Continuing Education Activity

Bacterial endophthalmitis is an intraocular infection that can have devastating consequences, leading to decreased vision and irreversible blindness if not promptly recognized. The sterile environment of the eye can be breached by penetrating trauma, surgery, endogenous sources via bacteria in the patient's circulatory system, or fungi invading and multiplying within the vitreous or aqueous humor. Notably, bacteremia or fungemia might be transient, leading to presentations devoid of systemic infection symptoms. Advanced molecular diagnostic methodologies, currently employed in research settings, facilitate expedited pathogen identification when conventional culture methods yield negative results. Therapeutically, the intravitreal administration of antibiotics constitutes the cornerstone of management, supplemented by surgical intervention in select scenarios. The causative pathogen influences the prognostic trajectory; for instance, endophthalmitis induced by coagulase-negative staphylococci typically portends a more favorable outcome than streptococcal-origin endophthalmitis. Given its potential for rapid progression and severe visual sequelae, endophthalmitis is categorized as an ophthalmologic emergency, necessitating decisive diagnostic and therapeutic interventions to preserve visual function. This course outlines and describes the evaluation and management of bacterial endophthalmitis and reviews the role of the interprofessional team in collaborating to provide coordinated care to enhance patient outcomes.

Objectives:

• Identify the etiology of bacterial endophthalmitis, differentiating between mild and severe pathogens.

• Select the appropriate history, physical, and evaluation of bacterial endophthalmitis.

• Compare the management options available for bacterial endophthalmitis.

• Implement interprofessional team strategies for improving care coordination and communication to mitigate long-term sequelae of bacterial endophthalmitis.

Introduction

Endophthalmitis constitutes a critically severe ocular infection with the potential to precipitate rapid and irreversible vision loss within mere hours or days following the initial presentation of symptoms. The condition is characterized by the infection of the eye's vitreous and/or aqueous humor, predominantly by bacterial or fungal pathogens.[1] In contrast, intraocular infections caused by viral or parasitic pathogens are categorized under uveitis rather than endophthalmitis. The etiology of endophthalmitis is deemed exogenous or endogenous. Exogenous endophthalmitis is more prevalent and results from introducing microorganisms into the eye, either from the ocular surface or from another external source. The condition is further categorized based on specific risk factors, leading to distinct subtypes such as post-cataract surgery, post-traumatic, and bleb-related endophthalmitis. Each category exhibits unique clinical presentations, microbiological profiles, and prognostic implications for visual outcomes, necessitating precise categorization for optimized management and therapeutic strategies.[2] In contrast, endogenous endophthalmitis arises from the hematogenous dissemination of pathogens during episodes of bacteremia or fungemia.

Temporal factors within study parameters influence the frequency of endophthalmitis types. Post the U.S. Food and Drug Administration's (FDA) approval of intravitreal anti-vascular endothelial growth factor (anti-VEGF) medications for neovascular age-related macular degeneration in 2004, a marked increase in the utilization of these and other intravitreal injections was seen. Consequently, some centers have observed that post-injection endophthalmitis cases have surpassed postoperative cases.[3] 

If diagnosed and treated promptly with appropriate antibiotics, patients with bacterial endophthalmitis can recover fully and preserve their vision. Given the time-sensitive nature of bacterial endophthalmitis, it is of the utmost importance for clinicians to recognize this ocular disorder and put the patient on the quickest path to recovery.[4]

Etiology

Bacteria are not present in a healthy eye's vitreous or aqueous humor, but seeding into the eye can occur from an exogenous or endogenous source. Exogenous seeding is the most common cause of bacterial endophthalmitis from the exterior ocular surface during penetrating ocular trauma, surgery, or intraocular injections. Although rare, bacterial endophthalmitis can also result from hematogenous spread from infections elsewhere in the body or intravenous (IV) drug use.[5] Approximately 40% to 80% of all endophthalmitis cases are caused by cataract surgery; of these cases, 70% are the result of coagulase-negative staphylococci, 10% are from Staphylococcus aureus, and 9% are from Streptococci. The second most common cause of endophthalmitis occurs after intravitreal injection, with coagulase-negative staphylococci and streptococci being the primary pathogens. Penetrating eye trauma is the third most common cause and constitutes anywhere from 2% to 15% of all cases of endophthalmitis.[6]

Coagulase-negative staphylococci predominate in this category, but other bacteria such as Bacillus, gram-negative bacilli, and fungi can cause infection. Bleb-related endophthalmitis is the fourth most common cause, with the bacterial etiology in descending order of S pneumonia, enterococci, or Haemophilus influenzae. Keratitis, resulting in organisms penetrating the cornea, is the fifth most common cause. However, 50% of keratitis-related cases are due to fungi with S aureus, Streptococci, and Pseudomonas, causing a minority of these infections. Endogenous blood-borne endophthalmitis is the rarest cause, with Klebsiella pneumonia being the most common aggressor, followed by Candida, Streptococci, S aureus, and E coli.[4][7]

In postoperative endophthalmitis, most cases (ranging from 48% to 70%) are attributed to infections by coagulase-negative staphylococci. A spectrum of gram-positive bacteria, including species of Streptococci, Enterococci, and S aureus, have been identified as causative agents in such instances. In the context of ocular trauma, the incidence of endophthalmitis is notably higher, with reported rates between 3% and 17%.[8] The incidence of endophthalmitis due to ocular trauma has shifted from coagulase-negative staphylococci to other staphylococcal species and Bacillus cereus. Notably, B cereus is observed to be 10 times more prevalent in post-traumatic endophthalmitis compared to its occurrence in post-surgical cases.[9]

Endogenous endophthalmitis, also called metastatic endophthalmitis, emerges from spreading infectious organisms to the eye from other sites within the body. Although less common than its postoperative or post-traumatic counterparts, accounting for only 2% to 8% of all endophthalmitis cases, endogenous endophthalmitis presents a significant risk of bilateral infection, occurring in 15% to 25% of such cases. Fungal pathogens are responsible for approximately half of all endogenous endophthalmitis cases, with Candida albicans being the primary fungal pathogen, accounting for 75% to 80% of fungal-related instances. On the other hand, gram-negative bacteria are associated with 32% to 37% of endogenous endophthalmitis cases. Infections caused by gram-negative organisms are concerning due to their association with poor outcomes, which can be challenging to treat.[10]

Epidemiology

Cataract surgery and intravitreal injections are the leading causes of endophthalmitis. However, endophthalmitis is a rare condition controlled by the advent of antibiotics. Today, of all patients undergoing cataract surgery, approximately 0.1% suffer from endophthalmitis. Traumatic penetrating eye injury can cause bacterial endophthalmitis in 1% to 18% of patients. Hematogenous bacterial endophthalmitis is the rarest form, with an incidence rate of 0.04% to 0.4%, and is associated with IV drug use, diabetes mellitus, immunosuppression, malignancy, prolonged hospital stay, or IV antibiotic administration.[4][7]

In the past 20 years,  a discernible escalation has been seen in the incidence of postoperative endophthalmitis. Other data from the 1990s indicated an infection rate of approximately 0.1% or 1 in every 1000 cataract surgeries. However, this figure notably increased to around 0.2%, equating to 1 in every 500 surgeries during the early 2000s. Furthermore, when compared to other ocular surgical procedures, cataract surgery has been identified as the predominant contributor to the incidence of postoperative endophthalmitis. Though a relatively rare visual condition, endophthalmitis demonstrates a variable incidence rate depending on its etiological category.[11] For instance, endophthalmitis following cataract surgery is estimated at approximately 0.1%, whereas the incidence following penetrating ocular trauma ranges from 1% to 18%. Globally, the predominant forms of endophthalmitis are postoperative and post-traumatic, with postoperative cases (most notably post-cataract surgery) constituting about 40% to 80% and post-traumatic cases accounting for 2% to 15% of all endophthalmitis instances. This data reflects findings from medical centers across diverse geographical locations, including Brazil, England, Israel, Iran, India, Australia, and South Korea.[12]

In some medical centers in Egypt, India, and China, post-traumatic endophthalmitis represents a significant proportion, comprising 40% to 60% of all endophthalmitis cases.[13] Cataract surgery is the single most important cause of bacterial endophthalmitis and has risk factors associated with preoperative, intraoperative, and postoperative stages:

Preoperative Risk Factors:  

• Blepharitis or lid abnormalities [14]
• Application of 2% xylocaine gel before povidone-iodine [15]
• Diabetes mellitus [16]
• Advanced age
• Immunocompromised status [17]

Intraoperative Risk Factors:

• Poor sterile technique [18]
• Posterior capsular rupture
• Vitreous loss and wound leak
• Use of intracameral miotics/staining dyes and epinephrine
• Contamination during the mixing of compounded medications

Postoperative Risk Factors:

• Postoperative wound leak
• Nonsilicon intraocular lens type

Endogenous endophthalmitis is associated with infectious diseases involving the liver, lungs, heart, brain, and urinary tract. Risk factors also include diabetes mellitus, immunosuppression, or a history of recent hospitalization or surgery. Hematogenous bacterial endophthalmitis is the rarest form, with an incidence rate of 0.04% to 0.4%. [19]

Pathophysiology

Exogenous seeding is the most common cause of bacterial endophthalmitis and depends on host factors, pathogen factors, and inoculum size. Bacteria such as coagulase-negative staphylococci typically colonize the conjunctiva and can be introduced to the inner ocular cavity during surgery, injections, or trauma. After cataract surgeries, research reveals that one-third of patients' aqueous humor was positive for coagulase-negative staphylococci. However, only 1-in-500 to 1-in-1000 cataract surgeries result in bacterial endophthalmitis. These numbers highlight how host factors, such as the immune response, can clear the small inoculum of bacteria.  Inoculum size has also been shown to overload the immune system and lead to infection.[20][21][22]  

Pathogen factors can play a role in the pathogenesis of bacterial endophthalmitis. Bacteremia is a rare cause of bacterial endophthalmitis, but the culprit is usually Klebsiella pneumoniae when it does occur. The magA gene endows the serotype K1 or K2 of K pneumoniae with a mucopolysaccharide-web capsule that allows hypermucoviscous virulence and is a common cause of pyogenic liver abscess in southeastern Asia. As many as 7% of patients with K1 or K2 Klebsiella pneumonia liver abscess will experience hematogenous spread to their retina. Experimental mice models confirm that eyes injected with Klebsiella hypermucoviscosity (HMV) phenotype have increased retinal function loss and inflammation than eyes injected with HMV-negative strains.[23]

Bacillus cereus can cause posttraumatic endophthalmitis and be present in IV drug users. B cereus is a major pathogen that can cause fulminant endophthalmitis. Quorum-sensing by Bacillus initiates toxin release and migration, contributing to the retina's rapid deterioration and destructive course of Bacillus endophthalmitis. The virulence factors of Bacillus species that accommodate this destruction include membrane-damaging toxins such as hemolysins, sphingomyelinases, and phospholipases. The quorum sensing-dependent transcriptional regulator PlcR regulates virulence factor production. Neutrophil recruitment and CXCL1 chemokine lead to inflammation and retinal damage in Bacillus endophthalmitis.[24]

In bleb-related endophthalmitis, S pneumoniae is the most common pathogen and can cause severe endophthalmitis. Virulence factors such as the pneumococcal capsule, pneumolysin, and autolysin all appear to contribute to the pathogenesis. Studies have found that initial tissue damage is less severe when infected with pneumolysin-deficient S pneumoniae versus pneumolysin-producing strains within the first 24 hours of the disease.[25][26]

Streptococcus pneumoniae central virulence includes exotoxins and enzymes and a polysaccharide capsule that prevents phagocytosis. S pneumoniae virulence also uses pneumolysin, which inhibits host responses involved with antibody synthesis and lymphocyte proliferation. Inflammation results from the cell wall components of S pneumoniae, causing the symptoms that patients seek care for.[27]

Pseudomonas aeruginosa endophthalmitis causes rapid tissue necrosis caused by Pseudomonas toxins such as pyocyanin, pyoverdin, exotoxin A, and elastase. These toxins disrupt membrane and epithelial barriers, leading to cytotoxicity.[27]

Histopathology

Histopathology of bacterial endophthalmitis reveals a series of pathological changes within the intraocular tissues. The process begins with bacterial infiltration into the eye, leading to an acute inflammatory response.

Here are the key histopathological features observed in cases of bacterial endophthalmitis:

• Inflammatory infiltrate: The vitreous cavity typically shows an infiltration of polymorphonuclear leukocytes (PMNs), indicative of an acute inflammatory response. The retina and choroid may also exhibit infiltration by inflammatory cells, including lymphocytes, macrophages, and plasma cells, in response to the infection.[28]
• Suppurative changes: Areas of suppuration may occur with the formation of abscesses within the vitreous body or the retina. Necrotizing inflammation can occur, characterized by tissue destruction and necrotic debris.[29]
• Vascular changes: Endophthalmitis can lead to vasculitis, with inflammation of the blood vessels in the choroid and retina. Vascular occlusion and hemorrhages may be present due to the inflammatory process.[30]
• Fibrin exudation: Fibrin deposition is noted within the vitreous cavity and anterior chamber, which can lead to a hypopyon (layering of white blood cells in the anterior chamber of the eye).[31]
• Retinal detachment: Progressive inflammation can lead to the separation of the sensory retina from the underlying retinal pigment epithelium (RPE), known as retinal detachment.[32]
• Tissue damage and necrosis: The bacteria and host immune response can lead to retinal and uveal tissue damage, focal to confluent areas of necrosis.[33]
• Granulomatous reaction: In some cases, particularly with certain types of bacteria, a granulomatous response is seen, characterized by the formation of granulomas with multinucleated giant cells.
• Fibrosis and scarring: Over time, the inflammation can lead to fibrosis and scarring within the eye, which can have long-term effects on vision.[34]
• Infiltration of the optic nerve: In severe cases, the optic nerve may show signs of inflammation and infiltration, potentially leading to optic atrophy.[35]
• Biofilm formation: Some bacteria can form biofilms on intraocular lenses or other implanted devices within the eye, resistant to immune cells and antibiotics.[36]

It is important to note that the histopathological features of bacterial endophthalmitis can vary depending on the bacteria's virulence, the host's immune status, and the infection's duration before treatment. Early and effective intervention is crucial in preventing the severe histopathological changes associated with this condition.

Toxicokinetics

Below are the important features of the bacteria causing endophthalmitis:

Absorption: In bacterial endophthalmitis, bacterial toxins and inflammatory mediators are produced locally in the eye and are not absorbed in the traditional sense but can diffuse into adjacent ocular tissues.[37]

Distribution: Bacterial toxins are typically confined to the intraocular compartments, particularly the vitreous and aqueous humor. The inflammatory response to these toxins can cause the breakdown of the blood-ocular barrier, leading to potential leakage and more widespread distribution of inflammatory cells and mediators.[34]

Metabolism: Bacterial toxins are not metabolized in the same way as drugs. Instead, they may be neutralized by antibodies or broken down by enzymes in the ocular fluids, or they may persist, contributing to ongoing inflammation and damage.[38]

Excretion: Bacterial toxins and inflammatory debris are removed from the eye by phagocytosis and possibly through the trabecular meshwork and Schlemm's canal, which are part of the eye's natural drainage system.

Local Toxicity: The virulence factors of the bacteria cause damage to ocular tissues, leading to the characteristic signs of endophthalmitis, such as vitreous clouding, retinal edema, and inflammation of the uveal tract.[39]

Pharmacokinetics of Antibiotics: Intravitreal injection of antibiotics allows for high local drug concentrations, bypassing the systemic circulation and reducing systemic toxicity. The half-life of antibiotics in the vitreous may be prolonged due to the vitreous body's relatively avascular nature and the vitreous fluid's slow turnover.[40]

Response to Treatment: The efficacy of antibiotic therapy in endophthalmitis can be influenced by the permeability of the bacterial cell wall, bacterial biofilm formation, and antibiotic-resistant strains.[41]

Understanding these aspects is crucial for effectively managing bacterial endophthalmitis, as they directly influence treatment strategies and outcomes. The goal is to maximize the local concentration of antibiotics to control the infection while minimizing the inflammatory damage caused by bacterial toxins and the immune response.[42]

History and Physical

A complete history and physical examination are critical in diagnosing and treating bacterial endophthalmitis promptly and effectively. Prompt diagnosis is crucial to prevent lifetime blindness. The most common symptom of endophthalmitis that patients complain of is decreased vision. Eye pain, discharge, or red-eye are also common but may be present or absent in different cases of bacterial endophthalmitis. The timeline of symptoms can also clarify whether the patient is suffering from a bacterial versus fungal etiology.[43]

Bacterial endophthalmitis presents in an acute timeframe versus fungal endophthalmitis, which has a much more subacute presentation, worsening over days to weeks. Clinicians should inquire about a history of ocular surgery, injections, or penetrating ocular injury in exogenous endophthalmitis. They should also ask about systemic symptoms such as fevers, chills, recent infections, recent surgery, recent hospitalization for sepsis, recent antibiotic use, and IV drug use that are often present in endogenous endophthalmitis cases.[4]

Evaluation

Exogenous Endophthalmitis

Patient presentation is commonly unilateral and can vary, ranging from asymptomatic to symptomatic, conjunctival injection, photophobia, corneal edema, iritis, vitritis, anterior chamber cells, floaters, or reduced vision. On examination, a hypopyon, representing a layer of white blood cells in the anterior chamber, can occur in most cases of bacterial endophthalmitis and up to 80% of post-cataract cases. Funduscopic examination reveals intraocular inflammation, obscuring the view of the retina with white blood cells that create a hazy look. The type of intraocular inflammation can be indicative, with bacterial endophthalmitis having diffuse intraocular inflammation. In contrast, fungal endophthalmitis presents with "clumps" of inflammation in the aqueous or vitreous. Using ultrasound can help identify vitritis or chorioretinal infiltrates.[4] Vitreous fluid obtained via vitrectomy has a higher diagnostic yield than needle biopsies. If a patient contracts endophthalmitis from anti-VEGF intravitreal injections, vitreous culture is helpful in the prognosis of visual outcomes but not necessarily influential in the clinical course.[44] Aqueous humor taps yield the lowest fluid to culture, most likely due to the increased distance from the nidus of infection. Blood cultures yield true-positive results in approximately a third of cases, whereas polymerase chain reaction can identify bacterial and fungal culture-negative cases.[45][46] 

Endogenous Endophthalmitis 

Endogenous endophthalmitis is often unilateral, but up to a third of cases have bilateral involvement. Diagnosing endogenous endophthalmitis requires a high degree of suspicion with the presence of systemic risk factors. However, a clinical diagnosis of endogenous endophthalmitis is always difficult as it has a high false-negative rate, and multiple clinic visits may be required to confirm the diagnosis. Some patients may present asymptomatically, while symptomatic patients might present with symptoms such as hypopyon, vitritis, conjunctival injection, corneal edema, iritis, anterior chamber cells, or reduced visual acuity. White infiltrate originating in the choroid and protruding into the vitreous cavity is a critical diagnostic finding of endogenous endophthalmitis. Endogenous endophthalmitis is generally not a significant concern in patients with life-threatening sepsis secondary to a bacterial etiology. Hence, the diagnosis of endogenous endophthalmitis may be delayed with other morbidities under acute management.

A 2015 study helped stratify the likelihood of endogenous endophthalmitis: [47]

• Positive endogenous endophthalmitis
• Uveal tissue abscesses
• Hypopyon greater than 1.5 mm [48]
• Vitreous exudates
• Visible arteriolar septic emboli
• Necrotizing retinitis
• Perivascular hemorrhages with inflammatory
• Panophthalmitis
• Corneal infiltrates of ulcer
• Possible endogenous endophthalmitis
• Hypopyon greater than 1.5 mm
• Vitreous haze with no visible exudates
• Chorioretinal lesions
• Optic neuritis
• White reflex in neonates
• Scleritis
• Probable endogenous endophthalmitis
• Conjunctival injection or chemosis
• Anterior chamber inflammation but no hypopyon
• Absence of vitreous haze
• Lid edema 
• Fever

The trajectory of endophthalmitis, its responsiveness to treatment, and the prognosis are subject to variability. The initial clinical manifestation of this intraocular infection is influenced by several factors: the virulence of the causative microorganism, the mode of its injection into ocular tissues, and the latency before therapeutic intervention. Additional factors influencing the resolution of the infection include the patient's age, the pathogen's susceptibility profile, and the pre-existing anatomical integrity of the eye.[49] Empirical evidence suggests that delaying treatment after infection can lead to suboptimal visual outcomes, although exceptions to this trend exist. At clinical presentation, the pathogen responsible is unidentified, necessitating the prompt administration of empiric broad-spectrum antimicrobials.[50]

The antimicrobial regimen for endophthalmitis typically comprises a combination of vancomycin, targeting gram-positive bacteria, and a third-generation cephalosporin, such as ceftazidime, against gram-negative bacteria. While fluoroquinolones possess broad-spectrum activity and demonstrate effective intraocular penetration, they are not conventionally primary agents for endophthalmitis, partly due to emerging resistance.[51] The prevailing consensus advocates for the intravitreal route of antibiotic delivery to achieve direct, high-concentration drug exposure within the vitreous cavity. This approach is favored over systemic, oral, or topical administration due to the inherent limitations of the blood-ocular barriers. These physiological barriers play a protective role but also limit the diffusion of systemically or topically applied therapies to the site of infection in the eye. Attaining bactericidal levels of antibiotics at the site of infection quickly is crucial to eliminate the pathogen and reduce intraocular damage and inflammation, especially in severe cases.[52]

Treatment / Management

Bacterial endophthalmitis necessitates prompt and early management with intraocular antibiotics, often combined with a pars plana vitrectomy. Patients should be hospitalized and have broad-spectrum IV, topical, and potentially intravitreal antibiotics initiated after collecting the appropriate cultures. The antibiotic of choice should be selected after the etiology of the infection is verified, and once cultures return, the clinician can make proper changes to antibiotic therapy.[53] Patients should receive topical cycloplegic such as atropine 1% twice daily and topical prednisolone acetate 1% every 1 to 6 hours. Intravitreal antibiotics offer higher intraocular concentrations and can be considered if they cover the correct etiology. Intravitreal antibiotics include ceftazidime 2.2 mg, vancomycin 1 mg, and amikacin 0.4 mg. Pars plana vitrectomy is beneficial because it reduces the infective and inflammatory load and provides material for diagnostic studies.[54]

Current Antibiotic Regimen

Contemporary therapeutic protocols for bacterial endophthalmitis typically incorporate the direct administration of intravitreal antibiotics. At a dosage of 1.0 mg per 0.1 ml, Vancomycin is employed for its extensive coverage against gram-positive pathogens, demonstrating a 99% susceptibility rate against gram-positive organisms implicated in endophthalmitis. Conversely, ceftazidime, dosed at 2.2 mg per 0.1 ml, provides broad-spectrum coverage for gram-negative bacteria. For endogenous endophthalmitis, systemic antibiotic administration is standard. However, instances of vancomycin-resistant Enterococcus causing endophthalmitis have been reported, indicating a variation in the effectiveness of traditionally used antibiotics due to emerging resistance.[55]

Ceftazidime, a third-generation cephalosporin, has historically shown complete susceptibility among gram-negative ocular isolates. Nonetheless, resistance has been documented, with a subset of gram-negative endophthalmitis cases exhibiting resistance to amikacin and ceftazidime. Structural advancements within the cephalosporin class have enhanced their efficacy against gram-negative bacteria, with both second and third-generation cephalosporins demonstrating this improved activity.[56] Intravitreal ceftazidime is generally regarded as safer compared to aminoglycosides, with toxicity observed only at elevated concentrations. Clinical evidence suggests a significant reduction in endophthalmitis risk when cefuroxime, a second-generation cephalosporin, is used intracamerally as a surgical prophylactic. The synergistic potential of antibiotic combinations, particularly vancomycin paired with either amikacin or ceftazidime, should be considered in managing rapidly progressing infections like endophthalmitis. However, the necessity is debated due to the high local concentrations achieved with intravitreal injections.[57]

Fluoroquinolones are another class promising endophthalmitis treatment, especially the later generations, which exhibit robust activity against a broad spectrum of ocular pathogens. Although antibiotics have been proven effective, antibiotic resistance has been increased. The prophylactic application of fluoroquinolones in surgical contexts and their potential in treating postoperative endophthalmitis remains contentious. The penetration of fluoroquinolones into ocular tissues varies widely, with moxifloxacin showing superior intraocular penetration compared to gatifloxacin in topical administration. Despite the efficacy of topical moxifloxacin in experimental models, the effectiveness of fourth-generation fluoroquinolones in achieving bactericidal vitreous concentrations remains inconsistent.[58]

Notably, gatifloxacin has been discontinued for systemic use due to its association with dysglycemia. Fluoroquinolones' capacity to traverse the ocular barrier without intravitreal injection underlines their value in specific clinical scenarios. Although primarily indicated for ocular surface infections, their use for endophthalmitis is considered off-label. Experimental studies have confirmed the safety and effectiveness of intravitreal fluoroquinolones in eliminating intraocular infections, suggesting that intravitreal administration of these and other antibiotics can be effective for intraocular infections when immediate, adequate bactericidal concentration at the infection site is crucial.[59]

Anti-Inflammatory Drugs

Intraocular inflammation, a crucial component of the host's defense mechanism against infection, can inflict retinal damage. Intravitreal administration of bacterial cell wall components provokes significant inflammatory responses within the ocular environment. However, this typically results in only transient and reversible retinal function impairment. Considering the potential for the inflammatory response to cause damage within the eye, intravitreal corticosteroids may be applied strategically to mitigate such immune-mediated injury. This can serve as an additional therapeutic strategy with antibiotic treatment. [60]

The clinical and experimental literature presents a divergent viewpoint on the utility of intravitreal corticosteroids in the context of endophthalmitis. While the safety profile of dexamethasone following intravitreal injection is well-established, with a consensus on its non-toxicity to retinal tissues, the efficacy of such interventions remains a point of contention. Disparate clinical findings have been reported, with some studies suggesting that intravitreal dexamethasone may be beneficial, whereas others argue its utility is negligible.[61]

Experimental investigations into the role of intravitreal steroids in bacterial endophthalmitis have similarly yielded inconsistent outcomes. Some studies support the efficacy of combined dexamethasone and antibiotic therapy in inflammation, while others report no significant advantage. Furthermore, combinations of intravitreal prednisolone and antibiotics did not demonstrate a reduction in inflammation in the setting of experimental bacillus endophthalmitis compared to antibiotic therapy alone. Although there is no definitive consensus, corticosteroids, such as dexamethasone 0.4 mg, are frequently used as an adjunct in managing endophthalmitis, reflecting a preference for anti-inflammatory properties in combination with antibiotic regimens.[62]

Role of Vitrectomy

In advanced presentations of endophthalmitis, pars plana vitrectomy (PPV) is frequently employed to excise necrotic microorganisms, compromised cellular material, and deleterious inflammatory by-products from the vitreous cavity. This intervention enhances optical clarity and diffusion within the posterior segment, expediting the restoration of visual function. Minimally invasive approaches to vitrectomy, such as 23- and 25-gauge systems, have gained favor due to their reduced invasiveness. Nonetheless, the inherent complexity of PPV entails certain procedural risks, even with these refined techniques.[1]

The Endophthalmitis Vitrectomy Study (EVS) led to increased use of vitrectomy for therapeutic purposes in endophthalmitis. Early vitrectomy improved visual acuity outcomes for patients with hand motion or light perception deficits. The postulated mechanisms underpinning the efficacy of vitrectomy in such scenarios include a hypothesized breach in the blood–ocular barrier, potentially enhancing the intraocular penetration of systemic antibiotics. A synergistic approach of immediate intravitreal antibiotics coupled with PPV is recommended for endophthalmitis secondary to ocular trauma with retained intraocular foreign bodies (IOFBs). This strategy, including timely foreign body removal, has been associated with significant visual recovery in most cases, notwithstanding a subset of patients who might experience visible decline after these interventions.[63]

Similarly, the prognosis for endophthalmitis secondary to ocular procedures other than cataract surgery appears to benefit from expeditious vitrectomy, especially when initial conservative management is ineffective. In endogenous endophthalmitis, the temporal aspect of vitrectomy plays a pivotal role, with early surgical intervention correlating to improved outcomes. The consensus within clinical literature increasingly supports immediate vitrectomy alongside appropriate intravitreal antibiotic therapy in severe cases of endophthalmitis, particularly those complicated by IOFBs. This aggressive treatment modality is deemed essential for optimizing recovery.[64]

Exploratory research has focused on the utility of vitrectomy in managing fungal endophthalmitis. The mechanical debridement of bacterial load, inflammatory mediators, and toxic substances through vitrectomy remains equally pertinent for bacterial infections. While novel, office-based sutureless vitrectomy systems show promise, their application in the treatment of endophthalmitis is yet to be substantiated within clinical practice. The current body of experimental research examining the efficacy of vitrectomy in bacterial endophthalmitis is limited, indicating the need for further investigation into the benefits conferred by this surgical intervention in managing infectious vitritis.[65]

Periocular injections or subtenon injections are options if necessary.[27] A current study showed the most common isolate in cases of endophthalmitis following evisceration was S pneumoniae, followed in order by Aspergillus and P aeruginosa, respectively.[27] Endophthalmitis can convert to panophthalmitis if the infection spreads to the sclera and the Tenon capsule.[19] Regarding panophthalmitis, the affected eye needs to undergo evisceration or enucleation, with studies suggesting the evisceration rate of panophthalmitis ranges from 14.3% to 23.2%.[19] All isolates showed susceptibility to ceftazidime and levofloxacin, and all MIC 90s for isolates in the current period compared with isolates from 1987 to 2001 remained identical. Despite early and appropriate treatment, outcomes were generally poor, with a high enucleation rate.[66] IV drug users are given aminoglycosides and clindamycin to cover the most likely causative organism, B cereus.

Differential Diagnosis

Bacterial endophthalmitis is an ocular emergency characterized by inflammation and infection within the eye. Differentiating it from other conditions with similar presentations is vital for effective treatment.

The differential diagnosis includes:

1. Sterile endophthalmitis: Similar presentation to infectious endophthalmitis, but occurs as a sterile inflammatory response to intraocular agents or surgery and lacks the growth of organisms on culture.[67]
2. Fungal endophthalmitis: It may present similarly but has a more indolent course. Risk factors include systemic immunosuppression, chronic antibiotic use, and IV drug use. The investigation includes fungal cultures and consideration of intravitreal antifungal therapy.[68]
3. Viral retinitis (eg, Cytomegalovirus, Herpes Simplex Virus): Presents with retinal necrosis and hemorrhages and may have less prominent pain than bacterial endophthalmitis. Requires PCR testing of ocular fluids for definitive diagnosis.[52]
4. Non-infectious uveitis: Inflammatory condition without infection. It may be associated with systemic autoimmune conditions.[69]
5. Acute retinal necrosis: A syndrome characterized by peripheral necrotizing retinitis, usually due to viral etiology. Progression to retinal detachment is typical.[70]
6. Toxic anterior segment syndrome (TASS): An acute sterile postoperative inflammation following cataract surgery due to a non-infectious substance entering the anterior segment. The pathology is distinguished from endophthalmitis by rapid onset and lack of vitreous involvement.[68]
7. Endogenous endophthalmitis: Arises from hematogenous spread from distant infectious sites. Often presents with bilateral involvement and systemic symptoms.[5]
8. Panuveitis: Involves inflammation of all uveal tracts and may mimic the appearance of endophthalmitis.[71]
9. Retained intraocular foreign body: Post-traumatic endophthalmitis must be differentiated from the simple presence of an intraocular foreign body without infection. Imaging studies such as CT or ultrasound B-scan can aid in diagnosis.[72]
10. Masquerade syndromes: Intraocular lymphoma can present symptoms similar to endophthalmitis but are neoplastic.[73]
11. Ocular ischemic syndrome: Presents with pain and vision loss but is due to vascular insufficiency rather than infection.[74]
12. Retinochoroidal infection: The infection involves the retina and choroid, mimicking the vitreous haze and retinal lesions in endophthalmitis. Causative organisms include herpes simplex cytomegalovirus, especially in immunocompromised patients, or toxoplasmosis. Diagnosis is based on serological tests, ocular fluid analysis, and the clinical picture.[75]
13. Non-infectious posterior or intermediate uveitis: These inflammatory conditions affect the posterior segment of the eye and can resemble the vitritis seen in endophthalmitis. They may be associated with systemic autoimmune diseases or idiopathic causes. Diagnosis is clinical, supported by imaging like OCT and fluorescein angiography, and excluded from infectious causes.[76]
14. Neoplastic conditions: Retinoblastoma, uveal melanoma, ocular surface squamous neoplasia (OSSN), lymphoma, choroidal hemangioma, optic nerve glioma, ciliary body, and iris tumors, among others.
15. Large cell lymphoma: It can present with vitreous cells and haze, similar to endophthalmitis, but typically in an older population. Diagnosis often requires a vitreous biopsy for cytology.
16. Retinoblastoma: Usually occurs in children and can present with leukocoria and vitreous seeding that may resemble endophthalmitis. Imaging with ultrasound and MRI, along with clinical examination, is crucial for diagnosis.[77]

A thorough history, detailed ocular examination, imaging, and laboratory investigations, including cultures and PCR testing, are essential in diagnosing bacterial endophthalmitis. The correct diagnosis guides targeted therapy, from antibiotics or antivirals to immunosuppressive treatments, depending on the underlying cause.

Prognosis

Studies on endophthalmitis resulting from S pneumoniae suggest a poor visual outcome. Miller et al, in their study on pneumococcal endophthalmitis, reported 3/27 (11.11%) eyes required evisceration. Pseudomonas endophthalmitis has a high enucleation rate, with one study suggesting that 64% of endophthalmitis caused by Pseudomonas will end up with evisceration and enucleation. Similarly, high evisceration rates post Pseudomonas endophthalmitis were also seen in other studies.[78][27] One study found that risk factors strongly associated with evisceration or enucleation include endogenous endophthalmitis, corneal ulcer, older age, poor initial visual acuity, female gender, and delayed treatment. However, patients with traumatic or postoperative endophthalmitis were less likely to be eviscerated or enucleated. Multivariate analysis indicates that patients suffering from a corneal ulcer, endogenous endophthalmitis, and poor initial visual acuity were much more likely to require evisceration or enucleation.[19]

The prognosis of bacterial endophthalmitis is variable and hinges on several critical factors. Prompt diagnosis and treatment are paramount for improving outcomes, as delayed therapy can result in rapid deterioration of vision and irreversible ocular damage.

• Pathogen virulence: Infections caused by highly virulent organisms, such as Bacillus species, tend to have a poorer prognosis due to rapid progression and extensive ocular damage. Conversely, infections with less aggressive bacteria, such as coagulase-negative staphylococci, may have better visual outcomes with timely and appropriate treatment.
• Initiation of therapy: The timing of intervention is crucial; early administration of appropriate intravitreal antibiotics is associated with more favorable visual outcomes.[79]
• Surgical intervention: The need for and timing of vitrectomy play a role in prognosis. The Endophthalmitis Vitrectomy Study indicated that immediate vitrectomy benefits cases presenting loss of visual acuity or light perception only.[80]
• Host factors: The patient's immune status can significantly influence the prognosis. Immunocompromised individuals or those with diabetes may experience more severe infections and complications, leading to a worse prognosis.
• Complications: The development of complications such as retinal detachment, persistent intraocular inflammation, or phthisis bulbi can lead to a poor visual prognosis.
• Visual acuity at presentation: Patients presenting with better initial visual acuity typically have a more favorable prognosis.
• Rehabilitation potential: Access to and the effectiveness of rehabilitation services, including low vision aids and occupational therapy, can maximize vision and improve the quality of life post-infection.[81]

Despite advances in diagnosis and management, bacterial endophthalmitis remains a condition with a guarded prognosis. Multidisciplinary care involving ophthalmologists, infectious disease specialists, and rehabilitation services is essential for optimizing patient outcomes. Continuous research into novel therapeutic strategies and diagnostic tools is also critical to improve the prognostic outlook for this severe ocular infection.

Complications

These complications are a management challenge and may require additional interventions, including surgery. Early recognition and aggressive treatment are critical to minimize the risks.

• Permanent visual impairment: The most feared complication, from partial vision loss to complete blindness.[82]
• Retinal detachment: This occurs due to inflammation and traction on the retina, potentially requiring surgical repair.[83]
• Vitreous hemorrhage: Bleeding into the vitreous cavity can obscure vision and complicate infection management.[84]
• Corneal edema and opacification: Inflammation can lead to damage that may become permanent and require corneal transplantation.[85]
• Cystoid macular edema (CME): Fluid accumulation in the macula can lead to distorted central vision.[86]
• Glaucoma: Increased intraocular pressure may develop acutely due to inflammatory debris or chronic trabecular meshwork damage.[87]
• Phthisis bulbi: A shrunken, non-functional eye due to severe injury or disease.[88]
• Choroidal effusion: Fluid accumulation in the choroidal space can lead to retinal detachment and decreased vision.[89]
• Endophthalmitis-related uveitis: Inflammatory response in the uveal tract can cause persistent discomfort and photophobia.[90]
• Ocular hypotony: Low intraocular pressure can occur due to ciliary body dysfunction or detachment.[91]
• Epiretinal membrane formation: Scar tissue over the retina can cause visual distortion.[92]
• Optic atrophy: Damage to the optic nerve from severe and prolonged inflammation leads to irreversible vision loss.[93]
• Proliferative vitreoretinopathy (PVR): Scar tissue formation can lead to retinal detachment and is challenging to treat.[94]
• Subretinal abscess formation: This can occur if the infection extends beyond the vitreous into the retinal tissue.[95]
• Sympathetic ophthalmia: A rare but immune-mediated severe condition affecting the non-infected eye.[96]
• Panophthalmitis: This is an extreme form of endophthalmitis that involves all layers and structures of the eye, leading to total loss of vision and a painful, non-functional eye that may necessitate enucleation.[97]
• Corneal ulcer: The infection may progress to involve the cornea, leading to ulceration. Corneal ulcers can be aggressive, leading to perforation and further spread of infection, and may require corneal grafting if structural integrity is compromised.[98]
• Orbital cellulitis: This infection spreads beyond the confines of the eye into the orbital tissues. Orbital cellulitis is a severe condition that can cause pain and swelling and lead to abscess formation, vision loss, and life-threatening complications if the infection spreads to the central nervous system.[85]

Postoperative and Rehabilitation Care

Postoperative Care

• Immediate postoperative period: Patients should be closely monitored for signs of improvement or worsening after intervention. Ocular pain, redness, discharge, and visual acuity should be assessed.
• Intravitreal antibiotics: Depending on the causative organism and the severity of the infection at presentation, follow-up doses may be necessary.
• Anti-inflammatory treatment: The use of corticosteroids, whether topical, periocular, or intravitreal, should be considered to reduce intraocular inflammation.
• Intraocular pressure (IOP) monitoring: Patients are at risk for increased and decreased IOP, which should be managed accordingly.
• Endophthalmitis vitrectomy study (EVS) guidelines: Adherence to these guidelines can help in decision-making regarding further surgical interventions such as repeat vitrectomy.[58]

Rehabilitation Care

• Visual acuity rehabilitation: Low-vision aids and services may be necessary, and patients should be referred to a low-vision specialist for evaluation and management.
• Patient education: Patients should be educated on the symptoms of complications that require urgent medical attention to ensure timely intervention.
• Psychosocial support: Endophthalmitis is a traumatic experience, and patients may benefit from counseling to cope with the potential loss of vision and the impact on quality of life.
• Physical rehabilitation: In cases with significant vision loss, orientation, and mobility training may be needed to ensure patient safety and independence.
• Long-term follow-up: Regular ophthalmic examinations are crucial to monitor for late-onset complications such as cataract formation, retinal detachment, or glaucoma.[58]

The goal of providing comprehensive postoperative and rehabilitation care is to maximize the visual outcome for patients with bacterial endophthalmitis and ensure the best possible quality of life.

Consultations

Early and effective management of bacterial endophthalmitis necessitates a collaborative approach.

The following consultations are recommended:

• Ophthalmology: Immediate consultation with a vitreoretinal specialist is paramount for managing suspected bacterial endophthalmitis. If the media are unclear, the ophthalmologist will perform a comprehensive ocular assessment, including slit-lamp examination, indirect ophthalmoscopy, and possibly B-scan ultrasonography.
• Infectious disease: Their expertise is crucial for interpreting microbiological results and modifying antimicrobial therapy based on sensitivities and resistance patterns.
• Microbiology: Close collaboration is needed for the timely processing and interpretation of ocular samples. Microbiologists also provide valuable insights into local antibiotic resistance trends, which can inform empirical antibiotic choice.
• Internal or primary care: Coordination with the patient's primary care provider is essential for managing comorbid conditions that may affect treatment, such as diabetes or immunosuppression.
• Pharmacy: A clinical pharmacist can assist with antibiotic dosing, especially in patients with renal impairment, and provide information on drug interactions.
• Emergency medicine: In acute settings, consultations may be necessary for initial stabilization and assessment before definitive ophthalmological intervention.
• Anesthesiology: For patients requiring urgent surgical intervention, such as vitrectomy, consultation with an anesthesiologist is necessary for perioperative management.
• Rheumatology or immunology: Specialists provide valuable input in cases where immune-mediated reactions are suspected of managing steroid therapy in patients with pre-existing autoimmune diseases.[13]

In this interdisciplinary setup, clear communication and a well-coordinated care plan are vital to ensure prompt and effective treatment to preserve visual function and prevent complications. Regular multidisciplinary team meetings can facilitate this process, enabling a seamless flow of information and an integrated care pathway for patients suffering from bacterial endophthalmitis.

Deterrence and Patient Education

The use of intracameral cefuroxime following cataract surgery reduced the incidence of postoperative endophthalmitis. Additional risk factors associated with endophthalmitis after cataract surgery included clear corneal incisions (CCI) and silicone intraocular lenses (IOL).[46] A study reviewing 45954 cataract procedures performed by the same surgeon discovered that the incidence of postoperative endophthalmitis could be reduced by 72% if the patient had pretreatment with periocular penicillin injections and topical chloramphenicol-sulphadimidine. The efficacy of this method was confirmed by a concurrent masked, randomized study of 6,618 cataract operations that demonstrates that the topical regimen alone was as ineffective as penicillin prophylaxis alone.[45] 

Prevention of postcataract endophthalmitis is complex to study, given the low incidence. In addition to the appropriate wound construction, a combination of antibiotics and povidone-iodine provides a reasonable approach to reducing the risk of this rare but severe infection.[99]

Deterrence and patient education are crucial components in preventing and managing bacterial endophthalmitis. Here are key points that can be addressed:

• Understanding endophthalmitis: Educating patients about the seriousness of bacterial endophthalmitis, its causes, symptoms, and the importance of early detection and treatment.
• Preventive measures: Stressing the importance of proper eye protection to prevent trauma, which is a significant risk factor for developing endophthalmitis. Discussing the role of meticulous perioperative antiseptic protocols for those undergoing ocular surgery and emphasizing the need for proper contact lens hygiene to reduce the risk of infection.
• Early symptoms recognition: Instruct patients on recognizing early signs of infection, such as redness, pain, vision changes, or discharge, and the necessity of immediate medical attention.
• Postoperative care compliance: Ensuring patients understand and adhere to postoperative care instructions following ocular surgery, including prescribing antibiotic eye drops.
• Managing chronic conditions: Patients with chronic ocular surface diseases or those who use topical corticosteroids should be informed about their increased risk and the need for regular ophthalmic evaluations.
• Systemic health: Educating patients about the potential for endogenous endophthalmitis arising from systemic infections and the importance of managing systemic health conditions such as diabetes.
• Follow-up and monitoring: Reinforcing the need for regular follow-up appointments to monitor for complications after ocular procedures or following the onset of symptoms suggestive of endophthalmitis.
• Patient empowerment: Encouraging patients to be proactive in their eye health, including seeking prompt attention for eye injuries or when suspecting an infection.

Educating patients on these aspects aims to reduce the incidence of bacterial endophthalmitis and improve outcomes for those who develop the condition. Patient education should be reinforced by all team members involved in the patient's care.

Pearls and Other Issues

Clinical Pearls

• Early diagnosis: Rapid recognition of symptoms and signs is crucial for prompt treatment to prevent vision loss.
• Microbiological testing: Immediate collection of ocular samples for culture and sensitivity is essential for targeted therapy.
• Antibiotic selection: Empirical broad-spectrum intravitreal antibiotics are the first line of treatment until culture results guide antibiotic therapy.
• Inflammation control: Using corticosteroids to manage intraocular inflammation should be balanced against the risk of exacerbating infection.
• Vitrectomy: Early vitrectomy can benefit cases with dense vitritis by improving drug penetration and removing the infectious load.[13]

Management Challenges

• Resistance patterns: Awareness of local antimicrobial resistance patterns is important for selecting effective empirical therapy.
• Systemic infection: Investigating and managing potential sources of endogenous infection is critical.
• Visual prognosis: Counseling patients regarding the potential outcomes and prognosis.
• Therapeutic window: Understanding the narrow therapeutic window for intervention to salvage vision.
• Follow-up: Frequent monitoring and follow-up are required to adjust treatment based on the clinical response and laboratory findings.[100]

Other Issues

• Prevention: Implementing strategies in surgical practice to minimize the risk of postoperative endophthalmitis.
• Patient education: Educate patients on the signs of endophthalmitis for early detection, especially after ocular procedures.
• Post-traumatic considerations: Special considerations for post-traumatic endophthalmitis, such as the presence of intraocular foreign bodies.
• Multidisciplinary approach: Collaboration with microbiologists, infectious disease specialists, and internists is necessary for complex cases.
• Research advances: Keeping abreast of advances in diagnostic and therapeutic techniques, including molecular diagnostics and newer antimicrobial agents.[101]

Enhancing Healthcare Team Outcomes

Bacterial endophthalmitis frequently poses a diagnostic dilemma. These patients may exhibit non-specific signs and symptoms such as blurry vision, eye pain, or leukocytosis. Bacterial endophthalmitis may be due to either endogenous or, more commonly, exogenous causes, such as trauma or surgery. While the ophthalmologist is almost always involved in caring for patients with bacterial endophthalmitis, consulting with an interprofessional team, including infectious disease, pharmacology, and the patient's primary care clinician, is essential.[41]

The pharmacist ensures that the patient receives the right antibiotics, cycloplegics, and steroid eye drops and performs medication reconciliation, reporting any issues to the interprofessional team. Nurses counsel on the appropriate dosing, administration of medications, patient questions, treatment progress, and report any problems to the clinician. Without a proper history, the ophthalmologist may be unsure what to look for or what additional diagnostic exams are needed. This problem gets more complicated when immunocompromised patients present with bacterial endophthalmitis. The outcomes of bacterial endophthalmitis depend on the cause. To improve outcomes, prompt consultation with an interprofessional group is recommended.