 48 29 30 OD OS OD OD OD OS OD OD Lithotripsy for renal calculi Lithotripsy for renal calculi Appendectomy Appendectomy Tooth extraction Tooth extraction Surgical termination of pregnancy Cesarean delivery 1 1 2 3 4 4 5 6
Organism Eye Age, y Sex Initial VA
TABLE 4. Characteristics of Patients With EE After Systemic Surgery (9 Patients, 11 Eyes)
DISCUSSION Although EE is responsible for only 2% to 6% of the total cases of endophthalmitis, its management poses a greater challenge because of the occult nature of the infection or complicating systemic disease conditions.2,10,11 Presence of EE in apparently healthy individuals may herald systemic sepsis.1 Hence the management of EE incorporates not only the control and treatment of the eye infection but also the search and eradication of the systemic sepsis. The absence of antecedent events such as surgery or trauma may delay the identification of EE in an inflamed eye in a systemically ill person.12 Early diagnosis and treatment are imperative for salvaging useful vision. The fact that etiology and features of EE may vary from 1 region of the globe to another puts further emphasis on reporting from different geographic areas.1,3Y6 Similar to other studies, our study too had a male preponderance with unilateral involvement.3,11,13,14 The right eye was more commonly involved than the left eye. Theoretically, the infectious load present in the blood stream should reach equally to both eyes, making bilateral EE more common. However, a predilection for right eye involvement has been reported by many.3,11,13 Greenwald et al15 attributed it to more proximal and direct blood flow to the carotid artery on the right side. Predisposing systemic disease conditions were noted in around half (31 patients, 53.4%) of our patients. Diabetes mellitus was the most common medical condition associated (14 patients, 24.1%), whereas abdominal surgery was the most common surgical predisposing condition (6 patients, 10.3%). The rest of the patients (27, 46.5%) did not have any predisposing systemic conditions. Leibovitch et al3 from Australia (13 cases), Zhang and Liu13 from China (19 cases), and Keswani et al14 from India (14 cases) found at least 1 predisposing systemic condition in all their patients. The occurrence ranges from 73% to 92.6% in various reports,1,4,11 whereas Okada et al2 and Jackson and colleagues1 in the reviewed literature found predisposing systemic conditions in only 56% (149 of 267) of the cases. A transient bacteremia that causes minimal systemic symptoms and clears quickly may go unnoticed by the patient. There is a high risk of misdiagnosis in such a situation where obvious predisposing conditions are absent. The common misdiagnoses are noninfectious uveitis and acute angle closure glaucoma.1
Source
Intervention
Final VA
Remarks
in 42.8% (12 of 28 eyes) of apparently healthy individuals, 18.2% (4 of 22 eyes) of patients with predisposing medical conditions, and 18.2% (2 of 11 eyes) of patients with predisposing surgical conditions (P = 0.28 and 0.14, respectively). Favorable anatomical outcome was noted in 65.7% (23 of 35) of the culture-positive eyes in contrast to 38.5% (10 of 26) of the culture-negative eyes. This difference was statistically significant (P = 0.03). A favorable functional outcome was noted in 37.1% (13 of 35) of the culture-positive eyes and 9.2% (5 of 26) of the culture-negative eyes (P = 0.12). Tables 4 and 5 give a clinical summary of patients with predisposing disease conditions, the organisms isolated, and their final outcomes. Candida albicans was isolated from both eyes of a patient who underwent lithotripsy for renal stones. One of these eyes developed choroidal neovascular membrane, which was treated with 3 injections of ranibizumab. Vision improved to 20/60 at final follow-up. One patient developed C. freundii EE 1 month after a lower segment cesarean delivery. This eye had scleral necrosis and thinning. We also noted an iris abscess in 1 eye of an 18-year-old patient with P. aeruginosa EE. However, he did not have any predisposing systemic conditions.
Endogenous Endophthalmitis in South India
Macular scar CNVM treated with ranibizumab Phthisis None Total corneal opacity Phthisis Macular scar None
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OS
OD OD OD OD OS OD OS OS
OS OD OS
OD
OD OD OD OD OS OD OS
OS OD
Eye
62
38 34 19 50 50 50 39 69
22 25 19
44
35 36 45 61 55 68 73
38 58
Age, y
F
M M M M M M F M
F F M
M
M F M M F M M
F F
Sex
NPL
20/120 PL CF NPL 20/120 PL PL PL
20/200 20/200 NPL
PL
PL PL PL PL PL PL NPL
20/20 NPL
Initial VA
None
C. tropicalis None P. acnes* Aeromonas None K. pneumoniae None None
E. coli None None
M. tuberculosis*
S. epidermidis P. aeruginosa K. oxytoca None E. faecalis S. aureus None
P. aeruginosa E. coli
Organism
None
Aqueous None Vitreous Eviscerated material None Sputum None None
Urine None None
Aqueous
Aqueous Vitreous Urine None Vitreous Eviscerated material None
Vitreous Aqueous
Source
Evisceration
Vitrectomy + intravitreal voriconazole Intravitreal antibiotics Vitrectomy Evisceration Intravitreal antibiotics Intravitreal antibiotics Vitrectomy + intravitreal antibiotics Vitrectomy + intravitreal antibiotics
Intravitreal antibiotics Intravitreal antibiotics Evisceration
Vitrectomy + intravitreal antibiotics
Intravitreal antibiotics Vitrectomy + intravitreal antibiotics Vitrectomy + intravitreal antibiotics Evisceration Vitrectomy + intravitreal antibiotics Evisceration Evisceration
Vitrectomy + intravitreal antibiotics Intravitreal antibiotics
Intervention
NPL
CF PL CF NPL 20/80 NPL CF 20/120
20/60 CF NPL
CF
PL 20/120 CF NPL NPL NPL NPL
NPL NPL
Final VA
Phthisis
BSK None None None None Phthisis None None
None None Juvenile diabetic
None
None None Corneal opacity None Phthisis None None
None None
Remarks
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*Detected on PCR. BSK indicates band shaped keratopathy; CF, counting fingers close to face; CNVM, choroidal neovascular membrane; F, female; HM, hand movement close to face; M, male; NPL, no perception of light; OD, right eye; OS, left eye; PL, light perception only.
Diabetes mellitus Diabetes mellitus, gastroparesis, urinary tract infection, septicemia Diabetes mellitus Diabetes mellitus Diabetes mellitus Diabetes mellitus, enteric fever Diabetes mellitus, septicemia Diabetes mellitus Diabetes mellitus, mitral regurgitation Diabetes mellitus, fungal infection of toes Enteric fever Enteric fever Diabetes mellitus, chronic renal failure Meningitis AIDS, pulmonary tuberculosis Gastroenteritis Urinary tract infection Pulmonary tuberculosis Hepatitis B, liver cirrhosis Diabetes mellitus Diabetes mellitus, chronic renal failure Diabetes mellitus
Medical Condition
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14 15 16 17 18 19 20 21
11 12 13
10
3 4 5 6 7 8 9
1 2
Patient
TABLE 5. Characteristics of Patients With EE With Predisposing Medical Conditions (22 Patients, 22 Eyes)
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The importance of microbiological tests cannot be overemphasized. Obtaining cultures establishes the infectious etiology and allows for the therapy to be individually tailored. It also shows us the changing patterns and sensitivities of the microorganisms. In large series of EE,1,2,4 blood cultures were more likely to be positive than vitreous. In our series, however, the ocular fluid samples tended to give positive culture results more than blood (58.6% vs 3.4%). This is because all the patients with suspected EE immediately underwent an aqueous tap in the outpatient department before any intravitreal therapy. The vitreous samples were collected during vitrectomy, which is known to yield higher culture-positive results than a needle biopsy of the vitreous.11 In addition, for most of the patients, systemic antibiotic treatment was started before referral to our tertiary center. A low microbial inoculum such as in prior antibiotic therapy or fastidious organisms may yield negative results. Some bacteria such as Staphylococcus epidermidis may sterilize spontaneously during the course of the infection.16 A faulty technique of collecting samples may also give negative results. Greenwald et al15 recommended ocular fluid cultures only when the organism cannot be isolated from a nonocular source. Considering the high number of patients with no apparent source of infection and negative blood cultures in our study, we propose ocular fluid sampling and culture as a routine in all cases of EE. This would also avoid a delay in instituting appropriate antibiotic therapy, which can occur in sequential sampling and culture of various specimens before the ocular fluids. Although a wide range of microorganisms have been shown to metastasize to the eye, there are differences in their distribution pattern depending on geography, time, age of the patient, predisposing conditions, and source of sepsis. Grampositive organisms such as S. aureus, Streptococcus pneumoniae, and other streptococcal species are the most common causes of EE in the West, whereas in the East, K. pneumoniae and E. coli are more common.1,3,4 The incidence of Bacillus cereus endophthalmitis has increased since the 1970s because of the increase in the number of intravenous drug abusers.1 There was a reduction in the number of adult cases caused by Neisseria meningitidis, but it remains an important cause of infection in children. A distinct association was noted between Klebsiella liver abscess and Klebsiella EE among the East Asian population. A literature review by Jackson et al1 found that almost two thirds of patients with Klebsiella EE had a liver abscess and half of them were also diabetic. There are no large case series of EE reported from any part of India, barring a few isolated reports of uncommon organisms.7Y9 In a 10-year retrospective study of culture-proven cases of exogenous and EE from the southern part of India by Ramakrishnan et al,17 EE comprised 2.6% of the cases. The most common cause for EE was Gram-positive cocci (63.6%, 7 of 11), of which S. pneumoniae (27.3%, 3 of 11) and S. aureus (18.2%, 2 of 11) were predominant. Gram-negative bacilli were responsible for 36.4% (4 of 11) of the EE, including P. aeruginosa (18.2%, 2 of 11), E. coli (9%, 1 of 11), and K. pneumoniae (9%, 1 of 11). In another study in South India by Bharathi et al6 among 9 cases of culture-proven EE, 7 isolates were Gram negative (P. aeruginosa, 2; Haemophilus influenzae, 2; Haemophilus parainfluenzae, 1; N. meningitidis, 1; K. pneumoniae, 1) and only 2 isolates were Gram positive (S. aureus and S. pneumoniae). A similar trend was seen by Anand et al,18 albeit in postoperative endophthalmitis from southern India. They found Gram-negative organisms in 41.7% (71 of 135) of the isolates, with P. aeruginosa the majority at 17.1% (29 of 135). In our series of EE, we also found Pseudomonas as the most common organism (13.8%, 8 of 58), followed by * 2015 Asia Pacific Academy of Ophthalmology
Endogenous Endophthalmitis in South India
Candida (8.6%, 5 of 58) and E. coli (6.9%, 4 of 58). Chen et al19 have reported a large series of endophthalmitis caused by P. aeruginosa, among which 12.5% (9 of 72) were endogenous. The ubiquitous distribution of the organism along with certain characteristics such as the ability to survive for long periods in aqueous solutions, the ability to invade any tissue, and the resistance to phagocytosis and host immune defenses are factors that make Pseudomonas a likely organism for EE. The role of intravitreal antibiotics and vitrectomy has been debated. Greenwald et al15 classified EE based on tissue involvement and strongly recommended withholding intraocular antibiotics in favor of more conservative therapy. They also found no compelling evidence that vitrectomy improved the outcome. In fact, no eye in their series of posterior diffuse EE recovered useful vision, regardless of management. The study by Lim et al20 from Korea noted that though vitrectomy did not have significant visual benefits, it did avoid the need for evisceration. In a recent review of published cases, Jackson et al21 also commented that intravitreal dexamethasone and vitrectomy were associated with a higher chance of retaining useful vision. In our study, we found that there was a definite improvement in ocular signs and visual acuity after vitrectomy and intravitreal antibiotics. The classification by Greenwald et al15 was not useful for us because all eyes in our series had severe diffuse posterior involvement. About two thirds (62.3%) of the patients in our study underwent vitrectomy, and a further 18% were managed with intravitreal and intravenous antibiotics. Nearly 30% of our patients (18 of 61 eyes) regained useful vision of 20/200 or better. Therefore, considering the constraints of a retrospective review of an uncommon condition, our data suggest that a combined aggressive medical and surgical treatment approach can result in preservation of useful vision even in severe EE. A favorable outcome was noted in patients with no known predisposing factors where the host defenses were not compromised and the infection was well contained. In addition, favorable outcomes were noted in culture-positive patients as opposed to culturenegative ones. A positive culture and sensitivity would enable the selection of proper antibiotics, leading to a better outcome. This is in contrast to Sharma et al5 who found superior visual acuity in culture-negative patients. These patients in their series may have had a sterile infection or low virulent bacterial infection. In our study, at the end of available follow-up, 20 eyes (32.8%) were lost. Most of these eyes had infection with P. aeruginosa and E. coli, which are known to be more devastating.18,19 We noted an iris abscess in 1 eye of an 18-year-old patient with P. aeruginosa EE, who did not have any predisposing condition. Ramonas and Freilich22 have reported S. aureus iris abscesses in a patient with bacterial endocarditis. Cumurcu et al23 have reported S. aureus iris abscess with gluteal abscess. Our patient may be the first reported case of an iris abscess in P. aeruginosa EE. Furthermore, 1 of our 3 patients with C. freundii EE had scleral necrosis and thinning. Chen et al24 have studied 6 cases of Citrobacter endophthalmitis and found corneal thinning and perforation in 1 of them. They have stated that endotoxins and proteases were responsible for the extensive damage to the ocular surface tissue. The present study was a hospital-based and record-based study and does not include the longevity data that would have further enhanced the understanding of the long-term effects and outcomes of EE. Our study has presented a clinical profile of EE in southern India. Gram-negative infection leading to a visually devastating result is common in this region. The fact that almost half of the patients were apparently healthy may warrant a more aggressive approach for the diagnosis of suspected EE. The www.apjo.org
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present study is also the first report of P. aeruginosa as the most common cause of culture-positive EE. These findings might be of use in the management of EE in this part of globe and add to the existing information about this rare but potentially devastating ocular disease. ACKNOWLEDGMENTS The authors acknowledge the help of Dr H.N. Madhavan, Dr K. Lily Therese from L & T Microbiology Research Centre, 18, College Road, Chennai. REFERENCES 1. Jackson TL, Eykyn SJ, Graham EM, et al. Endogenous bacterial endophthalmitis: a 17-year prospective series and review of 267 reported cases. Surv Ophthalmol. 2003;48:403Y423.
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10. Shrader SK, Band JD, Lauter CB, et al. The clinical spectrum of endophthalmitis: incidence, predisposing factors, and features influencing outcome. J Infect Dis. 1990;162:115Y120. 11. Zhang YQ, Wang WJ. Treatment outcomes after pars plana vitrectomy for endogenous endophthalmitis. Retina. 2005;25:746Y750. 12. Chee SP, Jap A. Endogenous endophthalmitis. Curr Opin Ophthalmol. 2001;12:464Y470. 13. Zhang H, Liu Z. Endogenous endophthalmitis: a 10-year review of culture-positive cases in northern China. Ocul Immunol Inflamm. 2010;18:133Y138. 14. Keswani T, Ahuja V, Changulani M. Evaluation of outcomes of various treatment methods for endogenous endophthalmitis. Indian J Med Sci. 2006;60:454Y460. 15. Greenwald MJ, Wohl LG, Sell CH. Metastatic bacterial endophthalmitis: a contemporary reappraisal. Surv Ophthalmol. 1986;31:81Y101.
2. Okada AA, Johnson RP, Liles WC, et al. Endogenous bacterial endophthalmitis. Report of a ten-year retrospective study. Ophthalmology. 1994;101:832Y838.
16. Meredith TA, Trabelsi A, Miller MJ, et al. Spontaneous sterilization in experimental Staphylococcus epidermidis endophthalmitis. Invest Ophthalmol Vis Sci. 1990;31:181Y186.
3. Leibovitch I, Lai T, Raymond G, et al. Endogenous endophthalmitis: a 13-year review at a tertiary hospital in South Australia. Scand J Infect Dis. 2005;37:184Y189.
17. Ramakrishnan R, Bharathi MJ, Shivkumar C, et al. Microbiological profile of culture-proven cases of exogenous and endogenous endophthalmitis: a 10-year retrospective study. Eye (Lond). 2009;23:945Y956.
4. Wong JS, Chan TK, Lee HM, et al. Endogenous bacterial endophthalmitis: an East Asian experience and a reappraisal of a severe ocular affliction. Ophthalmology. 2000;107:1483Y1491.
18. Anand AR, Therese KL, Madhavan HN. Spectrum of etiological agents of postoperative endophthalmitis and antibiotic susceptibility of bacterial isolates. Indian J Ophthalmol. 2000;48:123Y128.
5. Sharma S, Padhi TR, Basu S, et al. Endophthalmitis patients seen in a tertiary eye care centre in Odisha: a clinico-microbiological analysis. India J Med Res. 2014;139:91Y98.
19. Chen KJ, Sun MH, Lai CC, et al. Endophthalmitis caused by Pseudomonas aeruginosa in Taiwan. Retina. 2011;31:1193Y1198.
6. Bharathi MJ, Ramakrishnan R, Shivkumar C, et al. Etiology and antibacterial susceptibility pattern of community-acquired bacterial ocular infections in a tertiary eye care hospital in South India. Indian J Ophthalmol. 2010;58:497Y507.
20. Lim HW, Shin JW, Cho HY, et al. Endogenous endophthalmitis in the Korean population: a six-year retrospective study. Retina. 2014;34:592Y602. 21. Jackson TL, Paraskevopoulos T, Georgalas I. Systematic review of 342 cases of endogenous bacterial endophthalmitis. Surv Ophthalmol. 2014;59:627Y635.
7. Kar S, Basu S, Sharma S, et al. Endogenous endophthalmitis caused by bacteria with unusual morphology in direct microscopic examination of the vitreous. Indian J Ophthalmol. 2011;59:329Y331.
22. Ramonas KM, Freilich BD. Iris abscess as an unusual presentation of endogenous endophthalmitis in a patient with bacterial endocarditis. Am J Ophthalmol. 2003;135:228Y229.
8. Dave VP, Majji AB, Pappuru RR. A rare case of Aspergillus terreus endogenous endophthalmitis in a patient of acute lymphoid leukemia with good clinical outcome. Eye (Lond). 2011;25:1094Y1096.
23. Cumurcu T, Demirel S, Doganay S. Iris abscess as an unusual presentation of endogenous endophthalmitis after intramuscular injection. Ocul Immunol Inflamm. 2010;18:190Y191.
9. Sambhav K, Mathai A, Reddy AK, et al. Endogenous endophthalmitis caused by Enterococcus casseliflavus. J Med Microbiol. 2011;60:670Y672.
24. Chen KJ, Sun MH, Hwang YS, et al. Endophthalmitis caused by Citrobacter species. Ocul Immunol Inflamm. 2008;16:147Y153.
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