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Endogenous endophthalmitis is a rare and dreaded ophthalmic emergency that usually results in vision-threatening sequelae. The diagnosis is often a challenge for all ophthalmologists and vitreoretinal surgeons and is generally secondary to underlying secondary systemic pathology. In a few cases, sometimes the cause may not be identified. It can manifest at any age and has varied predisposing risk factors. The etiology is multifactorial with a broad spectrum of microorganisms. Medical or surgical management depends on the manifestation and severity of the pathology. Prompt diagnosis, meticulous management, and regular follow-up are mandated for managing this serious entity. This activity describes the risk factors, etiology, clinical manifestations, investigations, and treatment protocols used by the interprofessional team. Objectives: Describe the pathogenesis of endogenous endophthalmitis. Review the clinical features of endogenous endophthalmitis. Summarize the treatment of endogenous endophthalmitis. Outline the complications and differential diagnosis of endogenous endophthalmitis. Access free multiple choice questions on this topic.

Endophthalmitis, a dreaded ophthalmic emergency, is defined as the intraocular infection of the coats of the eyeball associated with diffuse vitreous inflammation. It can manifest in significant ocular and systemic complications.[1] The mode of spread can be exogenous or endogenous.[2] Exogenous endophthalmitis can result from trauma, post-surgery, or secondary to keratitis. In contrast, endogenous endophthalmitis, also called metastatic endophthalmitis, results from hematogenous spread of microorganisms secondary to underlying systemic pathology like diabetes, immunosuppression, renal pathology, etc. Suspected cases should undergo imaging like ultrasound B scan, aqueous and vitreous tap for culture and sensitivity, vitreous biopsy, or polymerase chain reaction whenever indicated for rapid diagnosis.[3] Prompt clinical diagnosis, targeted investigation, meticulous management, and regular follow-up is mandated to safeguard vision in these cases. Medical management includes topical and systemic antibiotics or antifungals, intravitreal antibiotics or antifungals, and surgical treatment of choice is pars plana vitrectomy. The collaboration of the treating ophthalmologist or vitreoretinal surgeon, microbiologists, pathologists, and the critical care physician plays a vital role in determining the patient's final systemic and ocular outcome.[4]

Endogenous endophthalmitis (EE) has a multifactorial etiology, and causative agents vary from region to region. The causative agents can be fungal or bacterial, with fungal organisms dominating the majority of cases.[4]  In studies from Asia, fungal EE accounts for nearly 11.1 to 17.54% of total cases.[5] The most common causative agent for bacterial EE is gram-positive streptococcus and staphylococcus. Gram-negative bacterial EE is more commoner in Asian countries.[6] Among fungal species, Candida albicans account for many cases being the most common yeast, and among the molds, Aspergillus flavus is the commonest.[7] Klebsiella pneumonia, a gram-negative rod bacterium, is another causative agent reported to cause EE. Klebsiella has been reported in patients with liver abscess, diabetes mellitus, infective endocarditis, and after a routine colonoscopy.[8] Recently, Rudez et al. reported a case of EE secondary to Clostridium septicum.[9] Yue et al. reported EE secondary to an opportunistic pathogen Citrobacter koseri.[10] In fungal EE, mold infections are more common after chemotherapy and in patients undergoing liver and cardiac transplants, hematological malignancy, or hematopoietic stem cell transplantation (HSCT). Aspergillus pneumonia has been blamed for causing EE in a small subset of patients.[11] Candida EE has been reported in patients on ventilators and neonates.[12] The most common systemic risk factors for EE are diabetes mellitus, immunosuppression, patients on long term corticosteroids, history of recent hospitalization, ventilator-associated pneumonia, urinary tract infection, malignancy like lymphoma and leukemia, colon adenocarcinoma, dental infection, scleral perforation, vertebral osteomyelitis, liver abscess, asplenia, hypogammaglobulinemia, cardiac or renal transplant, acquired immune deficiency syndrome, chronic alcoholism, intravenous catheters and drug abuse (Bacillus cereus).  Mishra et al. reported a case of EE secondary to multifocal staphylococcal brain abscess associated with septic foci.[13][14][15][16][17][18]

The most common systemic risk factors for EE are diabetes mellitus, immunosuppression, patients on long term corticosteroids, history of recent hospitalization, ventilator-associated pneumonia, urinary tract infection, malignancy like lymphoma and leukemia, colon adenocarcinoma, dental infection, scleral perforation, vertebral osteomyelitis, liver abscess, asplenia, hypogammaglobulinemia, cardiac or renal transplant, acquired immune deficiency syndrome, chronic alcoholism, intravenous catheters and drug abuse (Bacillus cereus).  Mishra et al. reported a case of EE secondary to multifocal staphylococcal brain abscess associated with septic foci.[13][14][15][16][17][18] Neonatal EE is an alarming entity in children with bacterial infections, candida infection, malnourishment, retinopathy of prematurity, low birth weight, septicemia. The most common bacteria reported are streptococci,  S. agalactiae, Pseudomonas, and Klebsiella. Azar et al., in their retrospective analysis, reported 3 cases of pediatric EE out of 26 cases. A small number of EE cases are also reported secondary to occult systemic infections, which are culture negative.[12][19][20] Recently few case series have been reported in patients with COVID-19 possible reason being immunosuppression.[21][22][23]

The reported incidence of EE is 2 to 8%.[1][4] The first case of EE dates back to 1856, which was secondary to recurrent Klebsiella infection.[24] A major review article in 2003 reported 335 cases of bacterial EE.[25] The infection can occur at any age with equal gender predilection. In a study comprising 27 subjects, the reported mean age of the patients was 63.[26] The ratio of involvement of the right to left eye is 2 to 1. The right eye is more commonly involved due to more proximal and direct blood flow from the right carotid artery. Approximately 25% of cases have a bilateral presentation.[27]

Endogenous endophthalmitis is a blood-borne metastatic infection from the primary inoculation site secondary to bacterial or a fungal pathology.[27] The microorganism primarily spreads through the posterior segment vessels. The right eye has more predilection due to dominant and direct blood flow from the right carotid artery. The direct infectious spread has also been reported from the brain to the optic nerve. The primary mechanism of damage in EE is septic emboli that migrate to the posterior segment vessels. This, in turn, acts as a focus for the spread of microorganisms to the neighboring tissues after breaching the blood-retinal barrier. Further, the microorganism proliferates and causes inflammation within these tissues. The infection then spread from the posterior segment to the anterior segment of the eye. One of the previous studies document no underlying source of infection in approximately 44% of the cases, but still, EE patients should undergo a detailed systemic evaluation to rule out the primary focus of infection.[28][29]

The symptoms of endogenous endophthalmitis vary from pain, redness, irritation, swelling photophobia, defective vision, floaters, and flashes. The clinical signs range from periorbital edema, scleral inflammation, chemosis, conjunctival congestion, corneal infiltrate, endothelial exudates, corneal edema, anterior chamber reaction, hypopyon, fibrinous membrane, iris exudates, iris nodules,  sluggish or fixed pupil, relative afferent pupillary defect, posterior synechiae, cataract, absent red reflex, vitreous haze, anterior vitreous cells, vitreous floaters, membranes and exudates.[30][14][31] Bacterial EE is known to cause more anterior chamber inflammation. Bilateral EE is more common with Mycobacterium tuberculosis. The most important diagnostic feature of EE is vitreous involvement. Aspergillus flavus is known to cause yellow/ white exudates in the vitreous, which vary from focal to diffuse. The hallmark feature of Candida EE is the presence of fluffy cotton wool-like white retinal exudates or colonies along with vitritis.[32] Subretinal and choroidal abscesses have also been reported in cases of endogenous bacterial endophthalmitis. In patients with relatively clear media with less severe vitreous involvement, other findings like subretinal, preretinal, flame-shaped hemorrhage, Roth spots, cotton wool spots, retinal and choroidal detachment can also be documented. MRSA has been associated with a high rate of retinal detachment when the presentation is delayed more than two weeks after the onset of symptoms.[33] EE can be broadly classified into three categories based on ocular signs and symptoms, as detailed below.[29] Petit et al. earlier has proposed a classification for fungal EE.[34] Table S. No Involvement

Apart from clinical diagnostic, EE is confirmed by imaging and lab investigations. Every case warrants a detailed slit lamp and dilated fundus evaluation. Sometimes the diagnosis is delayed since the clinical picture can have a lot of differentials, and multiple assessments are required before reaching a conclusive diagnosis. The prime importance should be given to systemic evaluation and management. Imaging Modalities B Scan Ultrasound B scan ultrasound is an essential diagnostic modality to pick up vitritis, membranes, exudates in the vitreous cavity, retinal detachment, choroidal detachment, and choroidal abscess. The exudates in the vitreous cavity are present as echoes on the B scan. EE is also known to cause a choroidal abscess, which appears as dome-shaped elevation on B scan similar to choroidal detachment.[35] Optical Coherence Tomography Optical coherence tomography (OCT) is an important imaging modality to delineate the retinal and subretinal space. OCT can help localize the exudates within subretinal layers, lesions of the retinal pigment elevation, retinal edema, vitreous cells and exudates, and choroidal involvement.[36] Anterior Chamber and Vitreous Tap An anterior chamber aqueous tap of 0.1-0.2 ml can be performed with a 23 G needle. Vitreous tap of 1-2 ml is performed with the help of a 25 G needle. The sample can also be obtained while performing vitrectomy and subjected to culture, sensitivity, and histopathological examination. Lingappan et al. proved that samples obtained with vitrectomy showed a better culture positivity (92%) than vitreous tap (44%). Similarly, Zhang et al. showed that the sample obtained needle biopsy had a lower diagnostic yield than vitrectomy as the vitrectomy samples were closer to the retinal surface.[37] Polymerase Chain Reaction The samples obtained through aqueous and vitreous tap can be subjected to a real-time polymerase chain reaction (RT-PCR), with very high sensitivity and specificity. RTPCR has proven high sensitivity and specificity for fungi as per the analysis by Sugita et al. In culture-negative cases of EE; it has proven to be a better diagnostic modality for detecting microorganisms. PCR results are obtained within 90 minutes, with better diagnostic yield than culture results with no risk of contamination. The major limitation of PCR is that an antibiotic susceptibility pattern cannot be obtained through this.[38]

The samples obtained through aqueous and vitreous tap can be subjected to a real-time polymerase chain reaction (RT-PCR), with very high sensitivity and specificity. RTPCR has proven high sensitivity and specificity for fungi as per the analysis by Sugita et al. In culture-negative cases of EE; it has proven to be a better diagnostic modality for detecting microorganisms. PCR results are obtained within 90 minutes, with better diagnostic yield than culture results with no risk of contamination. The major limitation of PCR is that an antibiotic susceptibility pattern cannot be obtained through this.[38] Blood Culture Blood culture is an important diagnostic modality for the diagnosis of systemic infection. Three consecutive samples can be obtained on three days under aseptic precautions for a better diagnostic yield. Besides blood culture, it is vital to obtain urine culture to identify occult microorganisms. According to a few previous studies, blood culture has shown a higher culture positivity than the vitreous sample, probably due to the sample volume obtained. Culture at extraocular sites has yielded a 21-100% positivity rate as per previous reports.[17] Upcoming Modalities 2-Deoxy-2-[18F] Fluoro-Dglucose Positron Emission Tomography/Computed Tomography Scan Mehta et al. recently documented using 2-Deoxy-2-[18F] fluoro-D-glucose positron emission tomography/computed tomography scan for systemic assessment of patients with presumed fungal EE  in patients with COVID-19 infection.[39]

Endogenous endophthalmitis is an emergency, and prompt diagnosis and meticulous management are required to safeguard vision in these cases. The treatment is governed by the stage of the disease, offending microorganism, mode and route of infection, and systemic status of the patient. A flowchart of how to manage endogenous endophthalmitis is depicted below. Management Protocol for Bacterial Endogenous Endophthalmitis Systemic Antibacterials Bacterial EE warrants treatment of systemic infection with antibiotics. Once the blood culture results are available, systemic antibiotics can be initiated. Moreover, severe ocular infection warrants the addition of intravitreal injections. Non-resolving cases with rapidly progressive bacteremia will require pars plana vitrectomy. Local Therapy Once infection EE is suspected, a sample for culture and sensitivity should be obtained, and intravitreal antibiotics should be initiated. Early intravitreal antibiotics should be initiated within 24 hours of presentation as they have been reported to have a better and favorable outcome. Before the etiology is established, broad-spectrum intravitreal antibiotics should be administered. Vancomycin 1mg/0.1 ml and cefazolin 2.25 mg/0.1 ml covers gram-positive bacteria, and 2.25 mg/0.1 ml ceftazidime or 0.4 mg/0.1 ml amikacin are the drug of choice for gram-negative bacteria. Vancomycin is the drug of choice for MRSA. However, there have been recent reports of vancomycin resistance staphylococcus aureus (VRSA) also.  The drugs commonly used for VRSA are daptomycin 200 ug/0.1 ml and quinupristin/dalfopristin 0.4 mg/0.1 ml. Fluoroquinolones are a broad spectrum with gram-positive and negative coverage. Once the culture results are available, targeted therapy should be started for rapid recovery.  Prompt diagnosis and targeted treatment are essential for a final better outcome. Antibiotics should be used cautiously in pregnant and lactating mothers. Penicillin group of drugs, cephalosporins, and erythromycin can be used safely in these patients. Cartilage abnormalities have been reported secondary to fluoroquinolones; hence they should not be used as the first line in pregnant women.[40][41][11] Management Protocol for Endogenous Fungal Endophthalmitis Candida Endogenous Endophthalmitis

Once the culture results are available, targeted therapy should be started for rapid recovery.  Prompt diagnosis and targeted treatment are essential for a final better outcome. Antibiotics should be used cautiously in pregnant and lactating mothers. Penicillin group of drugs, cephalosporins, and erythromycin can be used safely in these patients. Cartilage abnormalities have been reported secondary to fluoroquinolones; hence they should not be used as the first line in pregnant women.[40][41][11] Management Protocol for Endogenous Fungal Endophthalmitis Candida Endogenous Endophthalmitis The drug of choice for candida EE is intravitreal amphotericin or voriconazole. Amphotericin B (AMB) deoxycholate is given in the dose of 5 to 10 ug/0.1 ml dextrose or sterile saline. The patient should be reassessed after 48 hours, and if needed, the dose can be repeated. AMB has been reported to cause nephrotoxicity, hypotension, and arrhythmia. Hence the patient should be closely monitored for these side effects. Intravitreal voriconazole is administered in a dose of 100-200 ug/0.1 ml sterile saline.[42][43] The other alternative recommended by the infectious disease society of America (IDSA) is fluconazole. The recommended dose is 400-800 mg per day. Hamada et al. recommended fluconazole as the first-line therapy because of its better side effect profile than AMB. In severe cases with non-resolving vitritis, pars plana vitrectomy is the treatment of choice. The treatment duration depends on the clinical picture, but a minimum of 6 weeks is recommended.[44][45] Endogenous Endophthalmitis Secondary to Aspergillus, Paecilomyces, and Fusarium The drugs implicated are voriconazole, AMB, and fluconazole. Voriconazole has proven high efficacy of approximately 100% in these cases. Pars plana vitrectomy with lensectomy or intraocular lens removal should be performed in non-resolving cases. In bedridden patients, those who are severely immunocompromised or unable to tolerate surgery, systemic antifungal therapy should be initiated.[46][47][48] Pars Plana Vitrectomy

The drugs implicated are voriconazole, AMB, and fluconazole. Voriconazole has proven high efficacy of approximately 100% in these cases. Pars plana vitrectomy with lensectomy or intraocular lens removal should be performed in non-resolving cases. In bedridden patients, those who are severely immunocompromised or unable to tolerate surgery, systemic antifungal therapy should be initiated.[46][47][48] Pars Plana Vitrectomy Pars plana vitrectomy (PPV) is the treatment of choice for non-resolving vision-threatening bacterial and fungal EE cases. PPV serves both diagnostic and therapeutic purposes. Pre-surgery or intraoperatively intravitreal drugs can be administered to reduce the microorganism load. Vitrectomy helps to reduce the microorganism load in the posterior segment and assists in rapid recovery. Vitrectomy is based on the vitreoretinal surgeon's discretion. Early vitrectomy has been reported to cause a reduced incidence of retinal detachment and has a better globe salvage rate. The incidence of enucleation and evisceration is also reduced. Sato et al. suggested early vitrectomy in Candida EE cases. Zhang et al. found better visual outcomes in patients who were subjected to early vitrectomy. Yoon et al. suggested early PPV in Klebsiella endophthalmitis, which may result in better visual effects.[49] Corticosteroids The role of intravitreal and systemic steroid use in EE is controversial, and there are no set guidelines for the same. Bacterial endotoxins and profound inflammation is known to cause retinal pigment epithelial damage and necrosis. Steroids combat inflammation, alleviate leucocyte migration, reduce cytokine storm and stabilize the blood-retinal barrier. Jackson et al. showed that patients with EE treated with steroids resulted in a better visual outcome. In contrast, Shuwan et al. showed no significant benefit with the use of steroids. Lindstedt et al., in their multicentric randomized trial, showed that intravitreal dexamethasone had no added benefit. Hence, in a nutshell, steroids should be used with caution in EE patients.[50][51]

Infectious Cytomegalovirus Herpes simplex virus Varicella-zoster virus Epstein bar virus Disseminated toxoplasmosis Disseminated viral retinitis Tuberculosis Lyme's Pythium[52][53][54] Non-infectious Vogt-Koyanagi-Harada syndrome Sarcoidosis Behcet syndrome[55] Idiopathic Toxic anterior segment syndrome Sympathetic ophthalmia[56] Juvenile idiopathic arthritis Posterior scleritis Postoperative endophthalmitis (after any surface or intraocular surgery) Masquerade Leukemia Lymphoma Retinoblastoma Choroidal melanoma Tumour necrosis with inflammation Intraocular foreign body White dot syndromes Punctate inner choroidopathy Serpiginous choroidopathy Multifocal choroiditis and panuveitis Subretinal fibrosis and uveitis Multiple evanescent white dot syndrome Acute posterior multifocal placoid pigment epitheliopathy Birdshot chorioretinopathy Asteroid Hyalosis Disseminated Intravascular Coagulation Thrombotic  Thrombocytopenic Purpura

The prognosis of endogenous endophthalmitis depends on the presentation time, clinical manifestation, the extent of vitreous involvement, and virulence of the offending microorganism. It's a complex entity to diagnose, and due to various comorbidities, it is often picked up late. However, studies have proven that yeasts have the best prognosis, followed by bacteria followed by molds which have the worst prognosis. Patients who present late and in whom diagnosis and treatment are delayed often land up with complete vision loss, and the prognosis is poor in these cases. The patients requiring vitreous tap are at risk for retinal detachment, and the prognosis is guarded in these cases. Zenith et al., in their analysis, showed that bacterial EE had a poor outcome and prognosis compared to fungal EE and these cases usually require enucleation and evisceration.[17] Yonekawa et al., in their study, proven that prompt diagnosis and treatment was associated with 64% of patients having visual outcomes better than counting finger (CF) in bacterial EE.[41] Similarly, Itoh et al. showed that early and aggressive vitrectomy within two weeks of diagnosis results in good final outcomes, and the prognosis is good in these cases.[57] Among the offending microorganisms, it has been reported that MRSA EE patients have a poor prognosis and high mortality. However, few studies have proven variable association between the two. Connell et al., in their analysis, showed that the majority of patients with Klebsiella EE required vitrectomy.[58] Ang et al. found that hypopyon in Klebsiella EE can be a prognostic predictor.[40]

Keratitis Non-resolving hypopyon uveitis Secondary glaucoma[59] Cataract[60] Lens abscess[61] Panophthalmitis Retinal detachment[62] Choroidal detachment Hypotony Phthisis bulbi Atrophic bulbi Painful blind eye

Endogenous endophthalmitis is a severe sight-threatening emergency, and all patients with suspected EE must be referred and evaluated by a vitreoretinal surgeon. The vitreoretinal surgeon has a vital role to play in the diagnosis and management of these cases.

The patients must be explained the serious nature of the pathology and warning signs and symptoms like pain, redness, swelling, sudden reduction in visual acuity, and photophobia. The patients must be explained that the condition will require hospital admission and intensive treatment in topical and oral drugs, intravitreal injection, and the need for surgery. The patient should be explained regarding visual prognosis and to have realistic expectations.[17]

Endogenous endophthalmitis is usually seen in patients with diabetes mellitus, immunosuppression, and other systemic pathologies. Nursing staff must keep a check on blood sugar, temperature, and other vital parameters. The treating physician must be highly suspicious of EE if the patient reports pain, redness, and sudden vision loss. Patients will all these symptoms must be referred to a vitreoretinal (VR) surgeon for meticulous management. The VR surgeon also plays a vital role in counseling and explaining the prognosis of the pathology to the patient. Nursing staff also plays a crucial role in counseling and regularly administering drugs to the patients in collaboration with the pharmacist. The patient's final visual and systemic outcome depends on the multidisciplinary approach by the physician, pharmacist, nursing staff, and the vitreoretinal surgeons.