Preparation of intravitreal pharmaceuticals.
This chapter comprehensively covers all aspects of endogenous endophthalmitis from systemic infectious agents, with an emphasis on reported and newer etiologies to broaden the diagnostic and investigative acumen of treating ophthalmic providers. The discussion includes the etiology of metastatic endophthalmitis and diagnostic investigations, including polymerase chain reaction (PCR), for identification of bacterial and viral infections involving the eye in both immunosuppressed in non-immunosuppressed patients. Additionally, we present clinical and diagnostic findings of fungal infections, protozoal infections, and helminthic infections. Pediatric cases are also reported and etiologies described. We discuss both etiology and diagnostic challenges. Current therapeutic modalities and outcomes are reviewed. While no two cases of metastatic endophthalmitis are the same, some similarities may exist that allow us to generalize how to approach and treat this potentially sight- and life-threatening spectrum of diseases and find the underlying systemic cause.
1. Introduction to endogenous endophthalmitis: etiology and treatment
Endophthalmitis is defined any infectious inflammation of vitreous, retina, or choroid that may or may not involve the anterior chamber. A useful classification is to define the infectious agent as exogenous or endogenous depending the route of infection. Exogenous endophthalmitis occurs from direct entry of pathogen(s) after disruption of ocular tissues, whether from trauma (like an open globe injury) or from surgical interventions (such as cataract or glaucoma surgery, intravitreal injection, or retinal surgery). Alternatively, endogenous endophthalmitis occurs when pathogens spread from other parts of the body to the eye (mainly by hematogenous spread but can also be neuronal in case of some viruses) with a subsequent compromise to the blood-ocular barrier. Since the choroid and the retina are highly vascularized, these structures may be seeded early in the systemic infection. In this chapter, we discuss endogenous endophthalmitis including the incidence, causes, and management of bacterial, viral, fungal, and other less common infectious agents.
2. Endogenous bacterial endophthalmitis (EBE)
While endogenous bacterial endophthalmitis comprises the minority (2–8%) of endophthalmitis cases, it is a devastating intraocular infection that often results in poor visual outcomes, loss of the eye, and even mortality [1, 2, 3, 4]. Nineteen percent of cases have a bilateral presentation . Prompt recognition and treatment is vital for improved visual outcome. Unfortunately, many patients with EBE are either initially misdiagnosed (up to 25% of cases) or have a delay in diagnosis (a median of seven days) [2, 3, 4]. EBE is most commonly misdiagnosed as non-infectious uveitis but can also be mistaken for acute angle closure glaucoma, conjunctivitis, or orbital cellulitis [3, 4]. In children, EBE is most often misdiagnosed as retinoblastoma [3, 4].
Familiarity with common clinical features is crucial for proper diagnosis of EBE. Blurred vison (89%) and pain (48%) are common presentations, although they are not always present . The most common systemic findings include fever (37%), often a low-grade fever and chills, and influenza-like features (20%) .
The absence of a clear view of the fundus is the most common ocular sign (40%), but other important exam findings include anterior chamber reaction (32%), hypopyon (35%), and vitritis (33%). Hypopyon color can be associated with different causative organisms. For example,
Endogenous bacterial endophthalmitis is also known as metastatic endophthalmitis, since an extraocular (systemic) focus of infection is typically the source. Liver abscesses are the most common sources of infection followed by lung and cardiac infections . Other foci include soft tissue infection, meningitis, urinary tract infection (UTI), brain, and renal abscesses. Moreover, patients diagnosed with EBE often have underlying medical conditions that lead to an immunosuppressed state such as Diabetes mellitus (DM), Human Immunodeficiency Virus (HIV) infection, autoimmune disease, and malignancy [3, 4]. Other predisposing factors for EBE include high-risk behaviors such as IV drug use (IVDU) and alcohol abuse .
These infections are often life-threatening, so investigations into underlying foci and risk factors are paramount. In fact, mortality rates as high as 5% have been reported in patients with EBE from an extraocular infection . Blood cultures remain the most reliable way to establish a diagnosis. These cultures are routinely performed in a hospital setting, and although they are more likely to identify the underlying pathogen compared to intraocular cultures, results can be negative in up to half of cases [3, 4, 5, 8, 9]. Intraocular cultures become very important in cases of negative blood cultures. They can be obtained from the anterior chamber by paracentesis (AC tap) or from vitreous collection, either by needle aspiration or during pars plana vitrectomy (PPV). Experimental and clinical studies of exogenous bacterial endophthalmitis have found vitreous cultures to have a higher yield compared to aqueous cultures [10, 11]. It is less clear whether these results apply to EBE eyes. Nevertheless, a review of 342 cases of EBE found anterior chamber samples obtained alongside vitrectomy to be positive in 21% of the cases while a positive vitreous sample was obtained during vitrectomy in 41% of the cases . Yet, AC tap has been advocated to be performed in eyes with more prominent anterior chamber inflammation and when the offending microorganism is still unknown . Moreover, AC tap is a less invasive procedure than vitreous sampling. Due to its high sensitivity, PCR has emerged as an adjunct to cultures in diagnosing EBE. It is capable of amplifying DNA from a single bacterium in a few hours. Hence, it can establish a diagnosis days before culture results become finalized and identify organisms in a culture-negative specimen, even after antibiotic treatment has been initiated [13, 14, 15, 16]. However, PCR has not replaced the utility of traditional cultures. It does not offer any insight into antibiotic sensitivity, which is important for antimicrobial stewardship, and its high sensitivity makes it vulnerable to false positive results from cross-contamination . Nevertheless, due to increased affordability and reproducibility in addition to the aforementioned benefits, PCR is becoming increasingly utilized even in developing countries [18, 19, 20].
Regional variations exist regarding bacterial organisms that cause EBE. For example, Gram-positive bacteria comprise the majority of infections in North America and Europe, while Gram-negative organisms predominate in East Asia [1, 5]. This discrepancy can be attributed to
The most common Gram-positive bacteria in EBE are
3. Treatment of endogenous bacterial endophthalmitis
Treatment of EBE has evolved significantly in the last century, particularly after the introduction of antimicrobial agents. Initially, systemic administration was common practice and is still necessary to save the patient’s life, but systemic therapy has lower efficacy of saving the eye. It has been established that antibiotic intraocular levels are insufficient to achieve any ocular clinical benefit [71, 72]. It is important to note that despite loss of vision, the infection in the eye should be treated to prevent meningitis and contiguous spread to the surrounding orbital tissues.
In the 1970s, Peyman et al. used animal models to better understand the blood-ocular barrier and to determine non-toxic doses of antimicrobials. They established the use of intravitreal antibiotic injections (IVI) as the standard of care for the treatment of endophthalmitis [73, 74, 75, 76]. In the 1990s, the Endophthalmitis Vitrectomy Study (EVS), which studied only exogenous endophthalmitis, established IVI (IVI- of Pharmaceuticals) as standard of care and reported no additional benefit for using systemic ceftazidime and amikacin . Nevertheless, the studied population was post-operative endophthalmitis patients, so the results may not be directly applicable to patients with EBE . Also, they used systemic steroids rather than intravitreal steroids, the latter of which are known to be beneficial in saving visual function by decreasing intraocular inflammatory mediators and the former are questionably prudent in a systemic infection.
Although the treatment of EBE remains controversial due to a paucity of clinical trials, systemic antibiotics remain essential, as many patients have an underlying systemic infection or a distal infectious focus. In fact, in a study that looked at 342 cases of EBE, the two patients who did not receive systemic antibiotics died, while the 51 patients who did receive appropriate systemic treatment survived, although this was not statistically significant (P = 0.10) . Currently, systemic antibiotics are seldom used as a monotherapy but are often used in combination with intravitreal antibiotics, and sometimes PPV .
Selection of appropriate antimicrobial agents for IVI depends on several factors, including the patient’s allergies, the targeted organism, and antibiotic sensitivity and resistance. The most commonly used antimicrobials in IVI for empiric treatment are vancomycin for Gram-positive and ceftazidime for Gram-negative microorganisms . Amikacin and gentamicin IVI can also be used for Gram-negative microorganisms . A tap-and-inject technique is recommended: An intravitreal tap is initially performed through the pars plana to collect a sample of the vitreous for Gram staining and culture, followed by IVI.
Intravitreal corticosteroids have also been used to counter the inflammatory reaction associated with EBE. Dexamethasone is typically the agent of choice. It has been shown to be safe for all ocular structures up to 4 mg and may reduce the need for repeated antibiotic injections as well as improve visual outcomes [3, 25, 78].
The requirement for surgical intervention is not well established in the treatment of EBE. The EVS recommended PPV for patients with light perception vision, but as mentioned previously, the study involved patients with postoperative bacterial endophthalmitis only . Nevertheless, there are several advantages of performing early vitrectomy on patients with EBE, including removing the infectious material from the vitreous and providing ample material for culture. A large series reported improved visual outcomes and lower rates of eviscerations and enucleation in a group of patients who received vitrectomy
4. Endogenous spirochete endophthalmitis
Spirochetes are unique bacteria with distinct long helically coiled cells. Members of the phylum Spirochaetes include
The most common ocular manifestation of syphilis is generally agreed to be posterior uveitis followed by panuveitis, although some report granulomatous iridocyclitis as being most common [83, 86, 87]. Isolated intermediate and anterior uveitis can also occur . Ocular syphilis can also present with necrotizing retinitis that can mimic acute retinal necrosis (ARN) or progressive outer retinal necrosis (PORN). However, these viral entities tend to progress quickly and are unresponsive to penicillin, whereas necrotizing retinitis secondary to syphilis tends to be slower and responsive to penicillin . Moreover, retinal vasculitis can occur with occlusive manifestations [89, 90]. Patients with ocular syphilis may have several distinct retinal findings that could assist in diagnosis, such as creamy white preretinal precipitates that can migrate over time . In addition, retinal lesions can heal with minimal retinal pigment epithelium involvement . Acute syphilitic posterior placoid chorioretinitis is also a distinct and rare retinal manifestation of ocular syphilis characterized by discrete oval lesions of the outer retina and the inner choroid . It is believed that these lesions occur secondary to inflammation from direct invasion of
One study examining 453 patients in an HIV clinic found incidence of syphilis to be 7.3%, of which 9% had ocular manifestations . HIV-positive patients also showed higher rates of concurrent ocular syphilis at a younger age than immunocompetent patients [84, 88, 95]. Moreover, several studies have demonstrated that HIV-positive patients are more likely to have isolated anterior uveitis than HIV-negative patients [88, 96]. Therefore, the CDC recommends that all patients with HIV should be screened for syphilis, and all patients with syphilis should be screen for HIV. Screening for other common sexually transmitted diseases such as gonorrhea and chlamydia should also be performed. HIV-positive patients are more likely to present with acute, bilateral uveitis with more aggressive ocular involvement than HIV-negative patients [84, 85]. However, the CD4 count has not been shown to affect the frequency of ocular syphilis in HIV-positive patients .
Diagnosis of syphilis is achieved by nontreponemal and treponemal tests. Nontreponemal tests include Venereal Disease Research Lab (VDRL) and rapid plasma reagin (RPR) tests, which are commonly used for screening. These tests are sensitive but not specific; therefore, a positive result must be confirmed with a treponemal test such as fluorescent treponemal antibody absorption test (FTA-ABS),
Ocular syphilis is categorized as a subtype of neurosyphilis and should receive prompt treatment, as delay in treatment may result in visual loss. Only 12% of patients diagnosed with neurosyphilis were found to have ocular involvement, and syphilitic meningitis does not always accompany ocular syphilis [97, 100]. Nevertheless, the CDC recommends a lumbar puncture to be performed on all patients with syphilis and ocular complaints, even in the absence of clinical neurological findings. Commonly, CSF-VDRL is the initial test followed by CSF-FTA-ABS if the former test is positive .
The recommended treatment by CDC for ocular syphilis includes intravenous aqueous crystalline penicillin G, 18 to 24 million units per day administered as 3 to 4 million units every four hours or continuous infusion over 10 to 14 days. An alternative regimen, if patient compliance is guaranteed, is 2.4 million units of intramuscular procaine penicillin G once daily in addition to 500 mg oral probenecid four times a day, both for 10 to 14 days.
Leptospirosis, caused by the spirochete
5. Endogenous mycobacterial endophthalmitis
The diagnosis of intraocular tuberculosis can be challenging, as it may have no pathognomonic eye findings. Instead, it has a protean presentation, which can appear similar to non-tubercular infections. Patients with HIV are more likely to develop intraocular TB than HIV-negative patients [3, 126]. However, severe intraocular TB can also occur in healthy individuals, which may cause a delay in diagnosis and treatment resulting in profound visual and organ loss [129, 130].
Uveitis is the most common ocular manifestation and can take the form of granulomatous anterior uveitis (12–36%), intermediate uveitis, posterior uveitis (11–20%) and most commonly, panuveitis (34–42%) . Retinal manifestations can include multi-focal choroiditis, chorioretinitis, serpiginous-like choroiditis and choroidal tubercles [131, 132, 133, 134, 135, 136]. Ocular tuberculosis can even be severe enough to cause panophthalmitis .
Together, these factors make accurate diagnosis of intraocular TB challenging. Nevertheless, certain ophthalmic findings can increase the likelihood of establishing the correct diagnosis. A study found that broad-based posterior synechiae, retinal vasculitis with or without choroiditis, and serpiginous-like choroiditis demonstrate a high likelihood of intraocular TB being present; however, the absence of these signs does not rule out the disease . Moreover, retinal vasculitis in intraocular TB mainly involves the veins with perivascular cuffing and vitritis, and focal choroiditis lesions tend to be under the vessels [131, 144]. A presumed intraocular TB diagnosis can be made when these signs are present in addition to a positive tuberculosis test such as Tuberculin Skin Test (TST), QuantiFERON-TB Gold, chest radiograph, or computed tomography of the chest.
Being aware of the limitations of each diagnostic test is vital. As mentioned previously, TST can produce false negative results in some patients. These patients typically have anergy as result of immunosuppression or disseminated TB, hence TST should not be used to rule out TB when suspicion is high . Moreover, spiral chest computed tomography is more sensitive in the detection of pulmonary TB and should be used in cases with normal radiography and high suspicion of the disease . PPV can be an important diagnostic and therapeutic intervention, as it was found to have a higher yield than vitreous tap in returning positive for mycobacteria (87.5% vs. 14.3%, respectively) . Moreover, PPV may have a similar role in improving visual outcomes and reducing the possibility of enucleation in intraocular TB as was demonstrated in EBE cases. PCR also has a high diagnostic value and can be more accurate than cultures in diagnosing intraocular TB .
In the absence of confirmatory tests such as direct visualization of the mycobacteria, positive response to antitubercular therapy (ATT) supports the diagnosis of presumed intraocular tuberculosis. In fact, any delay in treatment to establish a definitive diagnosis is discouraged. One study found that systemic antibiotics were started in 47.6% of endophthalmitis of unknown etiology cases prior to establishing a definitive diagnosis . Antitubercular therapy comprises a four-drug regimen: isoniazid, rifampicin, ethambutol, and pyrazinamide. The role of steroids as part of ATT remains controversial. Some studies have found that steroids can be effective in reducing TB-associated mortality and recurrences of uveitis as well as treating macular edema [141, 147], while another multi-center study found the use of steroids was associated with higher treatment failure rates . Failure rates were higher when steroid treatment was started prior to initiation of ATT compared to after . Therefore, judicious use of steroids is recommended as part of ATT. In fact, there might be two different pathophysiological mechanisms behind the intraocular inflammation: an active mycobacterial infection of the eye and an immunological response to the pathogen located elsewhere in the body [3, 143]. Thus, steroids may be more beneficial in the latter case. Higher treatment failure rates were also observed in patients with choroidal involvement and associated vitreous haze . Caution and close observation of patients on ATT is required as isoniazid and ethambutol can cause toxic optic neuropathy . Nevertheless, TB-associated endophthalmitis has a very poor outcome. The majority of cases (83.7%) end in either evisceration, enucleation or exenteration of the eye . Of note, this figure is significantly higher than for EBE which is reported to be 20% .
Nontuberculous mycobacteria (NTM) have also been shown to cause endogenous endophthalmitis . They can be divided into slow and rapid growers . The latter group comprises the most cases of overall ocular infections and carries worse visual outcomes [152, 153]. However, rapid growers are mainly associated with exogenous endophthalmitis and can occur in healthy individuals . On the other hand, endogenous endophthalmitis is typically secondary to infection by slow growers and occurs almost exclusively in immunocompromised patients. The source of infection is often unknown but disseminated infections have been documented [150, 154]. Some of the NTM slow growers implicated in endogenous endophthalmitis include
6. Endogenous viral endophthalmitis (EVE)
Viral infections represent a significant cause of posterior segment endogenous endophthalmitis due to their systemic spread, and viruses are more likely than other organisms to spread via a neuronal pathway. Viral infections can appear as isolated ocular manifestations or as part of a systemic infection. For example, Herpes Simplex virus 1 (HSV-1) and Varicella Zoster virus (VZV) spread via transaxonal route while Cytomegalovirus (CMV) and Epstein Barr virus (EBV) spread via hematogenous route within lymphocytes . Infections causing posterior segment infections can lead to manifestations of the choroid, retina, and vitreous due to their highly vascularized nature [160, 161]. Prompt recognition and treatment can lead to improved visual outcomes in patients, but EVE is often misdiagnosed as non-infectious uveitis, anterior uveitis, or conjunctivitis, leading to poorer outcomes .
Patients with EVE often have an underlying immunosuppressed condition, so they should be evaluated for underlying immunosuppression if not already known . DM, corticosteroid use, diminished lymphocyte response, HIV/AIDS, and malignancy can all encourage viruses to proliferate . Patients with a history of travel to endemic areas or close contact with farm animals (particularly swine herders) should be evaluated for EVE . Cases of EVE following systemic Ebola and COVID-19 infections have also been documented [163, 164]. There have been cases of viral endophthalmitis following intravitreal steroid injections that are exogenous in nature . Identifying the common clinical features can aid in the prompt diagnosis of EVE. Common features include photophobia, decreased visual acuity, and eye pain . Other presenting ocular features include conjunctival hemorrhages, peripapillary hemorrhage, narrowing of the inferior retinal vessels, anterior segment inflammation, focal lesion of the posterior pole, vitreous inflammation, occlusive vasculitis, keratic precipitates, chorioretinal scarring, ocular hypertension, and neovascularization [160, 163, 164]. EVE frequently presents as unilateral disease on presentation but can become bilateral as it progresses [160, 165, 166, 167].
Successful treatment of EVE requires prompt diagnosis using fluid from a vitreous tap . PCR is the main laboratory test that has been effective in establishing diagnosis of viral infection such as HSV, VZV and CMV . One study examined aqueous and vitreous fluid samples for HSV-1, HSV-2, VZV, EBV, CMV, and Human Herpesvirus 6 found PCR to have sensitivity and specificity of 91.3% and 98.8%, respectively in detection of herpes viruses as well as toxoplasma and fungal elements . Viral serology of the vitreous is effective in confirming the pathogen involved in 80–90% of cases [160, 169, 170] and frequently changes the working diagnosis (23%) or confirms an uncertain diagnosis (39%) . Moreover, PCR sensitivity can be further improved when combined with the calculation of Goldmann-Witmer coefficient (GWC) and immunoblotting for ocular fluid and serum antibodies. The GWC is a comparison of specific antibodies levels to total immunoglobulin in both aqueous humor and serum samples. Multiplex PCR allows testing of several organisms from a single ocular sample; however, this process, similar to monoplex PCR, does require the knowledge of a particular virion’s sequence information prior to testing in order to design the primer necessary to generate a PCR product . Fundus photography, retinal imaging, and optical coherence tomography (OCT) are all useful in diagnosing and monitoring EVE [160, 172].
Treatment of EVE requires systemic antivirals, intravitreal antivirals (or intraocular antiviral implants), and systemic corticosteroids for inflammation . In the 1990s, Peyman and many others noted improvement of cytomegalovirus (CMV) retinitis after treatment with intravitreal ganciclovir and systemic antivirals [76, 173, 174, 175, 176, 177, 178, 179]. Studies also confirm the efficacy of systemic valaciclovir for appropriate management of EVE . The role of systemic and intravitreal acyclovir for treatment of herpes virus retinitis has also been documented [174, 178]. Management of both ocular and systemic complications is essential for a favorable prognosis . Long-term preventative antiviral therapy may be considered if patients present with recurrent inflammation. Patients may require anti-vascular endothelial growth factor agents for macular edema or neovascularization  and may also undergo vitrectomy for proper management. Vitrectomy should be considered when patients present with severe inflammation, retinal detachment, or traction that may create a detachment. Vitrectomy with silicone-oil tamponade and scleral buckle placement has been proven successful . Caution should be taken in eyes of patients with a history of Ebola virus disease who present with evolving dark retinal regions, as these are characteristic of viable
Several viruses have been implicated in the development of EVE. Most commonly, it is due to reactivation of the herpesvirus family, specifically varicella zoster virus (VZV), herpes simplex virus (HSV I and HSV II), CMV, and Epstein–Barr virus (EBV) [160, 180, 181]. The outcome of viral reactivation is influenced by multiple factors including strain virulence, human leukocyte antigen, and host immune response. HSV- EVE is generally well treated with systemic antiviral and corticosteroids with the resolution of symptoms . However, as the virus remains latent in the trigeminal and dorsal root ganglion, recurrence is possible . VZV-EVE may occur in adults with chickenpox but is rare in children . It is more common in adults and may precede shingles in immunocompromised patients, but Acute Retinal Necrosis (ARN) can occur in patients with normal immune function; HSV I, HSV II, and VZV can cause ARN . VZV generally has a poorer prognosis compared to HSV. EBV-EVE generally has a good prognosis and resolves rapidly with near-complete recovery . Most people (90%) are CMV seropositive (it is thought to be latent in bone marrow) so it periodically actively replicates in both immunocompromised and normal patients. Therefore, culture of CMV shed in the patient’s urine does not mean active systemic CMV infection to support the diagnosis of CMV retinitis. Patients can experience systemic symptoms, but ocular manifestations are more likely to be the initial finding . CMV retinitis has historically had poor visual outcomes, although new antiretroviral therapies have decreased its incidence and improved outcomes . Patients may experience reactivation of herpesvirus infections following other viral infections, such as COVID-19 .
Other causes implicated with EVE include pseudorabies, Zika virus, Dengue, Ebola, Chikungunya, and COVID-19 [163, 164, 165, 185]. Unlike herpesvirus infections, patients typically do not present with a history of immunosuppression. However, history is significant with respect to travel to endemic areas or known exposure to infected individuals [163, 164, 165, 185]. The posterior vitreous cavity may act as a reservoir for some viral infections. Zika and COVID-19 infections are notable for the presence of viral RNA in the tears . In contrast, patients with Ebola Virus Disease (EBD) in the eye are negative for Ebola of the tears and conjunctiva . However, virions have been recovered from the anterior chamber in eyes of recovered Ebola patients and poses a risk for cataract surgeons .
Patients with ocular viral infections are also at risk for reactivation of other bacterial or fungal agents in the eye. Cases of toxoplasmosis following Ebola infection have been documented in a small subset of patients . Compared to more common causes, novel causes of EVE (Dengue and COVID) have no prospective, randomized therapeutic trials. As such, definitive therapies are not well established, and prognosis can range from full resolution to permanent vision loss [165, 185]. COVID-19 and Zika are more likely to cause poor visual outcomes compared to standard causes [164, 165]. Prompt diagnosis and early treatment are important for good visual outcomes of EVE.
7. Endogenous fungal endophthalmitis (EFE)
Fungi can lead to infection of the posterior chamber through hematogenous spread; in fact, this represents the most frequent cause of EFE [186, 187]. Most cases of fungal endogenous endophthalmitis have a predisposing systemic risk factor. Common risk factors for EFE include recent hospitalization, systemic surgery, indwelling catheter, broad-spectrum antibiotic use, steroids, parenteral nutrition, cytotoxic therapies, and gastrointestinal disease . Lower abdominal procedures, including genitourinary procedures (e.g. uterine curettage, urinary tract dilation, lithiasis removal), and toe-nail extraction due advanced onychomycosis have been implicated with EFE . Most cases of fungal endogenous endophthalmitis have a predisposing systemic risk factor . Diagnosis of EFE is frequently missed, as these characteristic findings might mimic non-infectious uveitis and orbital cellulitis . In the pediatric population, common misdiagnoses are orbital cellulitis, congenital glaucoma, conjunctivitis, and retinoblastoma . Misdiagnosis rates range from 16% to 63% [4, 191].
Patients who experience misdiagnosis can experience a delay in diagnosis (mean of 13 days) [186, 192], but familiarity with the clinical features of EFE can aid in avoiding this. Patients frequently complain of blurry or decreased vision (77%), redness (49%), eye pain (34%), floaters (26%), and photophobia (12%) . Systemic symptoms also include frequently mild and relapsing fever, scalp lesions, and other pain . In a study that examined 65 eyes with EFE found most eyes to have diffuse anterior and posterior segment inflammation (71%), followed by focal posterior inflammation (28%) and focal anterior segment inflammation (2%) . Eyes with EFE can have some characteristic exam findings that can help in establishing a proper diagnosis. For example, eyes with EFE from
Due to their systemic nature in immunocompromised patients, cases are more likely to be bilateral compared to other causes of endogenous endophthalmitis, but the majority are still unilateral . Unlike bacterial causes, EFE is less associated with a known focal systemic lesion. About 44% of patients with EFE from
An accurate diagnosis of the causative agent is essential to the treatment of EFE. Culture positivity for
Pathogenic dimorphic fungi have also been implicated in EFE. Unlike opportunistic causes, pathogenic dimorphic fungi are usually regionally restricted. These infections can cause endophthalmitis in both immunocompetent and immunocompromised hosts. EFE is primarily a result of a disseminated pulmonary infection [196, 206]. Examination of the eye for dimorphic fungi shows fluffy yellow/white aggregates with retinal hemorrhages.
Treatment of endogenous fungal endophthalmitis in the eyes of pediatric population have shown favorable resolution with systemic and intravitreal antifungals, intravitreal steroids, and early surgical intervention. However, there is no specific guideline for dosing of pediatric patients with EFE with systemic and intravitreal antibiotics . While patients with EFE have shown resolution of symptoms, as noted, with systemic and intravitreal antifungal medications, eyes that present with poor vision or are refractory to injected antifungals should undergo vitrectomy . Surgical intervention via early PPV has been proven to have therapeutic efficacy .
Of all the fungal causes, infections with
8. Endogenous protozoal endophthalmitis
Protozoans, unicellular eukaryotic organisms, are a major cause of intraocular infections worldwide. Different protozoa have special animal hosts with varying routes of infection. Travel and dietary history as well as patient habits are important in establishing a diagnosis, since most transmission occurs through contaminated food and water sources in endemic areas. Protozoa such as
Other clinical classifications of toxoplasmosis include acquired cases in immunocompetent and immunocompromised patients. Toxoplasmosis is mainly asymptomatic in healthy patients. Painless cervical lymphadenopathy is the main clinical manifestation if symptoms do occur. Retinochoroiditis is also a common feature, since
Retinochoroiditis is frequently subclinical but can result in retinal detachment and loss of vision [228, 234]. Other symptoms may include pain, photophobia and epiphora. Ophthalmic exam is vital in the diagnosis of retinochoroiditis, which typically presents as a focal white lesion with overlying vitritis. When vitritis is severe, a classic finding of “headlight in the fog” can be seen. Healed lesions become atrophic and develop a scar bordered with black pigment. Atypical lesions found in elderly and immunocompromised patients have distinctive characteristics including hemorrhages, multiple foci and features present in acute retinal necrosis (ARN) such as peripheral retinitis, vasculitis and vitritis [235, 236]. Early management of toxoplasmosis in immunodeficient patients is vital, as disseminated disease has 100% mortality if left untreated.
Recurrences of retinochoroiditis are common, roughly 80%, with a median interval of two years . New lesions tend to occur at the border of an old, scarred lesion. Recurrences are more common after cataract extraction and in patients older than 40 years of age as well as in previously affected eyes [237, 238, 239]. Nevertheless, late sequelae and recurrences from congenital infection tend to be bilateral, more severe, and involve the macula, whereas acquired infections are usually unilateral, spare the macula, and are not associated with an old chorioretinal scar [228, 232, 240].
The diagnosis of toxoplasmosis is mainly clinical based on characteristic retinal lesions; however, serology can confirm the exposure to the protozoa. Various methods exist for detecting IgG and IgM immunoglobulins against
These serological tests only reveal previous exposure to
There is a lack of evidence supporting the utility of routine antibiotic and steroid regimens in the treatment of acute retinochoroiditis . Not all cases necessarily warrant treatment; for example, small lesions in the periphery that are not vision-threatening tend to be self-limited and will heal spontaneously in immunocompetent patients [250, 251, 252]. Most clinicians will treat patients with disease persisting more than one month and associated with reduced visual acuity. Other indications for treatment include lesions that are vision-threatening such as those affecting the macula or the optic nerve, lesions larger than one disc diameter, lesions in monocular patients, presence of multiple lesions, lesions associated with moderate to severe vitritis, active lesions over a large vessel, or lesions in immunocompromised patients . The classic triple therapy comprises oral pyrimethamine, sulfadiazine, and prednisolone. Pyrimethamine is prescribed with folinic acid to prevent bone marrow toxicity (anemia). Alternative treatments include oral trimethoprim-sulfamethoxazole (TMP-SMX), azithromycin, or clindamycin, all of which have shown favorable results [254, 255, 256]. Intravitreal treatment has also been studied for the treatment of ocular toxoplasmosis [257, 258]. Combined clindamycin and dexamethasone intravitreal injections were found to be comparable to a regimen of oral pyrimethamine and sulfadiazine [258, 259, 260]. Intravitreal TMP-SMX with dexamethasone also demonstrated benefit [261, 262]. Intravitreal injections can be favorable in pregnant patients due to their reduced systemic toxicity compared to oral medication [263, 264]. Photocoagulation around the foci of the scars and vitrectomy have also been performed; however, these studies are limited and did not show any preventive effect . Fulminant ocular toxoplasmosis may occur with corticosteroid monotherapy, in which case vitrectomy may be warranted .
9. Endogenous helminthic endophthalmitis
Helminths at either the larval or adult stage can lead to the infection of ocular tissues through adjacent structures or may have a predilection for ocular tissue as they migrate through the vascular system . Helminths generally only have a unilateral eye presentation, but there is no observed difference in eye predominance . Although infrequent, helminth infections are more common in areas of consumption of contaminated water, raw meat, and freshwater fish [268, 269], so travel history to endemic areas is essential to ascertain the source of the infection. However, due to movement via rapid transport, such history might not be present . Helminth endogenous endophthalmitis is much less frequent compared to bacterial, viral, and fungal causes. Pediatric populations are more likely to have zoonotic infections, such as
Due to the nature of these parasites, pathological lesions show a wider variety of clinical presentations compared to other causes of EE. Perhaps the most common cause of helminth infection is
Two helminths with ocular manifestations are
One helminth unique to the pediatric population is
The most common helminths in the pediatric population are
Helminths have also shown surprising manifestations in immunocompromised hosts. One patient with a history of systemic lupus erythematosus (SLE) presented with decreased bilateral vision in both eyes. Fundoscopy showed granulomas in the posterior poles bilaterally, with new granulomas developing in subsequent exams. Serology was positive for
Another subset of immunocompromised patients who are at risk for helminth-induced endogenous endophthalmitis is the IVDU population. One patient with a history of IVDU reported two weeks of worsening right eye pain with decreased visual acuity. Endophthalmitis was suspected and a vitreous tap was performed. Gram stain showed no organisms, but rare white blood cells were present. Initial labs, bacterial and fungal cultures were negative. The patient was admitted for the endogenous spread of infection and placed on IV antibiotics. The patient’s repeat serology was found to be positive for
Immunocompromised patients with significant animal contact who present with suspicion of endogenous endophthalmitis should be considered for a helminth cause [4, 9]. Treatment of ocular toxocariasis should be tailored to the clinical presentation of the host, and patients with inflammation should be placed on steroids to reduce the risk of retinal detachment. Anti-helminthic agents and IV antibiotics have been successful, but surgical intervention may be necessary if complications occur .
Endogenous endophthalmitis can be a result of a systemic infection from a myriad of infectious agents including bacteria, viruses, fungi, protozoa, and helminthic organisms. Systemic infection should be suspected when there is no history of surgical intervention or trauma. Unlike exogenous endophthalmitis, the onset of clinical manifestations may be insidious and difficult to diagnose. This is particularly true in nonverbal patients.
Clinical presentations may be bilateral or unilateral. Vitreous and retinal involvement are potentially sight threatening and appropriate investigations should be performed to find the distal infection focus or systemic source(s) of the endogenous endophthalmitis and treatment usually involves systemic agents aimed at the offending organism as well as intravitreal pharmacotherapy and/or pars plana vitrectomy (PPV) to both obtain a microbiological sample both to identify the organism and to therapeutically debride the vitreous cavity of the organism, inflammatory cells, and destructive cytokines. Occasionally a chorioretinal biopsy may be required to identify the organism. Despite aggressive treatment, the eye (s) may lose vision, and some may require enucleation.
|Step 1: Withdraw 0.4 ml from an amikacin vial (100 mg/2 ml)|
|Step 2: Add the step 1 solution to a second 10 ml syringe containing 9.6 ml < 0.9% NaCl for injection USP (Preservative Free)|
|Step 3: Withdraw 0.1 ml from step 2 solution (2 mg/ml), which will now contain 200 |
|Ceftazidime 2.2 mg/0.1 ml||Step 1: Reconstitue 1000 mg ceftazidime powder with 8 ml of 0.9% NaCl for injection USP (Preservative Free)|
|Step 2: Withdraw all 8 mL of that the solution prepared in step 1 and add saline to create total volume of 10 ml. Then, withdraw 1 ml of that solution in a second syringe with 3.5 ml of 0.9% NaCl for injection USP (Preservative Free) (Total volume 4.5 mL)|
|Step 3: Withdraw 0.1 from the step 2 solution (22.2 mg/ml), which will now contain 2.2 mg/0.1 ml of ceftazidime|
|Clindamycin 450 ||Step 1: Withdraw 0.3 ml from a vial of clindamycin (150 mg/ml)|
|Step 2: Add the step 1 solution to a second 10 ml syringe containing 9.7 ml of 0.9% NaCl for injection USP (Preservative Free)|
|Step 3: Withdraw 0.1 ml from step 2 solution (4.5 mg/ml), which will now contain 450 |
|Gentamicin 100 ||Step 1: Withdraw 0.25 ml (10 mg) from a gentamicin vial (40 mg/ml)|
|Step 2: Add the above 0.25 ml to a new 10 ml syringe containing 9.75 ml of 0.9% NaCl for injection USP (Preservative Free) (Final concentration 1mg/ml)|
|Step 3: Withdraw 0.1 from step 2 solution (1 mg/ml), which will now contain 100 |
|Vancomyci 1 mg/0.1 ml||Step 1: Dilute a vial of vancomycin powder (500 mg) with 10 ml 0.9% NaCI for injection USP (Preservative Free) Final concentration (50 mg/ml)|
|Step 2: Withdraw 1 ml solution prepared in step 1 (50 mg/ml) into a new 5 ml syringe and add 4 ml of 0.9% NaCl for injection USP (Preservative Free) Final concentration (10 mg/ml)|
|Step 3: Withdraw 0.1 from the step 2 solution (10 mg/ml), which will now contain 1 mg/0.1 ml of vancomycin|
|Dexamethasone 1000 ||Step 1: Withdraw 0.1 ml from a dexamethasone vial up containing 10 mg/ml vial|
|Amphotericin B 5 ||Step 1: one vial of 50 mg amphotericin B is diluted with 10 ml of sterile water (Preservative Free) Final concentration (5 mg/ml = 0.5 mg/0.1 ml)|
|Step 2: Withdraw 0.1 ml of step 1 solution (0.5 mg/0.1 ml) and add it to 9.9 ml of sterile water (Preservative Free) Final concentration (0.05 mg/ml)|
|Step 3: Withdraw 0.1 ml from step 2 solution, which will now contain 5 |
Pearl 2: Avoid attaching antibiotics to the original vitreous biopsy needle while in the eye due to increased risk of retinal injury. It is preferred to withdraw the biopsy needle and re-enter the eye with a new needle for antibiotic delivery.
Pearl 3: Injection of drugs should be limited to the smallest possible volume and the bevel of the needle should be placed toward the lens, not toward the retina w.
Pearl 4: Do not combine dexamethasone and vancomycin in the syringe due to precipitation, but aminoglycosides and dexamethasone can be used in the same syringe. Of note, hemorrhagic occlusive retinal vasculitis has been reported with intravitreal gentamicin treatment
Pearl 2: Vitrector can be safely placed behind the IOL in pseudophakic eyes.
Pearl 3: We recommend intravitreal and systemic therapy in endogenous endophthalmitis cases, especially in mycotic cases.
Pearl 4: Fluconazole 200 g/ml can be safely used in the infusion fluid during vitrectomy of eyes with endogenous fungal endophthalmitis.
-Vitreous tap should be performed initially followed by intravitreal injection of one-quarter the recommended antibiotic dose for non-vitrectomized eye along with 1 mg dexamethasone.
-When purulent exudates are present in the vitreous cavity, we recommend the removal of silicone while using infusion fluid with recommended doses of antibiotics and steroids.
-The recommended infusion fluid composition for EBE: 20 g/ml vancomycin, 9 g/ml clindamycin, 8 g/ml gentamicin, 64 g/ml of dexamethasone.
-Silicone oil can be injected immediately after removal of infected eye’s silicone oil or when inflammation is controlled.
Pearl 6: We recommend the reduced antibiotic dosage (25%) for retreatment in all vitrectomized eyes.
Pearl 2: Place the tissue specimen in the culture or fixation solution of choice and then promptly send it for microbiology and histology.
Pearl 3: Minimize any trauma to the biopsy during the procedure and transport.
Pearl 4: Often no further laser treatment or cryotherapy is required at the biopsy site.
Pearl 5: Instruct the patient to lay on the appropriate side to tamponade the site with gas during sleep.
Pearl 6: Closely follow up patients for any signs of retinal detachment.
|Infusion Fluid Upper limit of drug dosages without toxicity in non-vitrectomized eyes*|
|Drug||Nontoxic Dose (μg/ml)|
|Amphotericin B methyl ester||75|
|Clindamycin/Gentamicin||9 / 8|
|Gentamicin/Oxacillin||8 / 10|
|Methicillin/Gentamicin||20 / 8|
|Penicillin/Gentamicin||80 / 8|
|Causative agents of endogenous endophthalmitis discussed in this chapter|
|Group B Streptococcus and other Streptococcus species|
|Herpes Simplex virus|
Citation: Gholam A. Peyman, Stephen A. Meffert, Mandi D. Conway. Vitreoretinal Surgical Techniques, Second Edition, 2007.