Bacterial endophthalmitis

INTRODUCTION — Endophthalmitis refers to bacterial or fungal infection of the vitreous and/or aqueous humors. In contrast, intraocular infections due to viruses or parasites (eg, cytomegalovirus [CMV] retinitis, toxoplasma chorioretinitis) are usually considered types of infectious uveitis rather than endophthalmitis.

The epidemiology, clinical features, diagnosis, and treatment of bacterial endophthalmitis will be reviewed here. Fungal endophthalmitis is discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis" and "Treatment of endogenous endophthalmitis and chorioretinitis due to Candida species" and "Treatment of exogenous endophthalmitis due to Candida species" and "Treatment of endophthalmitis due to molds".)

OVERVIEW — Most cases of endophthalmitis are exogenous, resulting from inoculation of organisms from an external or ocular surface source. Examples of exogenous endophthalmitis include cases following eye surgery, intravitreal injections, or penetrating eye trauma. The remaining cases are endogenous, resulting from bacteremic or fungemic seeding of the eye. In endogenous endophthalmitis, organisms usually seed the highly vascular choroid first then extend anteriorly into the vitreous.

Patients with bacterial endophthalmitis usually have an acute onset of symptoms, with vision loss and eye pain occurring over hours to several days. Acute bacterial endophthalmitis is a vision-threatening condition and must be managed as an emergency. The clinical outcome depends upon both the virulence of the infecting organism and the speed with which appropriate therapy is initiated.

Bacterial endophthalmitis can be divided into several categories:

●Acute post-operative (primarily post-cataract surgery) endophthalmitis

●Chronic pseudophakic endophthalmitis

●Post-intravitreal injection endophthalmitis (eg, after antivascular endothelial growth factor or corticosteroid injections)

●Bleb-related endophthalmitis

●Post-traumatic endophthalmitis

●Keratitis-related endophthalmitis

●Endogenous endophthalmitis

Endophthalmitis after cataract surgery, intravitreal injection, and eye trauma are the most common types of endophthalmitis [1]. While post-cataract surgery endophthalmitis was the most common type of endophthalmitis reported in most series prior to 2005, post-injection endophthalmitis cases now exceed post-cataract surgery endophthalmitis cases at many centers that perform both procedures [2].

ACUTE ENDOPHTHALMITIS AFTER CATARACT SURGERY

Pathogenesis — The eye is divided into anterior and posterior segments. Aqueous fills the anterior segment of the eye, whereas the vitreous fills the posterior segment (figure 1). The aqueous is continuously produced and reabsorbed (turnover time is approximately 100 minutes), while there is no turnover of the vitreous. The vitreous is much more susceptible than the aqueous to infection by exogenously introduced bacteria, partly because of this lack of regeneration [3].

Cataract surgery, which is performed through the anterior segment of the eye, often results in transient bacterial contamination of the aqueous by the patient's conjunctival flora, yet endophthalmitis rarely results. Three studies involving a total of 180 patients reported that bacteria were isolated from the anterior chamber at the end of cataract surgery in 8 to 43 percent of cases, yet none of the study patients developed endophthalmitis [4-6]. The organism burden in the aqueous is usually low, as demonstrated by quantitative cultures [4].

Risk factors — If a communication with the vitreous is inadvertently created during cataract surgery (eg, a break in the posterior lens capsule), the risk of endophthalmitis is increased several fold. The risk of post-operative endophthalmitis in cases with a vitreous communication was seven-fold higher in a series involving over 55,000 cataract surgeries in China [7] and 11-fold higher in a study of 1.5 million cataract surgeries in Korea [8]. Combination cataract and retina surgery, which involves surgery through both aqueous and vitreous, also increases the risk of post-operative infection (odds ratio [OR] 2.60; 95% CI 2.15-3.16) [9]. Other reported risk factors include advanced age, diabetes, renal failure, and wound dehiscence or leak [8-11]. Sutures are rarely placed during cataract surgery as the incisions are small and considered self-sealing, and whether sutures confer a lower or higher risk for post-operative endophthalmitis is controversial [8,12-15]. A nationwide study from Korea found that sutures were used in only 3 percent of cataract surgeries performed 2014 to 2017; sutured cases had a higher incidence of post-operative endophthalmitis but the authors cautioned that sutures might be more often used in high-risk cases (eg, those with larger incisions) [8].

Symptoms and signs — The onset of symptoms occurs within one week of surgery in 75 percent of cases. Patients usually give a 12 to 24 hour history of decreasing vision and eye "ache" (they may deny eye "pain"), but otherwise feel well and are afebrile.

On physical examination, findings are confined to the affected eye. The lids often appear normal, although they may be slightly swollen. The conjunctiva may be injected or edematous (conjunctival chemosis), although these findings can also represent residual post-operative changes. Visual acuity is decreased, and a hypopyon (layering of white blood cells in the anterior chamber) is often present (picture 1). The view of the retina is usually hazy, and, in 80 percent of patients, no retinal vessels can be seen [14]. Slit lamp examination reveals intraocular white blood cells and protein (called "cells" and "flare," respectively, by ophthalmologists).

Laboratory and imaging findings — Laboratory findings, including the erythrocyte sedimentation rate, are usually normal. However, one-third of patients with endophthalmitis have a white blood cell count greater than 10,000/microL [16].

An ultrasound of the eye ("B-scan") usually shows increased echogenicity of the vitreous due to intraocular inflammation. This test can be helpful when the view of the vitreous is obscured by abnormalities in the anterior segment.

Diagnosis — Endophthalmitis is a clinical diagnosis based on signs and symptoms that is confirmed by positive aqueous or vitreous culture. However, a negative culture does not exclude the diagnosis.

To obtain a culture, the ophthalmologist can aspirate the aqueous (0.1 mL sample) and/or vitreous (0.2 to 0.3 mL) with a needle in the office or perform a pars plana vitrectomy in the operating room. Some vitreous aspirates are "dry taps" because the vitreous is gel-like, unlike the aqueous which is liquid. A vitrectomy entails the use of a vitrector, an instrument inserted into the vitreous that simultaneously cuts (eg, 5000 cuts per minute) and aspirates some of the vitreous. A small undiluted vitreous sample (vitreous "biopsy") may be collected at the start of the case, then balanced salt solution is infused into the eye for the remainder of the case (to maintain eye turgor). This results in a very dilute vitreous sample termed vitreous "washings", and these are collected into a canister or collecting bag. By the end of the case, the vitrectomy canister or collecting bag contains 50 to 100 mL of dilute vitreous washings (figure 2).

Microbiology laboratories at eye specialty hospitals generally process these intraocular specimens as follows [17]:

●For vitreous and aqueous aspirates and undiluted vitreous biopsy samples, one drop is placed on a glass slide for Gram stain, another drop is placed on a slide for calcofluor stain (for fungi), and the rest of the sample is cultured aerobically and anaerobically on various media (eg, blood, chocolate, and Sabouraud agar, thioglycolate or meat broth).

●For dilute vitreous washings, a 5 mL sample is centrifuged and the resulting pellet is used for stains and cultures, while the remainder of the 50 to 100 mL of vitreous washings are vacuum filtered through a 0.45 micron filter, and the filter paper is cut up and place on the various media for culture.

Vitrectomy has the highest yield for a positive culture (90 percent of specimens), whereas only 75 percent of vitreous aspirate specimens are positive [16]. An aqueous aspirate has the lowest yield for a positive culture. In cases with positive vitreous cultures, simultaneous aqueous cultures are positive in only 40 percent [16]. Gram stains are positive in approximately 50 percent of cases.

Molecular diagnostic techniques, such as polymerase chain reaction (PCR), may have an increasing role in diagnosis of endophthalmitis, although these techniques are not yet widely available. These methods also can amplify bacteria that are conjunctival contaminants and lead to false-positive results. The value of PCR was evaluated in a study that used eubacterial primers to examine aqueous and vitreous samples from endophthalmitis cases and noninfectious controls [18]. PCR was positive in all 20 culture-positive cases, but also in one of the 20 controls. PCR can be complimentary to culture and combining the two techniques increased the diagnostic yield to 87 percent in one study [19,20].

Differential diagnosis — The major entity in the differential diagnosis of post-cataract surgery endophthalmitis is toxic anterior segment syndrome (TASS).

TASS is a type of sterile post-operative inflammation that primarily involves the anterior segment of the eye, and it is due to the eye’s reaction to a sterile "toxin" or contaminant introduced during surgery [21]. Symptoms of TASS occur very early (12 to 48 hours post-operatively), and clinical features typically include marked limbal to limbal corneal edema, marked increased intraocular pressure (although in initial hours, this may be low), no hypopyon, and no intravitreal inflammation [21]. These clinical features may help distinguish TASS from bacterial endophthalmitis. However, failure to treat a bacterial endophthalmitis can have devastating consequences so TASS is usually a diagnosis of exclusion.

Microbiology — Coagulase-negative staphylococci are the major pathogens in most series of post-cataract surgery endophthalmitis. This is because most of these cases are due to the patient's own conjunctival flora, and coagulase-negative staphylococci are the predominant organisms colonizing the conjunctiva [22-24]. In the Endophthalmitis Vitrectomy Study (EVS), a multicenter randomized trial of post-cataract endophthalmitis performed in the United States from 1990 to 1994, 69 percent of the 420 patients enrolled had positive cultures [25]. Organisms isolated included:

●Coagulase-negative staphylococci – 70 percent

●Staphylococcus aureus – 10 percent

●Streptococci – 9 percent

●Other gram-positive organisms – 5 percent

●Gram-negative organisms – 6 percent

Microbiology results were similar in a study among Medicare patients who developed endophthalmitis after cataract surgery between 2003 and 2004. Staphylococci accounted for approximately 65 percent of cases, and gram-negative bacilli only about 6 percent [26]. The relative frequency of various pathogens may vary by locale. For example, enterococci caused only 2 percent of endophthalmitis cases in the EVS but caused 28 percent of post-cataract cases in a study from Sweden [10]. This high percentage of enterococci may reflect the common use of intraocular cefuroxime prophylaxis during cataract surgery in that country. In India, several studies have noted a relatively high percentage of gram-negative bacilli and fungi in endophthalmitis after cataract surgery (36 and 8 percent, respectively, in one study) [27].

Treatment — Acute endophthalmitis is a medical emergency.

Overall approach — We recommend the following approach to therapy for patients with post-operative bacterial endophthalmitis:

●Cultures – Cultures of the vitreous should be obtained by needle aspiration or vitrectomy as soon as endophthalmitis is suspected. If the primary site of inflammation is the aqueous, aqueous cultures may also be helpful. (See 'Diagnosis' above.)

●Direct injection of antibiotics into the vitreous – The most important component of treatment is direct injection of antibiotics into the vitreous. Antibiotics should be injected into the vitreous as soon as endophthalmitis is suspected and vitreous cultures are obtained. Empiric intravitreal antibiotics include vancomycin 1 mg plus ceftazidime 2.25 mg. Amikacin 0.4 mg may be given in place of ceftazidime, but this is rarely used as initial empiric therapy due to toxicity concerns. (See 'Intravitreal antibiotics' below.)

●Vitrectomy in severe cases – Vitrectomy should be performed for eyes with severe vision loss on presentation (light perception vision or worse). Intravitreal antibiotics are injected at the end of the vitrectomy as above. Some experts also favor vitrectomy in patients with severe endophthalmitis (eg, marked and/or rapidly worsening intravitreal inflammation) even if initial vision is better than light perception. Vitrectomy should also be considered for eyes that are initially treated with intravitreal antibiotics alone (ie, "tap and inject") but that fail to improve after 24 to 48 hours. (See 'Vitrectomy' below.)

●Role of implant removal – The IOL implant does not need to be removed, except in cases of chronic endophthalmitis or those due to fungi. (See 'Chronic pseudophakic endophthalmitis' below and "Treatment of exogenous endophthalmitis due to Candida species" and "Treatment of endophthalmitis due to molds".)

●Role of adjunctive systemic antibiotics – The value of adding adjunctive systemic antibiotics in treating post-operative bacterial endophthalmitis is unknown. Some groups, such as the European Society of Cataract and Refractive Surgeons (ESCRS), have recommended adjunctive systemic antibiotics for severe cases of post-cataract surgery endophthalmitis for reasons discussed below [28] (see 'Adjunctive systemic antibiotics' below).

●Refractory cases – If the eye is not improving by 48 hours after the initial intravitreal antibiotic injection (ie, unchanged or worsening intraocular inflammation based on the ophthalmologist's examination), a second injection of intravitreal antibiotics or a surgical vitrectomy (if this has not already been performed) with a second injection of intravitreal antibiotics should be given at the end of the procedure.

In fulminant cases, these options may be considered at 24 rather than 48 hours. For this second injection of intravitreal antibiotics, either intravitreal vancomycin and/or ceftazidime should be given, based on culture results. A second injection of amikacin is usually avoided due to toxicity concerns but would be indicated, for example, for endophthalmitis due to ceftazidime-resistant gram-negative bacilli. A repeat culture of the vitreous should also be obtained.

Intravitreal antibiotics — The ophthalmologist first obtains a vitreous sample for culture and then injects antibiotics into the vitreous. Intravitreal antibiotics can be injected either as an office procedure (vitreous aspiration and antibiotic injection, also called "tap and inject") or in the operating room following vitrectomy.

The empiric intravitreal antibiotics used are vancomycin 1 mg plus ceftazidime 2.25 mg; rarely, amikacin 0.4 mg is given in place of ceftazidime. Each agent is diluted in 0.1 mL of sterile water or saline. Ceftazidime is preferred over amikacin because of the small risk of macular infarction with injected aminoglycosides. Antibiotic concentrations in the vitreous decline rapidly following injection, so most last only 24 to 48 hours. Thus, one injection of antibiotics may not maintain levels in the vitreous long enough to kill all bacteria. A repeat injection of vancomycin or ceftazidime may be indicated after 48 hours if there is persistent or worsening intraocular inflammation; a second injection of amikacin is avoided given concerns for retinal toxicity. The choice of antibiotic for repeat intravitreal injection is based on the culture result.

One case of hemorrhagic occlusive retinal vasculitis (HORV) following intravitreal injection of vancomycin plus ceftazidime for post-operative endophthalmitis has been described [29]. This case was reported along with 22 other patients (35 eyes) who developed HORV 1 to 21 days after prophylactic intracameral vancomycin for uncomplicated cataract surgeries [29]. The syndrome has been termed vancomycin-associated HORV, appears to be very rare, and is thought to represent a delayed immune reaction to the vancomycin. All cases, except for the one post-endophthalmitis case, have been associated with intracameral vancomycin as prophylaxis. (See "Retinal vasculitis associated with primary ocular disorders", section on 'Hemorrhagic occlusive retinal vasculitis'.)

Vitrectomy — For patients with severe endophthalmitis, vitrectomy is an important component of treatment and leads to better visual outcomes. This was demonstrated in the Endophthalmitis Vitrectomy Study (EVS), as detailed below, although the results were questioned because of design flaws. Vitrectomy debrides the inflamed vitreous, similar to incision and drainage of an abscess. There is general consensus that vitrectomy should be performed on presentation for eyes with light perception only vision, based on findings of the EVS, but some groups (such as the ESCRS) also favor vitrectomy for cases of severe endophthalmitis even if presenting visual acuity is better than light perception [28].

The EVS was a multicenter trial involving 420 patients with endophthalmitis following cataract surgery that evaluated the therapeutic role of vitrectomy and the value of adjunctive systemic antibiotics [16]. All patients received the same intravitreal antibiotics. For evaluating the role of vitrectomy, patients were randomized to a "tap" (vitreous aspirate or biopsy) group versus a "vitrectomy" group. Although "tap" is commonly understood to mean a needle aspirate of the vitreous (an office procedure), the "tap" group also included patients who received a vitreous "biopsy" using a vitrector (essentially a mini-vitrectomy) in the operating room. Two-thirds of the "tap" group received vitreous biopsies and only one-third needle aspirates [30,31]. The EVS authors concluded that there was no difference in visual outcome between the vitrectomy and "tap" groups, except in patients who presented with the worst vision (light perception only). In these patients, vitrectomy was superior to tap, with only 20 percent of vitrectomy group patients suffering severe visual loss versus 47 percent of "tap" group patients. In patients who presented with hand motion or better vision, the authors concluded that vitreous "tap" was sufficient. However, objections have been raised to this conclusion, since the comparison was really vitrectomy versus mini-vitrectomy in the majority of patients. The question remains whether patients who present with hand motion or better vision, especially those who present with a rapidly worsening course, might also benefit from vitrectomy (plus intravitreal antibiotics) rather than intravitreal antibiotics alone [32,33].

The EVS also demonstrated that vitrectomy plus intravitreal antibiotics sterilizes the vitreous more quickly than vitreous "tap" plus intravitreal antibiotics. Approximately 10 percent of each group had a second procedure and vitreous culture during the first week due to persistent inflammation. Of these patients, vitreous cultures were persistently positive more often in the "tap" group than the vitrectomy group (71 versus 13 percent), even though both groups had received the same intravitreal antibiotics [30].

A retrospective study also suggested that a single injection of intravitreal antibiotics may be insufficient to sterilize the vitreous in some cases, even when the organism is susceptible to the antibiotics given [34]. In this study, of 29 patients with endophthalmitis who had the same bacterial organism isolated on two consecutive vitreous cultures, 76 percent had undergone needle aspirate and antibiotic injection rather than vitrectomy as the initial procedure.

Adjunctive systemic antibiotics — Systemic antibiotics alone are not effective in treating bacterial endophthalmitis. Whether systemic antibiotics provide any benefit as adjunctive therapy to intravitreal antibiotics is unknown, although there are theoretical reasons why they may be beneficial. Systemic antibiotics that cross the blood-eye barrier may prolong intravitreal antibiotic concentrations achieved following intravitreal antibiotic injection [28]. This may be helpful in killing bacteria in the vitreous. The likelihood of systemic antibiotics achieving significant levels in the vitreous is increased in the setting of intraocular inflammation and in aphakic eyes (ie, eyes in which the native lens has been removed, as in post-cataract surgery) [35]. No trials have adequately evaluated clinical outcomes with appropriate systemic antibiotics. The EVS evaluated adjunctive systemic antibiotics (intravenous amikacin plus ceftazidime) versus no systemic antibiotics and concluded that systemic antibiotics did not add benefit [16]. However, this result has been questioned because the antibiotics chosen were poor choices for treating staphylococci, the cause of 80 percent of EVS cases [25]. In addition, one of the systemic antibiotics chosen (intravenous amikacin) does not cross the blood-eye barrier so it is ineffective in treating endophthalmitis. It has been suggested the EVS might have demonstrated a beneficial effect of systemic antibiotics if those antibiotics had included intravenous vancomycin [36].

Since the EVS, only retrospective reviews of adjunctive systemic antibiotics have been published. A study from western Australia that reviewed 213 cases of post-cataract surgery endophthalmitis from 1980 to 2000 found that patients who received various adjunctive oral antibiotics had better visual outcomes compared with those who did not receive adjunctive antibiotics [31]. However, it is difficult to draw any conclusions from this study given the lack of a uniform antibiotic regimen and the retrospective study design. Another study reviewed 72 cases of post-cataract surgery endophthalmitis between 2000 and 2009 treated with intravitreal injection of antibiotics (excluding patients treated with initial vitrectomy in addition to intravitreal antibiotics) [36]. All patients received an oral fluoroquinolone for 10 days after intravitreal injection of antibiotics; ciprofloxacin was used between 2000 and 2004 (in 48 patients) and moxifloxacin was used between 2005 and 2009 (in 24 patients). There were no significant differences in patient or surgical characteristics between the two groups. After controlling for potentially confounding factors such as ciprofloxacin resistance, moxifloxacin use was significantly associated with a good visual outcome (20/40 or better; adjusted OR 4.07, 95% CI 1.11-14.9). Because of problems with EVS study design mentioned above, there are differing opinions regarding the value of adjunctive systemic antibiotics.

Visual outcome — About half of eyes with post-cataract surgery endophthalmitis will eventually recover 20/40 vision, whereas 10 percent of eyes will be left with 5/200 (20/800) vision or worse [16]. The visual outcome of post-operative endophthalmitis depends on the virulence of the pathogen: the worst outcomes are seen in cases due to streptococci of any type and the best outcomes occur in cases due to coagulase-negative staphylococci or cases that are culture negative [16]. In the EVS, good visual outcomes (20/100 or better) occurred in 80 percent of cases due to coagulase-negative staphylococci or that were culture negative, but only 50 percent due to S. aureus, 56 percent due to gram-negative bacilli, and 30 percent due to streptococci of any type [37].

CHRONIC PSEUDOPHAKIC ENDOPHTHALMITIS

Etiology — Chronic pseudophakic endophthalmitis is a rare complication of cataract surgery. During cataract surgery, most of the opacified native lens (cataract) is removed, leaving behind some residual native lens and the posterior portion of the lens capsule. An artificial intraocular lens (IOL) is placed in front of this in the posterior chamber, the space between the lens and iris. "Pseudophakic" refers to the IOL. Chronic pseudophakic endophthalmitis is usually caused by Cutibacterium acnes. A few cases have been caused by coagulase-negative staphylococci and diphtheroids. This infection is characterized by low-grade intraocular inflammation that may persist for months. It is often misdiagnosed as noninfectious iritis and typically improves with topical corticosteroid therapy but flares each time corticosteroids are stopped. It may be months before the correct diagnosis is made.

Symptoms and signs — Symptoms include decreased vision in nearly all patients and eye pain (usually mild) in approximately half of patients. Eye examination with a slit lamp reveals white blood cells in the anterior chamber and, in nearly all patients, a characteristic white plaque in the posterior lens capsule. A hypopyon and white blood cells in the anterior vitreous (anterior vitritis) are also seen in some patients.

For years, this process was thought to be a reaction to the remaining native lens tissue and was called toxic lens syndrome or phacoanaphylactic endophthalmitis. That the inflammation typically decreased with topical corticosteroid therapy added support to this misdiagnosis. Vitreous culture was negative or grew only C. acnes, initially thought to be a contaminant. Subsequent Gram stain and electron microscopy studies of the removed lens capsule showed small gram-positive rods, consistent with C. acnes, adherent to the capsular remnants [38].

Diagnosis — Diagnosis is often difficult and is based on clinical suspicion supported by cultures of the aqueous or posterior lens capsule. However, cultures of the aqueous are often negative, even in cases where subsequent electron microscopy of the removed lens or lens capsule demonstrates organisms [39]. Anaerobic cultures should be included if possible. The highest yield for culture is usually by sampling the white plaque in the posterior lens capsule, but this can only be obtained by surgery (removal of the IOL and posterior lens capsule). Aspirate of the aqueous can be performed in an outpatient ophthalmology procedure room using a topical anesthetic.

Treatment — Treatment requires at least vitrectomy and intravitreal vancomycin, although 50 percent of cases recur with this treatment alone [40,41]. Removing part of the lens capsule (partial capsulectomy), in addition to vitrectomy and intravitreal vancomycin, reduced the recurrence rate in one study to 14 percent [41]. However, in another study, this treatment was associated with a 44 percent recurrence rate [42]. Exchanging the IOL for a new one improved outcomes considerably. The combination of total capsulectomy, IOL exchange or removal, vitrectomy, and intravitreal antibiotics cured all cases in both studies. This was true whether this treatment was used as initial therapy or as treatment of recurrence after other therapy had failed. Systemic antimicrobial therapy is not indicated.

POST-INTRAVITREAL INJECTION ENDOPHTHALMITIS

Etiology — Neovascular, or "wet" macular degeneration, accounts for about 10 percent of cases of macular degeneration. Regular (usually monthly) injections of anti-vascular endothelial growth factor (VEGF) medications into the vitreous are often used to treat wet macular degeneration. Each injection carries a risk of endophthalmitis similar to that of cataract surgery. A study using a Medicare database of 41,000 injections found the risk of post-injection endophthalmitis to be 0.09 percent per injection [43]. Since these injections are usually repeated monthly for many months, there is a substantial cumulative risk of post-injection endophthalmitis over time. In many centers, post-injection endophthalmitis is seen more often than post-operative endophthalmitis.

Corticosteroids may be injected intravitreally for a variety of reasons, and these injections may carry a higher rate of post-injection endophthalmitis than anti-VEGF injections. A study utilizing a de-identified medical claims database from a large private US insurer found an endophthalmitis rate of 0.02 percent after 387,714 anti-VEGF injections (ie, over fourfold lower than the rate in the Medicare database study above), but an endophthalmitis rate of 0.13 percent after 18,666 corticosteroid injections, suggesting that steroid injections carry a higher risk of post-injection endophthalmitis [44]. However, a significant limitation of the study was that culture results were not available, so a comparison of culture-positive endophthalmitis rates was not possible. Cases of post-injection sterile intraocular inflammation mimicking culture-negative endophthalmitis were therefore counted in the study, and this would affect interpretation of the results. Sterile inflammation appears to occur more often after corticosteroid than anti-VEGF injections. Two other studies of intravitreal corticosteroids reported that sterile inflammation occurred after 1.1 to 2.7 percent of triamcinolone injections [45,46], rates much higher than those usually reported after anti-VEGF injections [47].

Microbiology — The bacteriology of post-injection endophthalmitis is similar to that of post-cataract surgery endophthalmitis, except that the proportion of cases due to viridans streptococci is much higher (30 percent versus 9 percent) [48]. (See 'Microbiology' above.)

Treatment — The optimal treatment of post-injection endophthalmitis is unknown but presumed to be similar to that for post-cataract surgery endophthalmitis (see above). Therefore, we recommend initial empiric treatment with intravitreal vancomycin plus ceftazidime, with repeat injections as needed as discussed above. For severe cases, we also recommend vitrectomy. The role of adjunctive systemic antibiotics is unknown.

Prevention — Viridans streptococci are part of the normal oral flora, and transmission of oral flora may occur during talking. Intravitreal injections occur in an office setting rather than the operating room, and masks have not been worn in most older series. Wearing a mask or observing complete silence in the room during the procedure reduces the risk of contamination by oral flora and reduces the incidence of post-injection endophthalmitis as well as cases due to streptococci [49,50]. It is important to try to reduce cases of streptococcal endophthalmitis as these have very poor visual outcomes. One study that evaluated outcomes by organism for all categories of endophthalmitis found that 75 percent of streptococcal endophthalmitis cases were left with 20/400 vision or worse [51]. There was no difference between the type of streptococci (viridans, beta-hemolytic, S. pneumoniae) and visual outcomes.

BLEB-RELATED ENDOPHTHALMITIS

Etiology — A filtering bleb is used to treat severe glaucoma that has failed medical management. It is a surgically created defect in the sclera, covered only by conjunctiva, which allows excess aqueous humor to leak out of the anterior chamber and be absorbed into the systemic circulation. It is usually placed in the superior portion of the eye and, when the upper lid is raised, it may be seen as a small bump in the sclera. A bleb can also rarely occur as a complication of other types of eye surgery.

A bleb may become infected (blebitis) (picture 2), and bacteria may enter the eye, resulting in endophthalmitis. The onset of endophthalmitis is usually abrupt and typically occurs months to years following surgery. In a retrospective study of late-onset bleb-related endophthalmitis, infection developed suddenly an average of two years post-operatively (range one month to eight years) [52].

The incidence of endophthalmitis after bleb surgery in various studies depends on the duration of follow-up and ranges from 0.06 to 13.2 percent [53-55]. One study used a Kaplan-Meier method to calculate incidence following bleb surgery, based on retrospective data on 239 eyes in 198 patients. The probability of developing endophthalmitis was 1.3 percent per patient-year, with a five-year probability of 7.5 percent [56].

Symptoms and signs — Patients with bleb-related endophthalmitis present with sudden onset of eye pain and decreased vision. The eye is often red with purulence over the bleb, although bleb-related endophthalmitis may occur without any signs of blebitis.

Diagnosis — The clinical diagnosis of endophthalmitis is confirmed by vitreous cultures, although vitreous cultures were negative in 45 percent of cases in one study [57]. Cultures of the infected bleb should also be obtained. Most studies of late-onset endophthalmitis report that 50 percent of culture-positive cases are due to streptococci (viridans streptococci or S. pneumoniae). Haemophilus influenzae and Moraxella catarrhalis are other major pathogens [57,58]. In contrast, one study found that streptococci caused only about 20 percent of cases, whereas S. aureus and Staphylococcus epidermidis caused approximately 30 percent each [52]. Cases of late-onset endophthalmitis due to Enterococcus faecalis or gram-negative bacilli other than H. influenzae or M. catarrhalis (eg, Serratia) have been reported [57], although these cases are unusual. Early onset bleb-related endophthalmitis, developing within four to six weeks of surgery, is uncommon, and all four culture-positive cases were caused by S. epidermidis in one study [57].

Treatment — No prospective study has determined optimal therapy. Although the Endophthalmitis Vitrectomy Study (EVS) is often cited for treatment approaches to all types of endophthalmitis, this study was of post-cataract surgery endophthalmitis only. In addition, there were design flaws in the study and results should be interpreted with caution even for post-cataract surgery endophthalmitis (see 'Treatment' above). The Japan Glaucoma Society has utilized a protocol that includes immediate vitrectomy plus intravitreal antibiotics (vancomycin plus ceftazidime), along with adjunctive systemic antibiotics, for cases of bleb-related endophthalmitis presenting with severe endophthalmitis [59]. We recommend intravitreal vancomycin plus ceftazidime (standard doses as in post-cataract surgery endophthalmitis), plus vitrectomy in severe cases. The role of systemic adjunctive antibiotics is unknown. Repeat intravitreal injections of antibiotics may be necessary depending on the response of the intraocular inflammation to initial therapy, and on culture results.

Outcome — The outcome of bleb-related endophthalmitis is typically poor, with only 13 percent of 32 patients in one study achieving 20/40 or better visual acuity [58]. Almost one-half of patients in this study were left with minimal vision (5/200 or worse), including 10 patients (31 percent) who lost all vision in the infected eye.

POST-TRAUMATIC ENDOPHTHALMITIS

Etiology — Endophthalmitis occurs after penetrating trauma to the globe of the eye in 3 to 10 percent of cases in most series [60,61]. A lower rate has been reported in a large series that used antibiotic prophylaxis after an open globe injury as discussed below [62]. Endophthalmitis is much more likely to occur after lacerating injury with a metal object than after injury from glass or blunt trauma. The risk of endophthalmitis is also increased by the presence of retained intraocular foreign bodies, delay in repair of more than 24 hours [63], and disruption of the lens [63-65].

Microbiology — Bacillus cereus is one of the major pathogens in most studies and causes a fulminant endophthalmitis [66]. B. cereus endophthalmitis is characterized by abrupt onset of symptoms 12 to 24 hours after eye injury and a ring corneal infiltrate. Most eyes lose all vision even with prompt treatment. Other causes of post-traumatic endophthalmitis include coagulase-negative staphylococci, streptococci, and gram-negative bacilli such as Klebsiella and Pseudomonas and molds [67,68].

Molds may cause post-traumatic endophthalmitis, although this is rare in temperate climates. The presentation of mold endophthalmitis is usually subacute. (See "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis", section on 'Clinical manifestations'.)

Treatment — Because of the fulminant nature of post-traumatic endophthalmitis, we advocate the same aggressive treatment as described above for bleb-related endophthalmitis.

Prevention — To prevent endophthalmitis after open globe (penetrating) eye trauma, we recommend two days of systemic prophylactic antibiotics (eg, intravenous vancomycin plus either intravenous ceftazidime or oral ciprofloxacin) after the penetrating eye injury. A review of 558 cases of open globe injuries revealed a very low rate (0.9 percent) of endophthalmitis following a protocol that included two days of prophylactic systemic antibiotics [62].

KERATITIS-RELATED ENDOPHTHALMITIS

Etiology — Corneal infections (infectious keratitis) may progress through the full thickness of the cornea to reach the aqueous, thereby causing endophthalmitis. The most common causes of these types of infections in most series are molds and Pseudomonas. Keratitis-related endophthalmitis is rare in temperate regions but more common in tropical regions, where it may account for up to 20 percent of all endophthalmitis cases [69].

Microbiology — In a series from Florida, only 0.5 percent of nearly 10,000 keratitis cases progressed to endophthalmitis, and the majority of these were due to molds, particularly Fusarium [70]. Keratitis-related endophthalmitis due to molds is discussed further (see "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis" and "Treatment of endophthalmitis due to molds"). In a series of 87 cases of keratitis-related endophthalmitis from Thailand, a pathogen was identified in 40 percent, most commonly Pseudomonas (15 percent of all cases), streptococci (5 percent), Aspergillus (6 percent), and Fusarium (5 percent) [69]. In a series from New Jersey of 38 keratitis-related endophthalmitis cases, two-thirds were culture-positive, including coagulase-negative staphylococci (21 percent), Staphylococcus aureus (5 percent), streptococci (5 percent), Pseudomonas (11 percent), and Fusarium (11 percent) [71]. In a series from Germany, keratitis-related endophthalmitis occurred in 11 patients (0.3 percent of all keratitis cases); eight had positive cultures (three each of S. aureus, coagulase-negative staphylococci, and Gram-negative bacilli not otherwise specified, one due to S. aureus) [72]. A study of 48 cases of keratitis-related endophthalmitis at four centers in Mexico and the United States reported 73 percent culture-positive, including fungi (26 percent), mixed Gram-positive and Gram-negative bacteria (31 percent), and Gram-negative bacteria (14 percent) [73].

Contaminated solutions used as contact lens solutions or eye drops have been rarely implicated as a cause of keratitis, and such cases may progress to keratitis-related endophthalmitis. The worldwide outbreak of Fusarium keratitis related to a particular brand of contact lens solutions from 2004 to 2006 resulted in some cases of keratitis-related endophthalmitis (see "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis" and "Clinical manifestations and diagnosis of Fusarium infection"). In February 2023, the Centers for Disease Control and Prevention (CDC) reported identification of 55 patients with various types of infections due to extensively drug-resistant Pseudomonas aeruginosa occurring between May 2022 and January 2023 that were associated with use of a particular type of artificial tears [74]. While details are not provided, these infections included keratitis, endophthalmitis, respiratory infection, urinary tract infection, and sepsis. Specimen types included bronchial wash, cornea, urine, blood, nonsterile sites, and rectal swabs but not intraocular samples. Details of the endophthalmitis cases have not been provided, so it is unclear if these were keratitis related.

To identify the pathogen in cases of keratitis-related endophthalmitis, cultures should be sent of corneal scrapings or of the explanted native cornea (at the time of corneal transplantation). Intraocular samples (aqueous, vitreous), if obtained, should also be cultured.

Treatment — The treatment of bacterial keratitis-related endophthalmitis includes treatment of the severe bacterial keratitis and also of the endophthalmitis. Antibiotics should be targeted to the pathogen and given topically and as intraocular injections (eg, vancomycin, ceftazidime); systemic antibiotics are sometimes added in severe cases, particularly those due to Pseudomonas and in cases with extension to the sclera. Surgery may be required, ie, corneal transplantation and/or vitrectomy, based on the ophthalmologist's assessment.

ENDOGENOUS BACTERIAL ENDOPHTHALMITIS

Etiology — Endogenous bacterial endophthalmitis results from bacterial seeding of the eye during bacteremia. Endogenous bacterial endophthalmitis is rare in the United States. One study reviewed data on 3.9 million cases of bacteremia in the United States National Inpatient Sample between 2002 and 2013 and found that 1 in 2000 cases (0.05 percent) of bacteremia were complicated by endophthalmitis [75]. The incidence was highest (1 in 500) in patients with bacteremia due to methicillin-resistant S. aureus. Another study of two large databases of hospitalized patients with hematogenous infections in the United States, from 2007 to 2011, found a rate of 0.04 percent for endogenous bacterial endophthalmitis [76].

Sources of bacteremia include endocarditis, urinary tract infections, abdominal abscesses (including liver), meningitis, indwelling catheters, procedures such as endoscopy that cause transient bacteremia, and illicit injection drug use. In the United States, endocarditis is a major cause of endogenous endophthalmitis, causing 40 percent of cases in one series and representing the most common cause in another [77,78]. However, in Taiwan, Singapore, Korea, and other East Asian nations, Klebsiella pneumoniae is the major cause of endophthalmitis associated with liver abscess, accounting for up to 60 percent of cases [79,80] (see "Clinical features, diagnosis, and treatment of Klebsiella pneumoniae infection", section on 'Endophthalmitis'). Injection drug use is a major cause of endogenous endophthalmitis in the United States, but the majority of such cases are caused by fungi (especially Candida species) rather than bacteria [81,82].

Microbiology — The microbiology of endogenous endophthalmitis varies with the patient population. In North America and Europe, streptococci (S. pneumoniae, S. milleri group, group A, group B) cause 30 to 50 percent of cases, S. aureus causes 25 percent, and gram-negative bacilli cause 30 percent [77,83]. In Asia, gram-negative bacilli, especially K. pneumoniae, cause the majority of cases [79,80,84,85].

Symptoms and signs — Patients with endogenous bacterial endophthalmitis may present with symptoms of their bacteremia or may only complain of eye pain and decreased vision. Half of patients in one series reported no systemic symptoms and over half saw an ophthalmologist first [77]. In another series, fewer than 20 percent of patients had fever on presentation, and 40 percent had an unremarkable general physical examination [83]. Patients who do not have systemic symptoms may initially be misdiagnosed as having noninfectious uveitis. Endophthalmitis should be considered in any patient complaining of decreased vision or eye pain in the setting of possible bacteremia or injection drug use.

Diagnosis — The diagnosis of endogenous endophthalmitis is established by clinical findings consistent with endophthalmitis (eg, vitritis, hypopyon) in the setting of positive blood cultures or by positive vitreous or aqueous cultures in patients presenting with endophthalmitis but who do not have a history of recent eye trauma or surgery. Blood cultures are positive in 75 percent of those tested, as are vitreous cultures [77].

Treatment — The treatment of endogenous endophthalmitis includes intravitreal and systemic antibiotics. The systemic antibiotics should be chosen to optimize treatment for the systemic infection, but if possible, should also include antibiotics that cross the blood-eye barrier. The duration of systemic antibiotics should be determined by the need to treat the underlying source of bacteremia (eg, six weeks in many cases of endocarditis). Systemic antibiotics alone will not effectively treat endophthalmitis, however, and all patients with endogenous endophthalmitis require intravitreal antibiotic injection.

Vitrectomy plus intravitreal antibiotic injection is indicated in most cases, rather than intravitreal antibiotic injection alone, because of the virulent nature of the pathogens involved. Vitrectomy debrides the vitreous and leads to better visual outcome in severe cases of endophthalmitis. Patients with bacteremia are often critically ill, however, and the patient’s ability to undergo a surgical procedure in the operating room (vitrectomy) must be taken into consideration when deciding between intravitreal antibiotics alone or vitrectomy plus intravitreal antibiotics.

If the eye worsens over the next 24 to 48 hours, a second intravitreal antibiotic injection should be given. A third injection may also be given if there is still no improvement after a similar time interval or if cultures from the second vitreous sample were positive. The basis for this approach is discussed above (see 'Intravitreal antibiotics' above and 'Overall approach' above).

FUNGAL ENDOPHTHALMITIS — Fungal endophthalmitis due to yeasts (eg, Candida albicans) is very different from that due to molds (eg, Aspergillus or Fusarium). While Candida endophthalmitis is usually treated successfully, mold endophthalmitis often results in the loss of vision. With the opioid epidemic in the United States, endogenous fungal endophthalmitis has become increasingly common [80]. Fungal endophthalmitis is discussed separately. (See "Epidemiology, clinical manifestations, and diagnosis of fungal endophthalmitis" and "Treatment of endogenous endophthalmitis and chorioretinitis due to Candida species" and "Treatment of exogenous endophthalmitis due to Candida species" and "Treatment of endophthalmitis due to molds".)

SUMMARY AND RECOMMENDATIONS

●Mechanism of infection – Endophthalmitis refers to bacterial or fungal infection within the eye, including involvement of the vitreous and/or aqueous humors. Most cases of endophthalmitis are exogenous, resulting from inoculation of organisms from the outside, via trauma, eye surgery, or as an extension of keratitis (corneal infection). In such cases, the aqueous humor may be seeded first before extension into the vitreous. (See 'Introduction' above.)

●Importance of prompt recognition and treatment – Most cases of endophthalmitis are due to bacteria and present acutely. Acute bacterial endophthalmitis is a vision-threatening condition and must be managed as an emergency. The clinical outcome depends both upon the virulence of the infecting organism and the speed with which appropriate therapy is initiated. (See 'Introduction' above.)

●Source of infection – Bacterial endophthalmitis can be divided into several categories:

•Acute post-cataract surgery

•Chronic pseudophakic

•Post-injection (eg, after intravitreal injection of anti-vascular endothelial growth factor medications)

•Bleb-related

•Post-traumatic

•Endogenous (see 'Introduction' above)

●Acute post-cataract surgery endophthalmitis

•Microbiology – Acute post-cataract surgery endophthalmitis is a common form of endophthalmitis and is almost always due to bacteria. Approximately 95 percent of cases are caused by gram-positive bacteria, particularly coagulase-negative staphylococci (70 percent). (See 'Microbiology' above.)

•Clinical features and diagnosis – Patients usually present within one week of surgery with decreasing vision and eye "ache." Cultures of the vitreous (and aqueous, if involved) should be obtained by needle aspiration or vitrectomy as soon as endophthalmitis is suspected. Endophthalmitis is a clinical diagnosis that is confirmed by positive aqueous or vitreous culture. (See 'Symptoms and signs' above and 'Diagnosis' above.)

•Antibiotic therapy – The most important component of treatment is direct injection of antibiotics into the vitreous. For empiric treatment, we suggest intravitreal vancomycin plus ceftazidime (Grade 2C). (See 'Intravitreal antibiotics' above.)

•Role of surgery – For severe cases, immediate vitrectomy (followed by intravitreal injection of antibiotics) improves the chances of preserving useful vision more than injection of intravitreal antibiotics alone. (See 'Vitrectomy' above.)

The value of adjunctive systemic antibiotics for post-cataract surgery endophthalmitis is unknown.

●Chronic pseudophakic endophthalmitis

•Chronic pseudophakic-related endophthalmitis is a rare complication of cataract surgery; "pseudophakic" refers to the intraocular lens (IOL). Chronic pseudophakic endophthalmitis is usually caused by Cutibacterium acnes. Treatment requires at least vitrectomy and intravitreal vancomycin, although 50 percent of cases recur with this treatment alone. Removal of the residual lens capsule and exchange or removal of the IOL may also be necessary for cure. Systemic antibiotics are not indicated. (See 'Chronic pseudophakic endophthalmitis' above.)

●Post-intravitreal injection endophthalmitis

•Endophthalmitis may occur after an intravitreal injection of medications to treat "wet" age-related macular degeneration. The bacteriology is similar to post-cataract surgery endophthalmitis except that the incidence of viridans streptococci is higher. Having all parties wear masks or refrain from talking during the procedure can reduce the rate of post-injection endophthalmitis, in particular streptococcal infection, which is associated with worse visual outcomes. Our treatment approach is the same as for post-cataract surgery endophthalmitis. (See 'Post-intravitreal injection endophthalmitis' above.)

●Bleb-related endophthalmitis

•A filtering bleb is a surgically created defect in the sclera that is used to treat severe glaucoma that has failed medical management. Bleb-related endophthalmitis can be caused by a range of gram-positive and gram-negative bacteria, but streptococci, Haemophilus influenzae, and Moraxella catarrhalis are major pathogens. Our treatment approach is the same as for post-cataract surgery endophthalmitis. (See 'Bleb-related endophthalmitis' above.)

●Post-traumatic endophthalmitis

•Post-traumatic endophthalmitis occurs after penetrating trauma to the globe of the eye in 3 to 10 percent of cases in most series, but a very low rate (0.9 percent) has been reported in a large series in which antibiotic prophylaxis was given after penetrating eye trauma. Bacillus cereus is one of the major pathogens in most studies and causes a fulminant endophthalmitis. Treatment includes immediate vitrectomy and intravitreal vancomycin plus either ceftazidime or amikacin. The value of adjunctive systemic antibiotics is unknown. To prevent endophthalmitis, we suggest initial systemic prophylactic antibiotics after penetrating eye trauma (Grade 2C). We typically use intravenous vancomycin plus either intravenous ceftazidime or oral ciprofloxacin for 48 hours. (See 'Post-traumatic endophthalmitis' above.)

●Keratitis-related endophthalmitis

•Keratitis-related endophthalmitis results from extension of infection into the aqueous. It is a rare complication of bacterial keratitis, occurring in less than 1 percent of cases, and is a more common complication of keratitis due to molds. While Fusarium and Aspergillus are important causes of fungal keratitis-related endophthalmitis, Pseudomonas is the most common cause of bacterial keratitis-associated endophthalmitis.

•Treatment includes topical and intraocular antibiotics targeted to the pathogen isolated; systemic antibiotics are added in some cases (eg, some cases of Pseudomonas or extension to the sclera). Corneal transplantation and vitrectomy are surgical procedures that may be necessary in some cases.

●Endogenous endophthalmitis

•Endogenous bacterial endophthalmitis is rare in the United States and results from bacterial seeding of the eye during bacteremia. In North America and Europe, streptococci and staphylococci are the major pathogens, while in many East Asian nations, Klebsiella pneumoniae is the primary pathogen. (See 'Endogenous bacterial endophthalmitis' above.)

•The treatment of endogenous endophthalmitis includes intravitreal and systemic antibiotics; systemic antibiotics alone will not effectively treat endophthalmitis. Vitrectomy plus intravitreal antibiotic injection is indicated in most cases, rather than intravitreal antibiotic injection alone, because of the virulent nature of the pathogens involved. (See 'Endogenous bacterial endophthalmitis' above.)