**Abstract**

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 nonimmunosuppressed 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.

**Keywords:** endophthalmitis, endogenous, bacterial, viral, fungal, protozoal, helminthic

### **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 [1–4]. Nineteen percent of cases have a bilateral presentation [5]. 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) [2–4]. 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 [3]. The most common systemic findings include fever (37%), often a low-grade fever and chills, and influenza-like features (20%) [3].

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, *Staphylococcus aureus, Serratia marcescens*, and *Klebsiella* endophthalmitis can be associated with pink or bloodtinged hypopyon, whereas *Mycobacterium tuberculosis, Streptococcus bovis,* and *Listeria monocytogenes* endophthalmitis can present with tan or pigmented hypopyon [6]. Moreover, organisms such as *Listeria monocytogenes* and *Bacillus cereus* are commonly associated with elevated intraocular pressures [7].

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 [3]. 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 [3].

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 [4]. 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 [3–5, 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 [3]. 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 [12]. 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 [13–16]. However, PCR has not replaced the utility *Endogenous Endophthalmitis: Etiology and Treatment DOI: http://dx.doi.org/10.5772/intechopen.96766*

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 [17]. Nevertheless, due to increased affordability and reproducibility in addition to the aforementioned benefits, PCR is becoming increasingly utilized even in developing countries [18–20].

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 *Klebsiella* being the most commonly reported organism behind EBE in East Asia [21]. In fact, up to 90% of EBE cases in East Asia were found to be result of *Klebsiella* spp., likely secondary to the high incidence of DM and hepatobiliary disease in that area [2, 6, 21]. Liver abscess is a common source for *Klebsiella*-induced EBE [2, 7, 22]. Other common Gramnegative species include *Pseudomonas aeruginosa, Neisseria meningitidis, Escherichia coli, Salmonella* spp.*,* and *Serratia marcescen*s. Patients with EBE from *P. aeruginosa* commonly have predisposing factors such as cystic fibrosis, immunosuppression, history of lung transplant, and endocarditis [23–25], although EBE by *P. aeruginosa* has been reported in an immunocompetent patient with an unknown source of infection [26]. *N. meningitidis* is also a common pathogen in children with EBE but has been on the decline with the advent of antibiotics [4]. It is important to suspect *N. meningitidis* in patients with sepsis, fever (which can be high and relapsing), rash involving the palms and soles, and meningismus; however, it is not always the culprit [27]. *N. meningitidis* has been isolated from eyes without the classic signs of meningococcemia [16, 28–32]. The majority of patients with *Escherichia coli* endogenous endophthalmitis have associated urinary tract infections and renal abscesses 4 . *Salmonella typhi* has been identified as a cause of endogenous endophthalmitis following typhoid fever [33, 34]. One study found that 7 out 14 patients were under one year of age [33]. Therefore, endogenous endophthalmitis should be suspected in all patients following typhoid fever, especially in infants. Other members of the *Salmonella* spp. have been implicated [35–37]. *Serratia marcescens* is commonly associated with nosocomial catheter-related infections in immunocompromised patients along with urogenital tract infections and IVDU [38–43].

The most common Gram-positive bacteria in EBE are *Staphylococcus aureus*, Group B streptococci, *Streptococcus pneumoniae, Listeria monocytogenes*, *Enterococcus faecalis*, *Bacillus cereus*, and *Nocardia* species [2, 44]. One study found that *S. aureus* was the single most common organism to cause EBE (25% of cases) [1]. *S. aureus* can be further divided into methicillin-sensitive *Staphylococcus aureus* (MSSA) and methicillin-resistant *Staphylococcus aureus* (MRSA). The latter group is typically more difficult to treat due to increased antibiotic resistance [45, 46]. MRSA infections are mainly found in hospitalized patients with predisposing risk factors such as DM, HIV, end-stage renal disease (ESRD), IVDU, skin/joint infections, and indwelling catheters; however, it has also been documented in immunocompetent patients without any known underlying risk factor [43, 47–52].

Group B *Streptococcus* endogenous endophthalmitis typically arises by hematogenous spread secondary to pneumonia, pharyngitis, UTIs, and skin infections [53, 54]. The endophthalmitis caused by this organism is commonly associated with endocarditis and septic arthritis [53, 54]. *Streptococcus pneumoniae* was found to be the most common isolated organism (20.8%) in a large Indian study that involved 173 eyes with EBE [55]. Interestingly, the majority of patients with EBE in this study were young (mean age 25 years) and without any predisposing illnesses (68%). However, patients who are immunocompromised and asplenic, are susceptible to EBE by this microorganism [56–58]. Endogenous endophthalmitis has also been observed in patients with *S. pneumoniae* meningitis [59, 60].

*Listeria monocytogenes* is a Gram-positive rod that is typically transmitted via ingestion of contaminated food. Chronic uveitis has been documented as a sequela of this bacterial infection and requires long-term topical steroid therapy [7]. Blood cultures (23% positive yield) have significantly lower yield than intraocular tissue sampling such as aqueous (86%) and vitreous (78%) [7]. The source of infection is typically not found [7].

*Enterococcus faecalis* is a natural inhabitant of the GI tract and is a rare cause of EBE. A few documented cases identify some of the sources to be secondary to cholecystitis, indwelling catheter, and prosthetic valvular endocarditis [52, 61, 62]. One case has also been documented after gastrointestinal illness [63].

*Nocardia spp.* are ubiquitous filamentous bacteria found in water, soil, and decaying vegetation. These microorganisms are typically known to disseminate from a pulmonary focus in immunocompromised patients; however, EBE in immunocompetent patients has also been documented [64]. Up to half of patients are transplant patients, and a quarter have underlying autoimmune diseases [65]. Chorioretinal lesions are a common manifestation of *Nocardia* EBE and are believed to be the most frequent bacterial cause of subretinal abscesses [59, 65, 66]. They are found to occur in around 69% of patients, often requiring retinal biopsy and vitrectomy for diagnosis and treatment [65]. *Bacillus cereus* is very common in patients with history of IVDU [60, 67, 68]. Infection by this microorganism is known for its rapidly progressive and explosive course, which can often lead to panophthalmitis [60, 68–70].

## **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 bloodocular 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 [73–76]. 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 [77]. Nevertheless, the studied population was post-operative endophthalmitis patients, so the results may not be directly applicable to patients with EBE [77]. 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) [4]. Currently, systemic antibiotics

#### *Endogenous Endophthalmitis: Etiology and Treatment DOI: http://dx.doi.org/10.5772/intechopen.96766*

are seldom used as a monotherapy but are often used in combination with intravitreal antibiotics, and sometimes PPV [3].

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 [3]. Amikacin and gentamicin IVI can also be used for Gram-negative microorganisms [4]. 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 [77]. 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 *versus* an IVI-only group [3]. For more on endophthalmitis treatment and management, please refer to the final section. [Addendum].
