Infectious Sources, Prognostic Factors, and Visual Outcomes of Endogenous Klebsiella pneumoniae Endophthalmitis

Infectious Sources, Prognostic Factors, and Visual Outcomes of Endogenous Klebsiella pneumoniae Endophthalmitis Ya-Han Li, MD,1,2 Yi-Hua Chen, MD,1 Kuan-Jen Chen, MD,1 Nan-Kai Wang, MD, PhD,1 Ming-Hui Sun, MD, PhD,1 An-Ning Chao, MD,1 Laura Liu, MD, PhD,1 Yu-Jr Lin, BS,3 Wei-Chi Wu, MD, PhD,1 Yih-Shiou Hwang, MD, PhD,1 Chi-Chun Lai, MD,1 Tun-Lu Chen, MD1 Purpose: To investigate the infectious sources and prognostic factors for poor visual outcome, including subjective symptoms, presenting clinical features, laboratory data, and treatments, in patients diagnosed with endogenous Klebsiella pneumoniae endophthalmitis (EKE) at a tertiary referral center in Northern Taiwan. Design: Retrospective, single-institution, consecutive case series. Participants: One hundred ten consecutive patients (124 eyes) diagnosed with EKE. Methods: One hundred ten patients (124 eyes) were reviewed retrospectively between January 1996 and April 2013. Main Outcome Measures: Visual acuity (VA), subjective symptoms, presenting clinical features, laboratory data, treatments, and requirement of evisceration or enucleation. Results: Of the 110 patients with EKE, 74 (67.3%) were men. Diabetes was the most commonly associated systemic disease (75/110 [68.2%]), and liver abscess was the major infection source (85/110 [77.3%]). In addition, 91 of 124 eyes (73.4%) had final VA worse than counting fingers (CF; poor visual outcome), and 20 eyes required evisceration or enucleation. The binary multivariate logistic regression (forward-Wald) model revealed that poor initial VA worse than CF (odds ratio [OR], 8.8; 95% confidence interval [CI], 2.2e36; P ¼ 0.002), positive vitreous culture results (OR, 9.8; 95% CI, 1.7e56.1; P ¼ 0.010), posterior focal EKE (OR, 0.15; 95% CI, 0.03e0.8; P ¼ 0.027), and the presence of intravitreal dexamethasone administration (OR, 0.19; 95% CI, 0.04e0.9; P ¼ 0.030) were the significant independent factors for visual outcomes. Conclusions: Liver abscess was the major infection source, and EKE typically has poor visual prognosis. Early diagnosis and prompt treatment may salvage useful vision in some eyes. Early diagnosis with fair initial VA and intravitreal antibiotic and dexamethasone combination therapy may have beneficial effects on visual outcomes. Ophthalmology Retina 2017;-:1e8 ª 2017 by the American Academy of Ophthalmology

Endogenous endophthalmitis, also referred to as metastatic endophthalmitis, is a rare complication of septicemia and a potentially sight-threatening intraocular infection. Endogenous endophthalmitis in East Asian and Western countries has shown distinct causative organisms.1,2 Gram-positive bacteria and Candida species were the most common pathogens among the Western countries with more favorable visual outcomes,3,4 and gram-negative bacteria were the main causative organisms in East Asian countries.5,6 Klebsiella pneumoniae, a well-known gram-negative bacterium, is highly prevalent in Asian countries,7e9 and its increasing worldwide incidence recently was reported.10,11 Among the East Asian population, diabetic patients with K. pneumoniae hepatobiliary infections have the highest risk of endogenous K. pneumoniae endophthalmitis (EKE) developing.7,12 The incidence of EKE among patients with systemic K. pneumoniae infections ranges from 3.8% to 11% in Asian countries.13e15 However, Jackson et al1 reviewed 5859 cases of bacteremia at St. Thomas Hospital in England and reported an incidence of endogenous  2017 by the American Academy of Ophthalmology Published by Elsevier Inc.

endophthalmitis of less than 0.01% of all cases. These observations indicate that K. pneumoniae is 100-fold more likely to have ocular involvement than other pathogens. This retrospective study investigated the infectious sources and prognostic factors for poor visual outcome, including subjective symptoms, presenting clinical features, laboratory data, and treatments, in patients diagnosed with EKE within a specific period (from January 1996 through April 2013) at a tertiary referral center in Northern Taiwan. According to our review of the relevant literature, the present study is the largest single case series of EKE conducted to date.

Methods The present study was a retrospective, consecutive, noncompetitive, interventional case series of patients who were diagnosed with EKE between January 1996 and April 2013 in a tertiary referral center in Northern Taiwan. The institutional review board of Chang Gung Memorial Hospital in Taoyuan, Taiwan, approved https://doi.org/10.1016/j.oret.2017.11.013 ISSN 2468-6530/17

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Ophthalmology Retina Volume -, Number -, Month 2017 this retrospective study protocol and waived the need for written informed consent from the patients. All clinical procedures were conducted according to the principles of the Declaration of Helsinki. Endogenous K. pneumoniae endophthalmitis diagnosis was confirmed if patients showed posterior ocular inflammation signs (including vitreitis and chorioretinitis with or without choroidal or subretinal abscess examined by indirect ophthalmoscopy or ultrasonography) and positive K. pneumoniae culture results from blood, vitreous or aqueous humor, or other extraocular sites. The primary extraocular source of infection was either identified, or bacteremia was documented without specific infection focus. We excluded patients with intraocular coinfection or documented septicemia with other microbes. The medical records of 115 patients (130 eyes) with EKE were reviewed. Six eyes of 5 patients were excluded from our study, including 4 patients who died during their hospital stay and 1 patient with bilateral EKE who did not receive a visual acuity (VA) checkup because of hypoxic encephalopathy. All patients received empirical systemic antibiotics. An ophthalmologic consultation was provided during patients’ hospital stays, on physician’s request or during a patient’s visit to the emergency or ophthalmology department because of ocular symptoms. Immediately after endophthalmitis diagnosis, vancomycin (1.0 mg/0.1 ml) and ceftazidime (2.25 mg/0.1 ml) or amikacin (0.4 mg/0.1 ml) were administered intravitreally. After body fluid culture results that were positive for K. pneumoniae were located, ceftazidime or amikacin was administered intravitreally, according to the status of ocular infection control. Some patients also received intravitreal dexamethasone (0.4 mg/0.1 ml) along with antibiotics initially or during retreatment. A standardized protocol was not followed to establish the duration and types of treatments; instead, a treatment regimen was determined based on the physician’s personal experience and the patient’s clinical course. Intravitreal antibiotic administration with or without dexamethasone was repeated every 48 to 72 hours, according to the severity and clinical response assessments of the retina specialists. Trans pars plana vitrectomy also was performed in cases of uncontrollable infection and poor clinical responses to intravitreal and systemic antibiotic administration. Evisceration or enucleation was performed in response to eyeball perforation or in patients with painful, sightless eyes and progressive endophthalmitis despite aggressive treatment. Data on the demographic and clinical features at presentation, medical history, laboratory data, and treatment of 110 patients (124 eyes) were obtained. Ophthalmic examinations included initial and final VA assessment, slit-lamp biomicroscopy, intraocular pressure (IOP), and indirect ophthalmoscopy or ultrasonography. Type of EKE was defined as anterior focal, anterior diffuse, posterior focal, posterior diffuse, or panopthalmitis.16 Poor visual outcomes were defined as VA worse than counting fingers (CF), whereas favorable prognosis was defined by VA of CF or better. The possible poor prognostic factors for visual outcomes also were evaluated using a Pearson chi-square test, Fisher exact test, and Student t test for univariate analyses. The binary multivariate logistic regression (forward-Wald) model was used to determine the independent risk factors. All analyses were performed using SPSS software version 23.0 (SPSS, Inc., Chicago, IL), and P  0.05 was considered statistically significant.

Results During the study period, 130 eyes of 115 patients were affected with culture-proven EKE. However, 4 of the 115 patients (3.5%) died during their hospital stay, and 1 patient had hypoxic encephalopathy; therefore, these 5 patients were excluded from the

2

study, and the remaining 110 patients with EKE (124 eyes) were included. Table 1 presents the patients’ characteristics, systemic diseases, presenting ocular features, and final visual outcomes. The poor prognostic factors for visual outcomes are summarized in Table 2.

Patient Characteristics The mean age of our study group was 56.812.6 years (range, 15e87 years). Men were the predominant patient gender (74/110 [67.3%]); however, women were more likely to have poor visual outcomes compared with men (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.2e9.8; P ¼ 0.015). Most of the patients had unilateral involvement (96/124 eyes [77.4%]) and were at significant risk for poor visual outcomes (OR, 5.4; 95% CI, 2.2e13.3; P < 0.001). In addition, 82 of 110 patients (74.5%) had underlying diseases associated with immunocompromised status; diabetes was the most common systemic disease (n ¼ 75 [68.2%]), followed by liver cirrhosis (n ¼ 12 [10.9%]). Furthermore, 11 of 14 patients (78.6%) with bilateral EKE had diabetes. The most common infection source of EKE was liver abscess (n ¼ 85; 92 eyes), followed by pneumonia (n ¼11; 12 eyes). Other infection sources included renal abscess (n ¼ 4; 5 eyes), necrotizing fasciitis (n ¼ 1), brain abscess (n ¼ 1), neck abscess (n ¼ 1), spleen abscess (n ¼ 1), retroperitoneal nonorganic abscess (n ¼ 1), and human immunodeficiency virus with multiple abscesses (n ¼ 1). Notably, the infection sources of 5 eyes of 4 patients were not identified, but K. pneumoniae bacteremia was documented. Patients with EKE not originating from liver abscess achieved poor visual outcomes compared with those whose EKE originating from liver abscess (OR, 3.6; 95% CI, 1.0e12.9; P ¼ 0.038). Moreover, the patients with diabetes showed marginally significantly poorer visual outcomes than the patients without diabetes (P ¼ 0.062). Other factors, such as age, length of hospital stay, liver cirrhosis, immunocompromised status, and events before 2003, did not seem to influence visual outcome significantly.

Presenting Clinical Features Common ocular symptoms included red eye (112/121 eyes [92.6%]), eye pain (95/122 eyes [77.9%]), and blurred vision (117/ 123 eyes [95.1%]). Because our hospital was a tertiary referral center, 25 of 110 patients were referred to our hospital from another medical care institution. Most of the patients demonstrated fever (103/121 eyes [85%]) or chills (83/119 eyes [69.7%]), as described in their referral sheet data or at initial presentation to our hospital. The patients treated at the other hospital were more likely to demonstrate bilateral EKE (OR, 3.0; 95% CI, 1.2e7.5; P ¼ 0.013). Eye pain (OR, 5.7; 95% CI, 2.3e14.4; P < 0.001), decreased VA (OR, 6.4; 95% CI, 1.1e36.6; P ¼ 0.039), and red eye (OR, 29.3; 95% CI, 3.5e246.2; P < 0.001) were poor prognostic factors, whereas fever and chills did not influence visual outcome.

Ocular Examinations The initial VA of 122 of the eyes was recorded; no light perception was found in 27 eyes, light perception was found in 30 eyes, hand movements was found in 24 eyes, CF was found in 18 eyes, the equivalent VA in Snellen units of 4/200 to 20/200 was found in 14 eyes, and a VA between 20/100 and 20/20 was found in 9 eyes.

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Endogenous Klebsiella Endophthalmitis

Table 1. Demographics, Systemic Illness, Clinical Features, and Outcomes of Patients with Endogenous Klebsiella pneumoniae Endophthalmitis Feature by Patient Demographics No. of patients Affected eye Right Left Mean age  SD (yrs) Gender Male Female Systemic illness Immunocompromised Diabetes Liver cirrhosis Old tuberculosis Cancer End stage renal failure HIV infection Origin of infection focus Liver abscess Pneumonia Renal abscess Other Bacteremia, origin unknown

No. of Patients (%) 110 124 62 (50) 62 (50) 56.812.6 74 (67.3) 36 (32.7)

75 12 2 2 2 1

(68.2) (10.9) (1.8) (1.8) (1.8) (0.9)

85 11 4 6 4

(77.3) (10.0) (3.6) (5.5) (3.6)

Feature by Eye Clinical features Mean  SD HbA1c in DM patients, % Presenting visual acuity Poor: worse than CF Good: CF or better Ocular hypertension Yes No Hypopyon Yes No Laterality Unilateral Bilateral Vitrectomy Early TPPV for infection control Late TPPV for sequelae Outcomes VA 3 months after infection Poor: worse than CF Good: CF or better Evisceration/enucleation Death (total 115 patients)

No. of Eyes (%) 10.82.6 81 (65.3) 41 (33.1) 47 (37.6) 53 (42.4) 59 (47.2) 64 (51.2) 110 (88.7) 14 (12.7) 28 (22.6) 8 (6.5)

91 33 20 4

(73.4) (26.6) (16.1) (3.5)

CF ¼ counting fingers; DM ¼ diabetes mellitus; HbA1c ¼ glycated hemoglobin; HIV ¼ human immunodeficiency virus; SD ¼ standard deviation; TPPV ¼ vitrectomy; VA ¼ visual acuity.

More than two third of the patients’ eyes (82/112 eyes [73.2%]) showed an initial VA worse than CF, which was an important risk factor for poor visual outcome (OR, 11.0; 95% CI, 4.3e27.9; P < 0.001). Intraocular pressure of more than 21 mmHg was defined as ocular hypertension, and 47 of 100 eyes (47.0%) demonstrated ocular hypertension at initial presentation. In addition, the mean IOP of the poor final VA group (26.212.4 mmHg) was 8 mmHg, which was significantly higher than that of the favorable final VA group (18.38.6 mmHg; P ¼ 0.001). Corneal edema and perforation were observed in 75 of 119 eyes and in 4 of 119 eyes (63.0% and 3.4%, respectively), 40 of 119 eyes (33.6%) demonstrated a clear cornea at presentation, and hypopyon was observed in 59 of 123 eyes (48.0%) at initial presentation. Furthermore, 71 of 124 eyes (57.2%) were classified as having posterior diffuse EKE, whereas 21 eyes (16.9%) demonstrated posterior focal EKE. Panophthalmic involvement was observed in 21 of 124 eyes (16.9%) at initial presentation or during follow-up, and 14 of 21 eyes underwent evisceration or enucleation. Corneal edema or perforation (OR, 6.9; 95% CI, 2.8e17.1; P < 0.001), ocular hypertension (OR, 6.5; 95% CI, 2.0e20.9; P ¼ 0.001), hypopyon (OR, 4.8; 95% CI, 1.9e12.1; P ¼ 0.001), posterior diffuse EKE (OR, 3.2; 95% CI, 1.4e7.4; P ¼0.005), and panophthalmic involvement (OR, unavailable; P ¼ 0.002) were the poor prognostic factors for visual outcomes. Posterior focal EKE showed rather favorable visual outcomes (OR, 0.09; 95% CI, 0.04e0.2; P <0.001).

Laboratory Examinations Most patients with fever at presentation to our emergency department routinely underwent blood tests and blood cultures. Most patients demonstrated leukocytosis (51/77 [66.2%]), and 2 patients

showed leukopenia. The white blood cell counts of the poor and final VA groups did not differ. Positive K. pneumoniae blood culture results were observed in 83 of 103 patients (80.6%). If endophthalmitis was diagnosed or suspected, intraocular fluids from the aqueous or vitreous humor or both sites were sampled before intravitreal antibiotic administration. The aqueous and vitreous tap specimens showed positive results for K. pneumoniae in 34 of 89 eyes (38.2%) and 45 of 95 eyes (47.4%), respectively; altogether, intraocular cultures showed positive results for K. pneumoniae in 48 of 106 eyes (45.3%). The positive results from vitreous cultures (OR, 14.3; 95% CI, 3.1e66.0; P < 0.001) and aqueous cultures (OR, 20.4; 95% CI, 2.6e160.3; P < 0.001) were risk factors for poor visual outcomes, whereas positive blood culture results did not influence the final VA. The susceptibility results of K. pneumoniae showed high sensitivity to amikacin (109/ 110 [99%]), ceftazidime (108/110 [98%]), and ceftriaxone (108/ 110 [98%]). The patients with diabetes showed rather poor control with a mean glycated hemoglobin (HbA1c) level of 10.82.6%. However, the mean HbA1c levels were significantly lower in the patients with diabetes who had a final VA worse than CF than in patients who had a final VA of CF or better (10.42.5% vs. 12.62.4%, respectively; P ¼ 0.048).

Treatments According to chart reviews, the subjective decreased VA to time of ophthalmologic consultation was 3.42.7 days (range, 1e15 days). The mean decreased VA to time of ophthalmologic consultation was 3.62.7 days in the poor final VA group, which was delayed, on average, for 1 day longer than that in the favorable final VA group (2.62.8 days), but did not differ statistically

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Ophthalmology Retina Volume -, Number -, Month 2017 Table 2. Prognostic Factors for Poor Visual Outcome Final Visual Outcome Factors Patient characteristics Agez Length of hospital stayz Gender Male Female Laterality Unilateral Bilateral Infection focus Not liver abscess Liver abscess Diabetes Yes No Liver cirrhosis* Yes No Immunocompromised Yes No Event before 2003 Yes No Presenting clinical features Subjective decrease of visionk Yes No Eye pain Yes No Red eyejj Yes No Feverjj Yes No Chillness Yes No Ocular and laboratory examinations Initial visual acuity worse than CF Yes No Ocular hypertension Yes No IOPz Cornea edema or perforation Yes No Hypopyon Yes No Type of EKE{ Anterior diffuse Posterior focal Posterior diffuse Panophthalmitis WBC count (109/l)z

4

No. of Patients

Multivariatey

Univariate*

Counting Fingers or Better

Worse than Counting Fingers

Odds Ratio (95% Confidence Interval)

54.9410.70 25.0310.66

57.7713.09 29.3414.93

83 41

27 (32.5) 5 (12.2)

56 (67.5) 36 (87.8)

1 3.5 (1.2e9.8)

96 28

17 (17.7) 15 (53.6)

79 (82.3) 13 (46.4)

5.4 (2.2e13.3) 1

28 96

3 (10.7) 29 (30.2)

25 (89.3) 67 (69.8)

3.6 (1.0e12.9) 1

86 38

18 (20.9) 14 (36.8)

68 (79.1) 24 (63.2)

2.2 (1.0e5.1) 1

0.062

14 110

4 (28.6) 28 (25.5)

10 (71.4) 82 (74.5)

0.9 (0.2e2.9) 1

0.755

93 31

21 (22.6) 11 (35.5)

72 (77.4) 20 (64.5)

1.9 (0.8e4.6) 1

0.155

65 59

18 (27.7) 14 (23.7)

47 (72.3) 45 (76.3)

1 0.8 (0.4e1.8)

0.614

117 6

28 (23.9) 4 (66.7)

89 (76.1) 2 (33.3)

6.4 (1.1e36.6) 1

0.039x

95 27

17 (17.9) 15 (55.6)

78 (82.1) 12 (44.4)

5.7 (2.3e14.4) 1

<0.001x

112 9

24 (21.4) 8 (88.9)

89 (73.6) 1 (11.1)

29.3 (3.5e246.2) 1

<0.001x

103 18

30 (29.1) 2 (11.1)

73 (70.9) 16 (88.9)

0.3 (0.07e1.4) 1

0.150

83 36

25 (30.1) 7 (19.4)

58 (69.9) 29 (80.6)

0.6 (0.2e1.4) 1

0.228

82 40

9 (11.0) 23 (57.5)

73 (89.0) 17 (42.5)

11.0 (4.3e27.9) 1

<0.001x

47 53

4 (8.5) 20 (37.7) 18.278.60

43 (91.5) 33 (62.3) 26.1812.42

6.5 (2.0e20.9) 1

0.001x

79 40

10 (12.7) 20 (50.0)

69 (87.3) 20 (50.0)

6.9 (2.8e17.1) 1

<0.001x

59 64

7 (11.9) 25 (39.1)

52 (88.1) 39 (60.9)

4.8 (1.9e12.1) 1

0.001x

1 31 71 21

1 (100) 20 (64.5) 12 (16.9) 0 (0.0) 16.2916.16

0 (0.0) 11 (35.5) 59 (83.1) 21 (100) 17.9734.89

NA 0.09 (0.04e0.2) 3.2 (1.4e7.4) NA

0.095 <0.001x 0.005x 0.002x 0.818

P Value

Odds Ratio (95% Confidence Interval)

P Value

8.8 (2.2e36.0)

0.002x

0.15 (0.03e0.8)

0.027x

0.267 0.141 0.015x <0.001x 0.038x

0.001x

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Endogenous Klebsiella Endophthalmitis Table 2. (Continued.) Final Visual Outcome

No. of Patients

Factors z

HbA1c level in DM patients (%) Positive blood culture results Yes No Positive vitreous culture results Yes No Positive aqueous culture results Yes No Treatment Time from decrease in VA to ophthalmologist consultz No. receiving IVIz TPPV needed for infection control Yes No Early IVI of antibiotics with dexamethasone Yes No

Counting Fingers or Better

Worse than Counting Fingers

Multivariatey

Univariate* Odds Ratio (95% Confidence Interval)

P Value

Odds Ratio (95% Confidence Interval)

P Value

9.8 (1.7e56.1)

0.010x

0.19 (0.04e0.9)

0.030x

x

12.622.38

10.352.47

0.048

95 22

26 (27.4) 6 (27.3)

69 (72.6) 16 (72.7)

1.0 (0.4e2.8) 1

0.993

45 50

2 (4.4) 20 (40.0)

43 (95.6) 30 (60.0)

14.3 (3.1e66.0) 1

<0.001x

34 55

1 (2.9) 21 (38.2)

33 (97.1) 34 (61.8)

20.4 (2.6e160.3) 1

<0.001x

2.562.77

3.632.66

0.085

1.521.15

1.821.61

0.334

29 87

3 (10.3) 26 (29.9)

26 (89.7) 61 (70.1)

3.7 (1.0e13.3) 1

0.035x

29 94

15 (51.7) 17 (18.1)

14 (48.3) 77 (81.9)

0.2 (0.08e0.5) 1

<0.001x

CF ¼ counting fingers; CI ¼ confidence interval; DM ¼ diabetes mellitus; EKE ¼ endogenous Klebsiella pneumoniae endophthalmitis; HbA1c ¼ glycated hemoglobin; IOP ¼ intraocular pressure; IVI ¼ intravitreal injection; NA ¼ not available; TPPV ¼ trans pars plana vitrectomy; VA ¼ visual acuity; WBC ¼ white blood cell. *Pearson chi-square test. y Binary logistic regression. z Student t test. x Statistically significant. jj Fisher exact test. { As defined by Greenwald et al.16

(P ¼ 0.085). Trans pars plana vitrectomy was performed in 29 of 116 eyes (25.0%) for infection control (OR, 3.7; 95% CI, 1.0e13.3; P ¼ 0.035), which was a significant risk factor for poor VA outcomes. In addition, 8 eyes that underwent late trans pars plana vitrectomy because of tractional retinal detachment were excluded from our analysis. Notably, 29 of 113 eyes that received intravitreal antibiotic and dexamethasone administration showed significantly favorable visual outcomes (OR, 0.21; 95% CI, 0.08e0.5; P < 0.001). Dexamethasone was administered along with the first, second, and third intravitreal antibiotic injections to 18, 8, and 3 eyes, respectively.

Multivariate Analysis for Poor Visual Outcomes Final VA was measured 3 months after treatment; 83 eyes had VA of no light perception, including 20 eviscerated or enucleated eyes, and 4 eyes had VA of light perception. In addition, 4, 5, and 12 eyes had VA of hand movements, CF, and 2/200 to 20/200, respectively. Eight eyes regained useful VA (range, 20/100e10/ 20), and 8 eyes regained excellent VA (range, 20/30e20/20). However, despite aggressive treatment, 91 of the 124 eyes (73.4%) showed a final VA worse than CF. In addition, 20 of the 124 eyes (16.1%) underwent evisceration or enucleation, and other sightless eyes were mostly phthisic. The significantly poor prognostic factors (P < 0.001) for visual outcomes obtained from the univariate analysis (Table 2) were

included in the multivariate analysis. Possible risk factors such as red eye or eye pain and positive vitreous or aqueous cultures were selected to avoid interference with the analysis. Binary logistic forward (Wald) regression analysis demonstrated that poor initial VA (OR, 8.8; 95% CI, 2.2e36.0; P ¼ 0.002) and positive vitreous culture results (OR, 9.8; 95% CI, 1.7e56.1; P ¼ 0.010) were significant risk factors for poor visual outcomes. Notably, posterior focal EKE (OR, 0.15; 95% CI, 0.03e0.8; P ¼ 0.027) and intravitreal antibiotic and dexamethasone administration (OR, 0.19; 95% CI, 0.04e0.9; P ¼ 0.030) were favorable prognostic factors, even in the multivariate analysis.

Discussion Endogenous K. pneumoniae endophthalmitis results from metastatic spread of K. pneumoniae from a primary site of infection. It is postulated that septic embolus enters the posterior vasculature and disseminates the organism into surrounding tissues after crossing the bloodeocular barrier. The infection then enters the choroid and retina causing chorioretinitis, then into the vitreous cavity presenting as vitreitis, and then spread through the anterior chamber manifesting as hypopyon.17 Our study revealed that despite earlier recognition of EKE, aggressive treatment efforts, and easily accessible

5

6

NA 11 (41) 19 (27) 11 (21) 1 (4) 12 (21) 20 (16) 13 (72) 24 (89) 55 (78); final VA, <4/200 35 (66) 17 (65) 39 (67) 91 (73) (13) (23) (33) (26) (30) (21) (13) 2 5 20 11 6 10 14 (63) (100) (90) (100) (85) (79) (75) 10 22 55 42 17 33 82 (31) (68) (56) (79) (40) (71) (68) 5 15 34 33 8 34 75 (63) (77) (80) (62) (80) (60) (67) 10/6 17/5 40/12 26/16 16/4 29/19 74/36 (18) (27) (71) (53) (26) (58) (124) Wong et al5 (1994e1997) Yang et al15 (1994e2001) Ang et al9 (1986e2007) Sheu et al14 (1991e2009) Lim et al8 (2005e2011) Chen et al7 (2002e2013) Current study (1996e2013)

NA ¼ not available; VA ¼ visual acuity.

16 22 61 42 20 48 110

NA 49 (89) 11 (25) 30 (68) 27 (61) 34/9 (79)

2 Cases þ review of literature Singapore Northern Taiwan Singapore Southern Taiwan Korea Southern Taiwan Northern Taiwan Margo et al18 (1980e1992)

No. of Patients (No. of Eyes) Nationality Authors (Years)

44 (55)

No. with Diabetes Mellitus (%)

No. with Liver Abscess (%)

No. with Bilateral Disease (%)

No. of Eyes with Final Visual Acuity Worse Than Counting Fingers (%) No. of Men/Women (% Men)

Table 3. Summary of Clinical Features in Patients with Endogenous Klebsiella pneumoniae Endophthalmitis Reported in the Literature

medical services, the visual outcome of patients with EKE has not differed substantially over the past 3 decades (Table 3), and the overall visual outcome in such patients remains dismal.5,7e9,14,15,18 Some studies have explored the poor prognostic factors for EKE. Initial VA and pathogen virulence are the well-known prognostic factors for endogenous endophthalmitis.7,8 Diabetes mellitus, poor initial VA, unilateral involvement, hypopyon, and panophthalmic involvement are proposed risk factors for poor visual outcome in EKE.9,14 Our findings are consistent with these studies. Moreover, according to our review of the relevant literature, this study is the largest case series of EKE to date; it also demonstrates that intravitreal dexamethasone administration has significantly favorable visual outcomes in EKE patients. In our study, fever was associated significantly with EKE originating from liver abscess (OR, 3.5; 95% CI, 1.2e10.2; P ¼ 0.015) compared with EKE not originating from liver abscess. The insidious onset of systemic infections other than liver abscess in patients with EKE may pose diagnostic difficulties and possible treatment delay that result in poor visual outcome. Compared with the patients with bilateral EKE, the patients with unilateral EKE experienced a significant treatment delay of 1.5 days (P ¼ 0.012; 95% CI, 2.5e9.2). The mean decreased VA-to-treatment time was 3.71.2 days and 2.20.5 days in unilateral and bilateral EKE cases, respectively. In addition, compared with the patients treated at our hospital, those treated at the other hospital were more likely to demonstrate bilateral EKE (P ¼ 0.013) because of a delay in treatment of 1.6 days (P ¼ 0.014; 95% CI, 2.8e6.5). A recent prospective study of acute postoperative bacterial endophthalmitis in patients undergoing cataract surgery revealed that corneal edema is one of the poor prognostic factors.19 However, corneal edema has not yet been reported as a poor prognostic factor in EKE cases. In the Endophthalmitis Vitrectomy Study, abnormally low or high IOP was one of the poor prognostic factors, whereas patients with good presenting VA, negative vitreous culture results, or coagulase-negative Staphylococci culture results showed excellent final VA.20 Although the Endophthalmitis Vitrectomy Study results are not applicable to endogenous endophthalmitis, similar results were observed among the patients with EKE in the present study. Corneal edema and increased IOP typically were associated with highly severe inflammation and infections in endophthalmitis; therefore, they were significantly poor prognostic factors in the current study. Our patients also showed ocular symptoms, including blurred vision (95.1%), red eye (92.6%), and eye pain (77.9%), at rates that are consistent with those reported in the Endophthalmitis Vitrectomy Study.21 In addition, ocular symptoms were poor prognostic factors in patients with EKE. In our study, HbA1c levels were not surveyed routinely; data on only 45.3% diabetes patients (34 of 75 patients) were documented. Most diabetic patients with documented HbA1c data had poor glycemic control, 19 of 34 patients (56%) had HbA1c levels of 10% or more, and 32 of 34 patients (94%) had HbA1c levels of 7% or more. Poor

No. of Eyes Eviscerated (%)

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Li et al



Endogenous Klebsiella Endophthalmitis

glycemic control increases the risk of metastatic disease in K. pneumoniae-induced liver abscesses.22 However, virulent capsular types of K. pneumoniae were more prevalent in liver abscess patients with optimal glycemic levels or even healthy participants without DM.23 This difference in virulence may be attributed to the poor visual outcomes (P ¼ 0.048) in the patients with diabetes in the present study who had lower mean HbA1c levels and who might have been infected by a more virulent K. pneumoniae strain. However, the K. pneumoniae serotype was not identified in our research. All patients received parenteral empiric antibiotic treatment as soon as sepsis was suspected. Drainage of liver abscess was performed in 42 of 85 patients (49.4%). We have another ongoing study focusing on patients whose EKE originated from a liver abscess. Our preliminary data show that drainage of liver abscess may shorten the hospital course, but does not affect the visual outcome or prevent enucleation. In the current study, K. pneumoniae proved highly sensitive to our routine empiric therapy used for systemic and intravitreal antibiotic injection (99% sensitive to amikacin and 98% sensitive to ceftazidime and ceftriaxone). Only 2 patients were infected by extended-spectrum b-lactamaseseproducing K. pneumoniae. One EKE case originated from K. pneumoniae-induced pneumonia with resistance to amikacin, third-generation cephalosporin (ceftazidime, ceftriaxone, and flomoxef), and aztreonam, and the patient was treated with systemic and intravitreal ciprofloxacin. The other EKE case originated from K. pneumoniae-induced splenic abscess with resistance to third-generation cephalosporin (ceftazidime and ceftriaxone) and aztreonam. We highlight 2 favorable prognostic factors: posterior focal type of EKE and early intravitreal injection of dexamethasone. Greenwald et al16 proposed favorable outcomes for anterior or focal endogenous endophthalmitis. Similar to our study, the posterior focal type of EKE showed better visual outcomes and may represent a relatively early stage of EKE. The use of intravitreal steroid injections for endophthalmitis treatment has been debated. A few studies reported favorable visual outcome results with endogenous endophthalmitis that had received intravitreal steroid treatment.2,15 However, small randomized control trials with presumed bacterial endophthalmitis more recently showed that there are no significant differences in eyes that received adjunctive intravitreal steroid injections compared with eyes that received antibiotics alone.24,25 Moreover, a retrospective comparative trial of 57 eyes with postoperative endophthalmitis reported worse vision after eyes had received adjunctive intravitreal steroid administration, compared with eyes that had received antibiotics alone.26 Although our case series was small, significant results were obtained regarding intravitreal dexamethasone administration in the multivariate analysis. In the patients who received early intravitreal dexamethasone injection, 78.6% of the eyes showed initial VA better than CF, and 73.7% of the eyes with initial VA better than hand movements showed a stationary or improved final VA. Furthermore, necessary evisceration or enucleation occurred less often in the patients who received intravitreal dexamethasone injections

(OR, 0.15; 95% CI, 0.02e1.2; P ¼ 0.042). Recently, Chen et al27 demonstrated that evisceration or enucleation prevention can be achieved in endogenous bacterial panophthalmitis with no light perception and scleral abscess through the administration of multiple intravitreal and periocular antibiotics and dexamethasone. Because EKE is a rare disease, it is challenging to conduct large randomized control trials. Furthermore, patient severity and systemic conditions vary, rendering it difficult to develop a definite protocol that can be applicable in all cases. However, this study also has several limitations because of its retrospective nature. Some parts of the detailed data may be missing or recall bias may exist. Furthermore, we were unable to achieve a head-to-head comparison because of the lack of EKE treatment guidelines and the rarity of this disease. Liver abscess was the major infection source, and EKE typically has poor visual prognosis despite relentless treatment efforts. Early diagnosis and aggressive treatments are crucial for retaining fair visual outcomes. This study revealed that most patients with favorable visual outcomes received dexamethasone along with the first or second intravitreal antibiotic injection. Therefore, we hypothesize that early adjunctive intravitreal steroid injection may improve visual outcome in patients with good initial VA and may reduce the requirement of evisceration or enucleation in eyes with initial poor VA. Furthermore, diabetic patients with optimal glycemic control may remain at a high risk of K. pneumoniae-induced liver abscess with a poor prognosis for visual outcome. Future randomized control trials with K. pneumoniae serotyping may be required to verify our hypothesis. References 1. Jackson TL, Paraskevopoulos T, Georgalas I. Systematic review of 342 cases of endogenous bacterial endophthalmitis. Surv Ophthalmol. 2014;59:627e635. 2. Jackson TL, Eykyn SJ, Graham EM, Stanford MR. Endogenous bacterial endophthalmitis: a 17-year prospective series and review of 267 reported cases. Surv Ophthalmol. 2003;48: 403e423. 3. Cho H, Shin YU, Siegel NH, et al. Endogenous endophthalmitis in the American and Korean population: an 8-year retrospective study. Ocul Immunol Inflamm. 2016. https://doi.org/10.1080/ 09273948.2016.1195000 [Epub ahead of print]. 4. Vaziri K, Pershing S, Albini TA, et al. Risk factors predictive of endogenous endophthalmitis among hospitalized patients with hematogenous infections in the United States. Am J Ophthalmol. 2015;159:498e504. 5. Wong JS, Chan TK, Lee HM, Chee SP. Endogenous bacterial endophthalmitis: an East Asian experience and a reappraisal of a severe ocular affliction. Ophthalmology. 2000;107: 1483e1491. 6. Chung KS, Kim YK, Song YG, et al. Clinical review of endogenous endophthalmitis in Korea: a 14-year review of culture positive cases of two large hospitals. Yonsei Med J. 2011;52:630e634. 7. Chen SC, Lee YY, Chen YH, et al. Klebsiella pneumoniae infection leads to a poor visual outcome in endogenous endophthalmitis: a 12-year experience in southern Taiwan. Ocul Immunol Inflamm. 2016. https://doi.org/10.1080/ 09273948.2016.1193616 [Epub ahead of print].

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Ophthalmology Retina Volume -, Number -, Month 2017 8. Lim HW, Shin JW, Cho HY, et al. Endogenous endophthalmitis in the Korean population: a six-year retrospective study. Retina. 2014;34:592e602. 9. Ang M, Jap A, Chee SP. Prognostic factors and outcomes in endogenous Klebsiella pneumoniae endophthalmitis. Am J Ophthalmol. 2011;151:338e344.e2. 10. Kashani AH, Eliott D. The emergence of Klebsiella pneumoniae endogenous endophthalmitis in the USA: basic and clinical advances. J Ophthalmic Inflamm Infect. 2013;3:28. 11. Odouard C, Ong D, Shah PR, et al. Rising trends of endogenous Klebsiella pneumoniae endophthalmitis in Australia. Clin Exp Ophthalmol. 2017;45:135e142. 12. Qian Y, Wong CC, Lai S, et al. A retrospective study of pyogenic liver abscess focusing on Klebsiella pneumoniae as a primary pathogen in China from 1994 to 2015. Sci Rep. 2016;6:38587. 13. Sng CC, Jap A, Chan YH, Chee SP. Risk factors for endogenous Klebsiella endophthalmitis in patients with Klebsiella bacteraemia: a case-control study. Br J Ophthalmol. 2008;92: 673e677. 14. Sheu SJ, Kung YH, Wu TT, et al. Risk factors for endogenous endophthalmitis secondary to klebsiella pneumoniae liver abscess: 20-year experience in Southern Taiwan. Retina. 2011;31:2026e2031. 15. Yang CS, Tsai HY, Sung CS, et al. Endogenous Klebsiella endophthalmitis associated with pyogenic liver abscess. Ophthalmology. 2007;114:876e880. 16. Greenwald MJ, Wohl LG, Sell CH. Metastatic bacterial endophthalmitis: a contemporary reappraisal. Surv Ophthalmol. 1986;31:81e101. 17. Chee SP, Jap A. Endogenous endophthalmitis. Curr Opin Ophthalmol. 2001;12:464e470. 18. Margo CE, Mames RN, Guy JR. Endogenous Klebsiella endophthalmitis. Report of two cases and review of the literature. Ophthalmology. 1994;101:1298e1301.

19. Combey de Lambert A, Campolmi N, Cornut PL, et al. Baseline factors predictive of visual prognosis in acute postoperative bacterial endophthalmitis in patients undergoing cataract surgery. JAMA Ophthalmol. 2013;131:1159e1166. 20. Durand M. Microbiologic factors and visual outcome in the Endophthalmitis Vitrectomy Study. Am J Ophthalmol. 1997;124:127e130. 21. Results of the Endophthalmitis Vitrectomy Study. A randomized trial of immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Endophthalmitis Vitrectomy Study Group. Arch Ophthalmol. 1995;113:1479e1496. 22. Lin YT, Wang FD, Wu PF, Fung CP. Klebsiella pneumoniae liver abscess in diabetic patients: association of glycemic control with the clinical characteristics. BMC Infect Dis. 2013;13:56. 23. Chuang C, Fan WC, Lin YT, Wang FD. The emergence of Klebsiella pneumoniae liver abscess in non-diabetic patients and the distribution of capsular types. Gut Pathog. 2016;8:46. 24. Albrecht E, Richards JC, Pollock T, et al. Adjunctive use of intravitreal dexamethasone in presumed bacterial endophthalmitis: a randomised trial. Br J Ophthalmol. 2011;95: 1385e1388. 25. Gan IM, Ugahary LC, van Dissel JT, et al. Intravitreal dexamethasone as adjuvant in the treatment of postoperative endophthalmitis: a prospective randomized trial. Graefes Arch Clin Exp Ophthalmol. 2005;243:1200e1205. 26. Shah GK, Stein JD, Sharma S, et al. Visual outcomes following the use of intravitreal steroids in the treatment of postoperative endophthalmitis. Ophthalmology. 2000;107: 486e489. 27. Chen KJ, Chen YP, Chao AN, et al. Prevention of evisceration or enucleation in Endogenous bacterial panophthalmitis with no light perception and scleral abscess. PLoS One. 2017;12: e0169603.

Footnotes and Financial Disclosures Originally received: August 20, 2017. Final revision: November 16, 2017. Accepted: November 20, 2017. Available online: ---. Manuscript no. ORET_2017_342. 1

Department of Ophthalmology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan.

2

Department of Ophthalmology, Mackay Memorial Hospital, Hsinchu, Taiwan.

3

Center for Big Data Analytics and Statistics, Chang Gung Memorial Hospital, Taoyuan, Taiwan. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Statistical analysis was supported by the Maintenance Project for Research Services Center for Health Information from Chang Gung Memorial Hospital, Taoyuan, Taiwan (grant no.: CIRPD1D0031). HUMAN SUBJECTS: Human subjects were included in this study. The institutional review board of Chang Gung Memorial Hospital in Taoyuan, Taiwan, approved the study and waived from the need for written informed

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consent from all patients. The study was performed in accordance with the tenets of the Declaration of Helsinki. Author Contributions: Conception and design: Li, K.-J.Chen Analysis and interpretation: Li, Y.-H.Chen, K.-J.Chen Data collection: Li, K.-J.Chen, Wang, Sun, Chao, Liu, Lin, Wu, Hwang, Lai, Chen Overall responsibility: Li, Y.-H.Chen, K.-J.Chen Abbreviations and Acronyms: CF ¼ counting fingers; CI ¼ confidence interval; EKE ¼ endogenous Klebsiella pneumoniae endophthalmitis; HbA1c ¼ glycated hemoglobin; IOP ¼ intraocular pressure; OR ¼ odds ratio; VA ¼ visual acuity. Correspondence: Kuan-Jen Chen, MD, Department of Ophthalmology, Chang Gung Memorial Hospital, No. 5 Fuhsing Street, Kwei-Shan, 333, Taoyuan, Taiwan. E-mail: [email protected].