A retrospective study was conducted in a tertiary medical center in Korea. We included patients who were diagnosed with EE from January 2000 through June 2017. All EE cases were reviewed from the electronic medical database of the hospital.

Patients with EE were admitted directly to the Department of Internal Medicine with a manifestation of extraocular infection or to the Department of Ophthalmology with a manifestation of ocular symptoms. All patients admitted to internal medicine department with a manifestation of extraocular symptoms complained of ocular problems including blurred or altered vision and ocular pain or injection at the time of admission or during hospitalization. We directly referred these patients to ophthalmologists to evaluate EE. Moreover, we routinely follow up patients with bacteremia after discharge. We could possibly find any abnormal ocular signs or symptoms. Considering that the disease course of EE is rapidly progressing and most of the patients with EE experience clinical ocular symptoms and signs, we could hardly miss diagnosis of EE. Consequently, we think all patients with symptomatic ocular problems of EE were included in our study during the consecutive study period. Endophthalmitis was defined as a purulent inflammation of the intraocular fluids (vitreous and aqueous) usually due to infection. Diagnosis of endophthalmitis was made by ophthalmologists. The keynote feature of EE is significant involvement of the vitreous humor identified through dilated funduscopic examination. EE was defined as endophthalmitis without a history of ocular trauma, intraocular surgery, or ocular procedure.

We reviewed the records of patients with clinical ocular symptoms and signs. Specifically, we reviewed the findings from the ophthalmologists and the systemic infection signs and pathogens isolated from blood, intraocular aspirates, and other pus cultures.

Patients with recent ocular trauma or a history of intraocular surgery within 1 year of presentation were excluded. Of the 39 patients ultimately included in this study, seven patients had a history of intraocular surgery; however, no surgeries had been performed within 1 year of presentation. Two patients had ocular trauma history. However, those instances of trauma had not occurred within 1 year prior to hospital admission, and there was no evidence of exogenous endophthalmitis.

Variables that represent prognostic factors for poor outcome were analyzed, including time to diagnosis after symptom onset [15], time to systemic antibiotics after symptom onset, time to the surgical procedure after symptom onset [1112], predisposing medical conditions (e.g., age, and underlying host diseases), other sites of involvement in the infection, pathogens in cultures (from blood, vitreous material obtained during the operation, cerebrospinal fluid (CSF), and/or pus aspirate), and levels of C-reactive protein (CRP) (Table 1).

We did not consider variables such as initial visual acuity, unilateral ocular involvement, rapid onset of ocular symptoms, or hypopyon as prognostic factors of EE, since they have already been described in many previous studies. We considered predisposing medical conditions, extraocular site of infection, and pathogens as important risk or prognostic factors of EE.

All microbiological analyses were performed at the hospital's microbiology laboratory. Microbiological diagnosis was made according to culture positivity and antimicrobial susceptibility. A culture was defined as positive if there was growth of the organism in more than one media, or if there was a confluence of growth on solid media at the inoculation site [16]. For ocular microbial analysis, samples were taken from the anterior chamber, aqueous humor, and vitreous humor through routine clinical practice. Vitreous humor sampling was done in 69.2% (27/39) of patients who underwent either intravitreal antibiotics or vitrectomy. After vitreous sampling, patients were routinely treated with intravitreal antibiotics (e.g., ceftazidime plus vancomycin).

Ophthalmologic evaluation was performed by ophthalmologists and included measurement of visual acuity, as well as assessment of the presence of ocular pain, floaters, photophobia, ocular discharge, and hypopyon. VA were determined using Snellen charts. Clinical features, such as initial VA, VA at discharge, and final VA at the end of follow-up, were evaluated. Vitrectomy was performed if the ocular condition began to deteriorate, according to the clinical discretion of the attending ophthalmologists.

Visual outcomes were classified as follows: 1) no light perception (NLP), 2) light perception (LP), 3) hand motion (HM), 4) counting fingers (CF), and 5) 20/200 or better, as measured by ophthalmologists. We defined HM, CF, and 20/200 or better as good ocular outcomes, whereas NLP and LP were defined as poor ocular outcomes, for the purpose of statistical analyses.

Statistical significance was set at P < 0.05; R statistics ver. 3.2.1 was used for the statistical analysis. Univariate and multivariate logistic regression analyses were performed to determine the odds ratios (OR) of ocular outcome of EE with 95% confidence intervals (CI). Decision tree analysis was used to identify significant prognostic factors that were associated with poor outcomes of EE. Classification tree analysis was then applied to our categorical outcome. A Chi-squared automatic interaction decision algorithm was chosen; therefore Chi-statistics were used to select optimal dividing nodes.

The Institutional Review Board of Kyungpook National University Hospital approved the study protocol (No. 2018-02-032). All clinical investigations were conducted in accordance with the guidelines of the 2008 Declaration of Helsinki.

A total of 39 patients, who presented to our hospital with EE over an 18-year period, were included in this study. All patients were hospitalized in the Departments of Internal Medicine or Ophthalmology. The median age of the patients was 59.0 [Interquartile range (IQR) 55.0; 70.0] years. They were predominantly male (n = 27/39, 69.2%). The patients underwent surgical interventions after the time of admission. The median follow-up period was 587 [IQR 189; 1947] days. The shortest follow-up period was 15 days, and the final visual outcome for this patient was 20/200. Therefore, there was only one visit after discharge, and then a follow-up loss occurred. Final VA examined by ophthalmologists during the follow-up period before death or follow-up loss was regarded as a final visual outcome.

Median days from symptom onset to diagnosis was 3.0 [IQR 1.0; 4.0] days. Delayed diagnosis was defined as more than 3 days after symptom onset to diagnosis of EE [1517]. Delayed diagnosis did not reach statistical significance as a factor influencing the visual outcomes of EE (Table 2). Median days from symptom onset to antibiotic treatment was 4.0 [IQR 2.0; 5.0] days. Delayed antibiotic treatment was defined as more than 4 days after symptom onset to antibiotic treatment [21112]. Median days from symptom onset to surgical treatment was 5.0 [IQR 2.5; 7.5] days. Delayed surgical treatment was defined as more than 5 days after symptom onset to surgical treatment [21112]. There was no statistically significant relation between VA and time to treatment (Table 2). Fever was the most frequent systemic clinical finding. The mortality rate in this study was 5% (n = 2/39), and these patients had liver abscess coinfections.

Common presenting ocular complaints consisted of decreased vision, injected eye, ocular pain, floaters, photophobia, and ocular discharge. Hypopyon was found in 17.9% of cases (n = 7/39). Six patients exhibited bilateral EE, whereas 33 exhibited uniocular EE. Right eyes were more commonly affected (n = 22/39, 56.4%); 11 patients exclusively exhibited left eye involvement. VA before symptom onset for EE was not accessible within the medical records. Twenty-nine of 39 patients (74.4%) initially presented with VA that was beyond the range of the Snellen chart, with seven patients (17.9%) having VA worse than light perception in either eye.

A total of six different risk factors were identified among the 39 EE patients. Six patients had no risk factors. Three patients had two risk factors (Table 3), including diabetes mellitus (33.3%), liver cirrhosis (15.4%), malignancy (12.8%), recent invasive surgery (12.8%), indwelling catheter (10.3%), and renal failure (7.7%). Five patients exhibited malignancy; two of these patients had undergone recent invasive surgery. Recent invasive surgery was defined as operations relating to non-ocular disease performed within 1 year before onset of EE. One patient had undergone a pylorus-preserving pancreatoduodenectomy; the other had undergone a prostatectomy. Notably, none of these five patients were currently undergoing immunosuppressive therapy. Immunosuppressive therapy was defined as a cytotoxic chemotherapy, immune-modulating medication within 6 weeks before admission. Indwelling catheter referred to a Foley catheter, central venous catheter or percutaneous drainage catheter. No patient had a history of organ transplantation or immune-modulating medications. Further, there were no human immunodeficiency virus (HIV) patients. Six patients (15.4%) exhibited no underlying medical conditions. Underlying medical conditions included any disease that may cause an immunosuppressive state such as malignancy, HIV, liver, renal, heart and lung diseases, diabetes mellitus and any disease resulting in immunosuppressive therapy. There was no statistically significant relationship between the underlying medical conditions and the clinical outcome in cases of EE.

Pathogens were identified from patient samples (blood and/or ocular samples, cerebrospinal fluid, or pus) in 23 of 39 patients (60%) (Table 4). Blood cultures of 29 patients were performed at the time of EE diagnosis. Of 29 blood cultures that were performed, 14 positive blood cultures indicated the presence of bacteremia. Of a total of 23 culture-positive cases, six exhibited positive growth from vitreous samples and were identified as pathogens. Notably, more cases exhibited positive cultures from blood samples (n = 14) than from vitreous samples.

Table 4 shows microorganisms that were identified from cultures of EE patients. In this study, EE was predominantly caused by Gram-negative bacteria (13 of 39 patients, 33.3%; Table 3). Fungi were identified as the causative agent in 10.3% of all cases (Table 4). Gram-positive bacteria were the causative agent in 15.4% of cases (Table 4). No anaerobes or mycobacteria were identified in patient samples. A total of 16 cases demonstrated no identifiable microbial growth in culture. In these 16 cases, there were nine positive cultures with normal skin flora, and we did not consider those as pathogens of EE. Causative pathogens were isolated from blood culture (14 patients), vitreous culture (six patients), pus culture (10 patients), and CSF culture (one patient). Of a total of 12 K. pneumoniae cases, there was only a single positive blood culture result that demonstrated the same sensitivity pattern as the organism that was cultured from the eye. A total of seven patients yielded pus cultures of an identical pathogen of blood or eye aspirates from extraocular infection sites (Table 5). Six of these cultures were grown from liver abscesses, and one was grown from a gluteus muscle abscess.

Intravitreal antibiotic therapy, in addition to systemic antibiotic therapy, was performed in 24 of 39 patients. Pars plana vitrectomy was performed in 14 of 39 patients who showed no response to initial systemic or intravitreal antibiotic therapy. Median period from symptom onset to vitrectomy was 5 [IQR 4.0; 8.0] days. Some patients could not be treated with surgical interventions because of severe sepsis. Of those managed with vitrectomy, the visual outcomes were as follows: five patients exhibited NLP, two exhibited LP, four exhibited HM, one exhibited FC, and two exhibited 20/200. Of the 14 patients who underwent pars plana vitrectomy, only two patients had improved visual outcome after vitrectomy. One patient progressed from HM to 20/200, the other from FC to 20/200. The remaining patients had no interval change of outcome or worse outcome following vitrectomy. Therefore, pars plana vitrectomy was not a good prognostic factor for ocular outcome (OR, 1.30; 95% CI, 0.34-5.03, P = 0.700 in univariate logistic regression).

According to our categorization method, the visual outcomes were poor in 20 out of 39 patients. Final ocular outcomes were as follows: 35.9% (n = 14/39) exhibited NLP, 15.4% (n = 6/39) exhibited LP, 15.4% (n = 6/39) exhibited HM, 7.7% (n = 3/39) exhibited FC, and 25.6% (n = 10/39) exhibited 20/200 or better (Table 6). The final outcome of VA, as assessed by Snellen chart, ranged from NLP to 20/200 or better.

An extraocular focus of infection was detected in 33 of 39 patients (Table 5). All associated infection sites were confirmed by imaging studies or aspiration cultures. The most common co-infection was liver abscess (n = 16/39), followed by acute pyelonephritis (12/39), cholangitis (4/39), endocarditis (2/39), pneumonia (2/39), septic lung (2/39), septic arthritis (2/39) and (equal incidence) gluteus muscle abscess, pelvic abscess, meningitis and prostate abscess (each 1/39). Eight patients showed two different extraocular infections sites. Combined extraocular infections were liver abscess, acute pyelonephritis, cholangitis, pneumonia, and infective endocarditis. We performed orbital CT scans or brain MRIs in seven patients and examined cerebrospinal fluid from four patients for central nervous system evaluation. One meningitis case was confirmed.

In our univariate and multivariate regression analyses, the presence of K. pneumoniae was a statistically significant independent factor associated with poor ocular outcomes of EE in a total of 39 patients, including culture negative cases (OR, 8.50; 95% CI, 1.79-63.11, P = 0.014 in univariate and OR, 7.20; 95% CI, 1.43-55.16, P = 0.027 in multivariate). K. pneumoniae remained a statistically significant risk factor in 23 culture positive only cases (OR, 13.3; 95% CI, 2.1-130.9, P = 0.012 in univariate and OR, 17.5; 95% CI, 2.1-398.8, P = 0.021 in multivariate; Table 2). Other factors did not reach statistical significance. The same results were found in our decision tree analysis, where K. pneumoniae was a significant dividing node for the prediction of ocular outcome (P = 0.017; Fig. 1).