TABLE 1. Classification of Endophthalmitis (Most Frequent Organisms In Various Clinical Settings)

1. Postoperative.
   1. Acute-onset postoperative endophthalmitis: Coagulase-negative staphylococci, Staphylococcus aureus, streptococcus species, gram-negative bacteria.
   2. Delayed-onset (chronic) pseudophakic endophthalmitis (>6 weeks postoperative): Propionibacterium acnes, coagulase-negative staphylococci, fungi.
   3. Conjunctival filtering bleb-associated endophthalmitis: Streptococcus species, Hemophilus influenza, Staphylococcus species
2. Posttraumatic (open globe): Bacillus species, staphylococci.
3. Endogenous: Candida species, S. aureus, gram-negative bacteria.
4. Miscellaneous.
   1. Keratitis: Staphylococcus and pseudomonas species
   2. Intravitreal injection (intravitreal triamcinolone, intravitreal ganciclovir, pneumatic retinopexy, etc): Coagulase negative staphylococci
   3. Suture removal: both bacteria and fungi

In reported large clinical series,^17–20 endophthalmitis after penetrating ocular trauma represents approximately 25% of all cases. In one large study of penetrating ocular trauma, endophthalmitis occurred in 10.7% of cases with a retained intraocular foreign body and 5.2% of cases without a retained intraocular foreign body.²⁰ The National Eye Trauma System Registry reported an endophthalmitis incidence of 6.9% (34 of 492 cases) after penetrating ocular injuries with retained intraocular foreign bodies.²¹ Metallic intraocular foreign bodies were as likely to be associated with infectious endophthalmitis (7.2%) as nonmetallic (7.3%) and organic matter (6.3%) foreign bodies.²¹ Rupture of the crystalline lens capsule is also a reported risk for endophthalmitis in open globe injuries.²²

Compared to the postoperative and posttrauma categories, endogenous endophthalmitis occurs with less frequency and, when it occurs, usually presents in debilitated or immunocompromised patients or in patients with a history of intravenous drug abuse.^23–27 In one large series, culture-proven fungal cases were more frequent than bacterial cases.²⁷

In the miscellaneous category, endophthalmitis after intravitreal injections can be subdivided into infectious and noninfectious categories. In a series of over 828 intravitreal triamcinolone acetonide injections, there were no cases of infectious etiology, but pseudohypopyon from migration of triamcinolone crystals into the anterior chamber occurred in 7 patients in this report.²⁸ Pooled data from 14,866 intravitreal injections in 4382 eyes revealed 38 cases of endophthalmitis.²⁹ Excluding cases reported specifically as pseudoendophthalmitis (e.g., pseudohypopyon), the prevalence of endophthalmitis was 0.2% per injection.²⁹ Noninfectious endophthalmitis cases after intravitreal triamcinolone are noted in several reports (Table 2). ^30–34

TABLE 2. Noninfectious Endophthalmitis After Intravitreal Triamcinolone Acetonide Injection for Macular Disease

The clinical diagnosis of endophthalmitis is confirmed by obtaining intraocular (aqueous and vitreous) specimens. A vitreous specimen is much more likely to yield a positive culture result than a simultaneously acquired aqueous specimen.³⁶ The vitreous specimen can be obtained either by needle biopsy or by using an automated vitrectomy instrument. A needle biopsy, or limited vitrectomy approach, can be performed in a treatment room, but a three-port pars plana vitrectomy is usually performed in the operating room. One report of 138 culture-proven endophthalmitis cases showed a positive culture result in 34.8% of anterior chamber specimens, 58.2% of vitreous specimens, and 80% of vitrectomy fluid specimens.³⁶

The technique for culturing intraocular specimens depends on the volume of the specimen and the suspected clinical diagnosis.^36,37 Direct inoculation of the intraocular fluid specimen onto culture media is a traditional approach and remains a very practical technique. The specific media used for direct inoculation are listed in Table 3. This approach is especially important when limited specimens (such as a needle vitreous or aqueous aspiration) are obtained. These specimens can be inoculated directly onto the appropriate media, including anaerobic media in cases of suspected Propionibacteriurn acnes endophthalmitis. Specimens obtained with automated vitrectomy instruments are diluted by the infusion fluid but can be processed by two methods. One method for processing the vitrectomy specimen uses a membrane filter system in which the vitrectomy specimen is passed through 0.45mm filter paper that concentrates the microorganisms and particulate matter. This filter paper is then sectioned and distributed on the appropriate media.

TABLE 3. Culture Media Used for Endophthalmitis Specimens

1. Chocolate agar: An enriched medium for the recovery of fastidious organisms (i.e., Neisseria gonorrhoeae and Hemophilus influenzae) from clinical specimens. The chocolate agar should be used as a general-purpose medium and as the medium of choice for the recovery of common endophthalmitis isolates when only a few drops of intraocular fluids are available for culture. It must be placed in a CO₂ jar or bag.
2. 5% Sheep blood agar: A general-purpose medium for the recovery of the most common bacterial and fungal endophthamitis isolates. It should be placed in the CO₂ jar or bag.
3. Thioglycollate broth: An enriched medium for the recovery of small numbers of aerobic or anaerobic (including Propionibacterium acnes) organisms from ocular fluids and tissues. The broth dilutes out the effects of antibiotics and other inhibitory susbstances. The broth should be kept a minimum of five days.
4. Anaerobic blood agar: A general-purpose medium for the recovery of anaerobic and facultative anaerobic organisms. This medium should be included for all chronic cases of endophthalmitis and/or where P. acnes is suspected. The viridans and B-hemolytic streptococci may grow better and faster on this plate. This medium is placed in an anaerobic jar or bag.
5. Sabouraud agar: A selective medium used to promote the growth of fungi (yeasts and molds) from clinical specimens.
6. Blood culture bottles: Contain specially prepared medium for the recovery of both aerobic and anaerobic bacteria and fungi. Intraocular fluids may be inoculated directly into blood culture bottles. Undiluted fluids should be inoculated into pediatric bottles and diluted fluids (6–12 mL of vitrectomy specimen) injected into a set of routine (adult) bottles. Identification is made after growth is established.

An alternative method involves direct inoculation of the initially aspirated vitrectomy specimen into standard blood culture bottles (Fig. 2).³⁷ This latter technique is particularly useful at night or on the weekend when the microbiology laboratory staff are not available to assist in the processing of the vitrectomy specimen. In a retrospective review of 83 cases, this blood culture bottle method for processing vitrectomy specimens yielded a 91% incidence of positive culture results.³⁷ This rate of positive culture results from clinically diagnosed endophthalmitis cases was similar to simultaneously processed specimens using the membrane filter system.

Immunologic as well as molecular genetic technologies enable rapid and specific identification of infectious agents. These real-time techniques have been used in both clinical and experimental settings, and their future use in this area appears promising.^38–40 Molecular genetic technology has made available specific DNA probes that will interact with the unique DNA sequence for a particular pathogen.⁴⁰ Clinical application of PCR techniques continues to evolve for the more rapid diagnosis of infectious endophthalmitis.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of marked intraocular cellular inflammation after ocular surgery includes sterile inflammation (related to retained lens fragments or vitreous hemorrhage), iris trauma, pre-existing uveitis, and foreign material introduced during surgery.^1,2 Retained cortical lens remnants are reported to cause more inflammation than nuclear remnants.⁴¹ These retained lens fragments may occasionally cause a marked inflammatory reaction with hypopyon, which may clinically resemble infectious endophthalmitis.^42,43 Blood in the anterior chamber or vitreous cavity may also be confused with endophthalmitis, especially when the blood is long-standing and associated with anterior segment trauma during preceding surgery. Similarly, difficult or prolonged surgery, which often includes vitreous loss or vitreous incarceration in the cataract incision, may increase postoperative inflammation.

Toxic Anterior Segment Syndrome (TASS) is an inflammatory reaction to noninfectious agents that enter the eye during intraocular ophthalmic procedures.^44–47 The typical clinical picture is the presence of diffuse corneal edema (“limbus to limbus”) and marked anterior chamber inflammation detected on the first postoperative day. Symptoms on the first postoperative day include variable pain and impaired vision. Additional hallmarks of the disease include fixed or almost fixed dilated pupil, severe elevation of intraocular pressure, and iris thinning or atrophy. The exact cause of TASS is controversial, but the most frequently implicated cause is the use of improperly cleaned or processed instruments, which allows denatured residual viscoelastic or enzyme detergents to enter the patient's eye during cataract surgery. Treatment consists of topical anti-inflammatory medications and careful follow-up to rule out the possibility of endophthalmitis. Similar to postoperative endophthalmitis, TASS is a rare problem that can have poor visual acuity outcomes because of persistent corneal edema and chronic intraocular inflammation. It is often difficult to distinguish TASS from endophthalmitis during the early postoperative course. In the Endophthalmitis Vitrectomy Study (EVS), endophthalmitis cases were diagnosed one day after cataract surgery in 5% of patients, within 2 days in 12% of patients, within 3 days in 24% of patients, and within 1 week in 61% of patients.^48–58 Further, in the EVS, more virulent organisms (e.g., gram-negative bacteria, Streptococcus species, and Staphylococcus aureus) were more likely to be diagnosed within 2 days of cataract surgery. These cases may also present with marked corneal edema as well as severe intraocular inflammation with varying levels of hypopyon. In the EVS, 31% of patients had a negative intraocular culture. It is possible that some of these cases may have had TASS but were clinically diagnosed as having endophthalmitis. In the EVS, 86% of patients presented with a hypopyon, but TASS may or may not present with a hypopyon early in the course of the disease.

In eyes with mild-to-moderate postoperative inflammation without hypopyon, intensive therapy with topical corticosteroids may be used initially. The careful sequential observation of such eyes will allow appropriate diagnostic and treatment approaches to be employed. Acute-onset postoperative endophthalmitis caused by more virulent organisms, such as Streptococcus species or gram-negative bacteria, will usually present with rapidly progressive clinical signs aiding in the early diagnosis of infectious endophthalmitis. Endophthalmitis caused by the coagulase-negative staphylococci may have fewer inflammatory signs and may have a delayed presentation, often creating difficulty in distinguishing between an infectious and a noninfectious etiology.

TABLE 4. Antibiotics Considered for Local Treatment of Endophthalmitis: Concentration and Dosages of Principal Agents

TABLE 5. Visual Acuity Outcomes Following Treatment of Endophthalmitis Caused by Various Gram-Positive Organisms*

TABLE 6. Visual Acuity Outcomes Following Treatment of Endophthalmitis Caused by Various Gram-Negative Organisms*

Repetitive injections of intravitreal antibiotics cause significant retinal toxicity in a rabbit model; eyes treated with a second or third vancomycin/aminoglycoside injection at 48-hour intervals showed progressive toxicity.⁷² In view of the low rate of persistent infection after initial combination therapy, repeat injection of intravitreal antibiotics are considered only in those cases with progressive inflammation caused by virulent organisms.⁷³ Based on the initial culture report, a single intravitreal antibiotic may be selected for this repeat injection.

Disadvantages of vitrectomy include the requirement for instrumentation, possibly available only in an operating room setting, which may be associated with a delay in initiating treatment. The view of the posterior segment is frequently obscured by fibrin and inflammatory debris on the surface of the intraocular lens or in the anterior chamber, making vitrectomy surgery difficult and potentially hazardous. The view of the posterior segment can be improved frequently by aspirating or peeling the inflammatory material from the anterior segment or surface of the intraocular lens (IOL).⁷⁴

Another disadvantage of vitrectomy is its effect on reducing the half-life of injected intravitreal antibiotics.⁷⁵ Doft and associates studied the ocular clearance of amphotericin B injected into the vitreous in a rabbit model of unmodified phakic eyes, Candida-infected phakic eyes, aphakic eyes, and aphakic vitrectomized eyes. With the use of high-pressure liquid chromatography to assess drug level, the half-lives of drug disappearance after a single amphotericin B 10-mg intravitreal injection were 9.1, 8.6, 4.7, and 4.1 days, respectively. The authors summarized that this rapid disappearance of amphotericin B from vitrectomized eyes must be considered in the clinical management of patients with fungal endophthalmitis.

Vitrectomy for endophthalmitis can be performed using either a two-port (vitreous cutter and infusion needle or irrigating light pipe) or three-port technique (sutured infusion cannula, endoilluminator probe, and vitreous cutter), depending on the surgeon's preference and the clinical circumstances. A pars plana vitrectomy (PPV) is often recommended for endophthalmitis cases with light perception visual acuity and with moderate (red reflex present and poor view of fundus detail) or severe (no red reflex visible) vitritis. In such cases, preoperative echography is generally performed to rule out retinal detachment and to document the presence or absence of a posterior vitreous detachment. When there is a posterior vitreous detachment, the vitrectomy surgeon can remove more opaque vitreous near the posterior pole and have greater confidence in avoiding contact with the retina. In EVS, the goal of the three-port PPV was to remove at least 50% of the formed vitreous.

A concentrated undiluted vitreous specimen can be obtained at the beginning of the procedure by manual aspiration into a syringe attached to the aspiration line of the vitrectomy handpiece. The intraocular specimens are evaluated using stained smears and direct cultures.

VISUAL ACUITY RESULTS IN THE EVS

The EVS reported that, among patients who presented with visual acuity of light perception (LP) only, the visual acuity outcomes after immediate PPV were better when compared to the tap/biopsy group.³⁷ In the light perception subgroup of patients, using vitrectomy was associated with a threefold increase in the frequency of achieving 20/40 or better acuity (33% vs. 11%), approximately a twofold chance of achieving 20/100 or better acuity (56% vs. 30%), and a 50% decrease in the frequency of worse than 5/200 acuity (20% vs. 47%). There was no difference in outcomes between immediate PPV and tap/biopsy for patients with an initial visual acuity of hand motions or better (Figs. 3 and 4). In this subgroup, patients had about the same chance of achieving 20/40 or better acuity (66% vs. 62%) and 20/100 or better acuity (86% vs. 84%) and a similar risk for severe visual loss to worse than 5/200 acuity (5% vs. 3%), whether they had immediate three-port PPV or vitreous tap/biopsy. However, there was a possible exception. Diabetic patients with initial visual acuity of hand motions or better obtained somewhat better visual acuity outcomes with vitrectomy compared to tap/biopsy. Final visual acuity of 20/40 or better was obtained in 57% of vitrectomy patients and 40% of tap biopsy patients. The difference was not statistically significant. It was suggested that either vitrectomy or tap/biopsy could be considered reasonable for diabetic patients.⁴⁹

At 9 to 12 months after presentation, clear media, as judged by a 20/40 view of the fundus by indirect ophthalmoscopy, was achieved slightly less frequently in the tap/biopsy eyes (83%) than in the vitrectomized eyes (90%), but this difference was not statistically significant. In no cases were vitreous opacities judged to be a principal cause of impaired vision at the final examination.⁵³

The use of systemic antibiotics (amikacin and ceftazidime) did not improve visual outcomes or media clarity in the EVS, even when subgroup analysis that considered microbiologic susceptibilities was performed.^48–58 The study concluded that systemic antibiotics provided no additional benefit to other routes of treatment.

COMPLICATIONS FROM ENDOPHTHALMITIS AND ITS MANAGEMENT

In the EVS, major adverse events included retinal detachment in 8.3% of patients, phthisis in 3% of patients, significant elevation of intraocular pressure (30 mm Hg or more) in 1% of patients, and enucleation or evisceration in 1% of patients. Compared to vitreous tap/biopsy, vitrectomy was associated with a slightly lower complication rate. Retinal detachment occurred in 7.8% of vitrectomy eyes compared to 9.0% of tap/biopsy eyes.⁷⁸ Enucleation was performed in 3 tap/biopsy eyes but not in vitrectomy eyes. EVS treatment recommendations were based on visual outcome, not small differences in complication rates among treatment modalities.

Macular abnormalities were the most common cause of visual loss in the EVS. These included macular edema, pigmentary degeneration, epiretinal membrane, and ischemia. Such abnormalities were more common with worse presenting visual acuity, occurring in up to 17% of patients with hand motions or better acuity and up to 40% of patients presenting with light perception acuity. In light perception eyes that did not receive vitrectomy (the subgroup that did most poorly), excess visual loss was due to anterior segment media opacification (15%) and phthisis or enucleation (23%). These events were observed much less frequently (0.7–7%) in the remaining treatment groups.

Two adverse events during or after endophthalmitis treatment may markedly influence visual acuity outcomes. Antibiotic toxicity and retinal detachment are significant because further visual loss may occur in spite of successful treatment of the infections. Macular infarction after the use of intraocular aminoglycosides (Fig. 5) is a clinically recognized complication manifesting as a relatively well-defined area of retinal whitening, often in the macula.^76,77 Reported cases of macular infarction secondary to administration of intraocular aminoglycosides have been observed after excessive intraocular doses; other cases were reported after apparent injection of a recommended safe dose. A localized increase in the drug concentration in dependent areas of the retina may play a role in aminoglycoside toxicity. If some of the perifoveal capillaries are spared, retention of some central vision is possible.

Retinal detachment may occur before, during, or after endophthalmitis treatment. The visual prognosis for eyes with retinal detachment in the setting of endophthalmitis is generally poor in reported series.^78,79 The rates of postvitrectomy retinal detachment may be reduced by performing only a partial vitrectomy when the view is compromised by corneal edema.

EARLY AND LATE ADDITIONAL PROCEDURES IN THE EVS

The EVS also evaluated the frequency of additional intervention following initial treatment.⁵³ Within one week of presentation, additional procedures were required in 8% of vitrectomized eyes versus 13% of eyes treated with tap/biopsy. Of 44 eyes (10% overall) that required repeat procedures, most (9%) underwent such procedures for worsening inflammation; the remainder (1.4%, 6 eyes) for other complications after the initial treatment procedure. As reported by the EVS, these remainder complications included glaucoma, wound leak, and retinal detachment. EVS eyes that required additional procedures soon after initial presentation had a poorer visual outcome, with only 15% of eyes achieving 20/40 or better visual acuity compared to 57% of eyes that did not require such procedures. The poorer outcome in eyes requiring secondary procedures could be attributed to the worse early course in such eyes, rather than to the secondary procedures themselves.

The incidence of late additional surgical procedures was 27% overall, and did not differ whether or not vitrectomy was performed or intravenous antibiotics administered. Overall, late additional procedures included posterior capsulotomy in 9% of patients, vitrectomy in 7%, retinopexy in 2%, scleral buckling in 1%, and glaucoma procedures in 1%. In about 2% of patients, vitrectomy for epiretinal membrane was performed. Including early additional surgical procedures, approximately one-third of EVS patients required further surgical intervention after initial treatment.

CLINICAL PRESENTATION AND VISUAL OUTCOME IN THE EVS

Clinical factors on presentation can be correlated with final visual outcome in the EVS. The single most important predictor of visual outcome was presenting visual acuity. Patients with LP visual acuity at presentation had twice the risk of decreased vision compared to those with hand motions or better. Overall, 23% of patients with LP acuity achieved 20/40 or better final acuity, compared with 64% of patients who had hand motions or better acuity.⁴⁸ The data confirmed that early treatment of endophthalmitis prior to severe visual loss is critical to maximize visual outcome and that such treatment is more important in influencing outcome than any other factor, including vitrectomy. Other clinical factors that independently predicted decreased final visual acuity were older age, history of diabetes, corneal infiltrate or ring ulcer, abnormal intraocular pressure, rubeosis, an absent red reflex, and an open posterior capsule.⁴⁹

MICROBIOLOGIC FACTORS IN THE EVS

The EVS evaluated the microbiologic spectrum and susceptibilities of infecting organisms. The findings provided a basis for choosing initial empiric antibiotic therapy and for evaluating subsequent changes in microbiologic spectrum in this disease. As observed in the EVS, the type of organisms and their distribution as well as visual outcomes by infecting species are shown in Table 7. Because both gram-positive and gram-negative organisms were encountered, antibiotic coverage for both types of organisms is recommended.

TABLE 7. Visual Outcome by Infecting Organism in the Endophthalmitis Vitrectomy Study*

Although the infecting organism type predicted visual outcome and response to vitrectomy, the presenting visual acuity was a more powerful, independent predictor of outcome. Presenting visual acuity appeared to serve as a useful proxy for factors such as the duration of infection, host response, and degree of ongoing tissue damage that are determinants of visual prognosis and response to vitrectomy. Other important EVS observations included:

1. A confirmed culture positivity rate of 69% overall, 82% if equivocal cultures were included.⁵⁴
   
2. A high frequency (approximately 70%) of coagulase-negative staphylococci in culture positive cases, with a high concordance of intraocular isolates with the patients' periocular skin flora being observed.⁵¹
   
3. A 9% rate of polymicrobial infection (infection with two or more strains or species in the same eye).⁵⁴
   
4. A high rate of susceptibility of infecting organisms (99.4%) to either of two antimicrobial drug combinations available for intravitreal administration, vancomycin plus amikacin, or vancomycin plus ceftazidime.⁵⁴
   
5. A statistically significant association between secondary IOL implantation and infection with organisms other than coagulase-negative staphylococci, such as S. aureus and streptococci.⁵⁴ Such organisms were associated with a much poorer visual prognosis.
   
6. Virtually identical visual outcome for culture-negative cases and cases infected with coagulase-negative staphylococci, suggesting that many cases of “sterile” endophthalmitis may actually be infectious in origin.⁵⁰
   
7. Topical preoperative surgical preparation with povidone-iodine had been administered in 85 of 211 (40.3%) EVS study patients for whom such data were recorded.⁵⁴
   
8. Prophylactic antibiotics had been administered in the cataract infusion fluid at the initial cataract surgery in 10 of 87 (11.5%) patients in which the data were available.⁵⁴

PITFALLS IN THE APPLICATION OF THE EVS FINDINGS

Measurements of presenting visual acuity were an important factor in the EVS and its recommendations regarding PPV. According to the EVS, patients who were unable to perceive hand motions at a distance of two feet were designated as having LP visual acuity. Such patients were shown to benefit from immediate PPV. Improperly designating such patients with actual LP acuity as having hand motions acuity would result in their inappropriate exclusion from receiving a potentially beneficial vitrectomy. In the EVS, discrimination between LP and hand motions acuity required that the illumination source be placed behind (not in front of) the patient and that the patient correctly identify four of five presentations of hand movements at a distance of two feet. A large proportion of patients in the EVS (70%) required such discrimination, having presented with either LP or hand motions acuity.⁴⁸

The EVS recommendations regarding the use of vitrectomy or systemic antibiotic therapy in acute-onset postoperative endophthalmitis may not be applied directly to other forms of endophthalmitis. The predominant infecting organism in acute-onset postoperative endophthalmitis, coagulase-negative staphylococci, accounted for 70% of the culture-positive cases in the study. Other common forms of endophthalmitis are not characterized by such a predominance of this organism. Bleb-related, traumatic, or endogenous endophthalmitis are more likely to harbor organisms of greater virulence, such as the toxin-producing Streptococcus or Bacillus species. In such cases, the benefits of vitrectomy might theoretically be greater because of its presumed ability to physically remove bacteria and toxins from the eye.

With respect to systemic antibiotic therapy, only amikacin and ceftazidime were evaluated in the EVS. The study made no recommendations regarding systemic antibiotics for endophthalmitis prophylaxis, or for chronic, traumatic, bleb-related, fungal, or endogenous endophthalmitis. The EVS was conducted prior to the availability of the fourth-generation fluorquinolones⁸¹ and linezolid,⁸² which can be administered systemically and may have better intravitreal penetration.

Significant intraocular levels of antibiotics can be achieved with frequent administration of highly concentrated solutions.⁸³ In eyes with intact corneal epithelium, lipid-soluble antibiotics, such as chloramphenicol, penetrate better than the less lipid-soluble drugs, such as the aminoglycosides. This difference is reduced when the corneal epithelium is damaged. For acute-onset postoperative endophthalmitis, topical vancomycin (25 mg/ml) in combination with an aminoglycoside (9 or 14 mg/ml) or ceftazidime (50 mg/ml) administered hourly is often considered. This regimen can then be adjusted to the specific organism after culture and sensitivity results are available. The fourth-generation fluoroquinolones, available commercially for topical use, can also be considered.

Corticosteroids can be administered to the eye by several routes (intravitreal, systemic, periocular, and topical). Clinical studies have reported mixed results regarding adverse effects when using intravitreal dexamethasone in conjunction with intraocular antibiotics. In a prospective randomized clinical trial of 63 bacterial endophthalmitis cases, intravitreal dexamethasone was shown to reduce inflammation scores early in the course of treatment but had no independent influence on the final visual outcome.⁸⁶ In a series of endophthalmitis cases caused by gram-negative organisms, Irvine and associates⁸⁷ reported no adverse effects using intravitreal dexamethasone, 400 μg, in conjunction with intravitreal antibiotics. In this report, visual acuity rates of 20/400 or better in eyes treated with adjunctive intraocular dexamethasone (70.0%) were compared with eyes not receiving adjunctive dexamethasone (44.2%). Similarly, Mao and associates⁸⁸ reported better visual acuity outcomes (% ≥ 20/400) after adjunctive treatment with intravitreal dexamethasone, 400 μg (87.5% vs. 52.6%), for S. aureus endophthalmitis.

In addition to intravitreal corticosteroids, periocular corticosteroids are also commonly used in the treatment of endophthalmitis. The periocular dosage may include dexamethasone, 12 mg or more, administered together with periocular antibiotics.¹ Topical corticosteroids are usually started on the first morning after the initial treatment of endophthalmitis. These drops may be alternated on an hourly basis with the use of topical antibiotics.

Systemic corticosteroids were used in the EVS in the treatment of all study patients with postoperative endophthalmitis. In one study, a combination of topical and systemic corticosteroids gave better results than no corticosteroids or only topical corticosteroid administration.⁸⁹ Because many patients with endophthalmitis also have diabetes mellitus,⁷ use caution when administering higher dosages of systemic corticosteroids.

In most cases of acute-onset postoperative pseudophakic endophthalmitis, intraocular lens removal is not necessary.² There is no evidence that leaving the intraocular lens in place reduces the chance of sterilizing the eye.⁹³ Removal of the posterior chamber IOL may be hazardous in inflamed eyes and may predispose to anterior and posterior segment complications. In selected cases of fungal endophthalmitis and in cases of P. acnes not responsive to more conservative therapy, IOL removal can be considered.^14–16 If recurrent infection occurs following PPV, partial capsulotomy, and intravitreal antibiotics, these cases may require removal of the entire capsular bag and the intraocular lens to achieve a cure.⁹⁴

ACUTE-ONSET POSTOPERATIVE ENDOPHTHALMITIS

This category of endophthalmitis occurs within 6 weeks of intraocular surgery. It can occur from a variety of intraocular surgical procedures ranging from radial keratotomy to cataract surgery. Pain is a frequent but inconsistent symptom and was absent in 25% of EVS patients. The visual loss is generally greater than that expected during the usual postoperative course. Organisms most frequently involved are the coagulase-negative staphylococci, S. aureus, Streptococcus species, and gram-negative organisms.

DELAYED-ONSET OR CHRONIC POSTOPERATIVE ENDOPHTHALMITIS

In this endophthalmitis category, patients may present weeks to months after cataract extraction, often with mild-to-moderate inflammatory signs and a chronic indolent course.^16,94 P. acnes, a gram-positive, anaerobic pleomorphic rod, is a common causative organism in this category. The clinical P. acnes syndrome of delayed-onset pseudophakic endophthalmitis, first described by Meisler and associates⁹⁴ in 1986, typically includes granulomatous inflammation with large keratic precipitates (Fig. 6) and a white intracapsular plaque that has been shown to be composed of organisms mixed with residual lens cortex. When infection with this slow-growing organism is suspected, anaerobic cultures of both the aqueous and vitreous should be obtained and held at least 2 weeks.

In a review of 19 patients with delayed-onset pseudophakic endophthalmitis (defined as those cases diagnosed 6 weeks or more after cataract surgery and excluding filtering bleb-associated cases), four different etiologic organisms were isolated.¹³ These included Propionibacterium species (63%), Candida parapsilosis (16%), Staphylococcus epidermidis (16%), and Corynebacterium species (5%).¹¹ Endophthalmitis due to Mycobacterium chelonae may also present as delayed-onset or chronic postoperative endophthalmitis with white opacities in the lens capsule or anterior vitreous; such cases may be initially misdiagnosed as P. acnes.⁹⁵

In the initial management of P. acnes pseudophakic endophthalmitis with a white intracapsular plaque, a PPV and a central capsulectomy together with intravitreal antibiotics (intravitreal corticosteroids are optional) is generally recommended.^14–16 Selective removal of the observed white plaque using the vitrectomy probe assisted by scleral depression may reduce the frequency of recurrent infection (Figs. 4A and 4B). Vancomycin 1 mg has been the initial antibiotic of choice because of its broad spectrum of coverage against gram-positive organisms and because it can be injected into the remaining capsular bag after the vitrectomy.^14–16 Vancomycin has been recommended over other antibiotics, but vancomycin's activity is diminished under anaerobic conditions. Isolates of P. acnes are also sensitive to methicillin, cefazolin, and clindamycin.

In clinically suspected fungal infections characterized by fluffy white vitreous infiltrates (Fig. 7), injection of intravitreal amphotericin B 5 μg should be considered. If the initial treatment approach does not eliminate the infection, total capsulectomy and intraocular lens removal or exchange can be considered in this staged approach.^96,97 Voriconazole or miconazole can be considered for amphotericin B–resistant organisms.^98–101

Other categories of delayed-onset endophthalmitis include cases associated with suture removal or severe bacterial keratitis, or exposed glaucoma drainage devices.¹⁰² Sutures for scleral fixation of intraocular lens haptics may erode through the conjunctiva and allow organisms entry into the eye.¹⁰³

CONJUNCTIVAL FILTERING BLEB-ASSOCIATED ENDOPHTHALMITIS

This category of endophthalmitis is similar to acute postoperative endophthalmitis in that these patients manifest a sudden onset of pain, visual loss, conjunctival congestion, purulent bleb involvement, and the typical diagnostic features of acute-onset endophthalmitis (Fig. 8).^10,11,104 Risk factors for this category of endophthalmitis include a history of conjunctivitis, contaminated topical glaucoma medications, the use of contact lenses, and inferior filtering bleb.^10,104 The incidence of bleb-related endophthalmitis after a glaucoma-filtration procedure with mitomycin C may be higher than for trabeculectomy without antifibrotic agents.¹⁰⁴ The organisms frequently involved in this type of endophthalmitis include streptococcal species^8,71 and Hemophilus influenzae. Because of the frequency of these virulent organisms and the generally poor visual acuity outcomes, PPV and intraocular antibiotics are often considered as the initial approach for conjunctival filtering bleb-associated endophthalmitis.

It is important to distinguish between a localized bleb infection (blebitis) and true endophthalmitis associated with an infected filtering bleb.¹¹ The former category can be treated with intensive topical, subconjunctival, and possibly systemic antibiotics while the latter category can be treated in a manner similar to acute-onset postoperative endophthalmitis (Fig. 9).

POSTTRAUMATIC ENDOPHTHALMITIS

The visual outcomes after treatment of posttraumatic endophthalmitis are generally worse than the other endophthalmitis categories. In addition to vitreous infiltrates and hypopyon, other signs of posttraumatic endophthalmitis include exudate around foreign body and retinal periphlebitis (Fig. 10). In the National Eye Trauma System²¹ review of endophthalmitis after penetrating injuries with retained intraocular foreign bodies, 9 of 22 (40.9%) culture positive cases achieved 20/400 or better visual acuity. Either Bacillus or staphylococci species were isolated in 21 of these 22 (95%) culture-positive cases. Endophthalmitis was much less likely to develop in eyes with primary repair within 24 hours of the injury (10/287 or 3.5%) than in eyes with primary repair more than 24 hours after the injury (22/164 or 13.4%; p < 0.0001). Major reasons for the poor visual acuity outcomes in these cases are the marked structural damage to the eye resulting from the initial injury, the delay in the primary wound repair, and the greater virulence of the organisms commonly associated with the traumatic endophthalmitis. Bacillus species, most commonly B. cereus, are cultured from 28% to 46% of eyes with posttraumatic endophthalmitis.^20,21,105 Bacillus species are ubiquitous, aerobic, gram-positive, spore-forming rods. Endophthalmitis caused by Bacillus species is characterized by a rapidly progressive course, ring corneal infiltrates (Fig. 11), and, generally, a poor visual outcome even with prompt therapy (Fig. 12).^105–109

A subgroup of trauma-related endophthalmitis is endophthalmitis associated with retained intraocular foreign bodies. Mieler and associates¹¹⁰ reported 27 consecutive cases of retained intraocular foreign bodies managed by prompt removal of the foreign body using PPV techniques. Positive vitreous cultures were obtained in seven of the 19 cases in which cultures were performed. Bacillus species were identified in two of these seven culture-positive cases. In spite of the positive intraocular cultures, no patient developed clinical endophthalmitis. In the National Eye Trauma System data, fewer patients with retained foreign bodies (10 of 287 patients [3.5%]) developed endophthalmitis when the primary surgical repair was within 24 hours after the injury compared with patients in whom the primary surgical repair was delayed more than 24 hours (22 of 164 patients [13.4%]).²¹ Signs of infectious endophthalmitis were described at the primary surgical repair in 31 of 34 patients (91.2%), but 3 of 34 patients (8.8%) developed signs of infection after the primary repair. These reports speculate that prompt surgical intervention, use of vitrectomy, and possible use of prophylactic intravitreal antibiotics in selected high-risk cases may reduce the incidence of endophthalmitis or reverse early undiagnosed endophthalmitis in the setting of a retained intraocular foreign body.

The role of prophylactic intravitreal antibiotics in penetrating ocular trauma cases is controversial.¹¹⁰ However, given the potential for severe visual loss in trauma-related endophthalmitis, it seems prudent to consider their use in selected cases resulting from material such as vegetable matter, foreign-body injuries incurred in an outdoor or rural environment, and penetrating ocular injury from eating utensils.^105–112 The combination of vancomycin 1 mg alone or in conjunction with either an aminoglycoside (amikacin 0.4 mg) or ceftazidime 2.25 mg can be considered when prophylactic intraocular therapy seems appropriate. In addition, systemic antibiotics (such as fourth-generation fluoroquinolones) may be considered.⁸¹

ENDOGENOUS ENDOPHTHALMITIS

Endogenous endophthalmitis is caused by fungi more often than bacteria.²⁷ The most common organism causing endogenous fungal endophthalmitis is Candida albicans; Aspergillus species is the second most common fungal cause.^22,27 Endogenous endophthalmitis is more commonly diagnosed in immunocompromised and debilitated patients or intravenous drug abusers (Table 8).

TABLE 8. Conditions Possibly Predisposing to Endogenous Endophthalmitis

The typical clinical features of Candida endogenous endophthalmitis include fluffy yellow or white vitreous opacities and creamy white chorioretinal infiltrates (Fig. 13). Anterior uveitis frequently accompanies the posterior segment findings. A large macular abscess and pseudohypopyon formation (layering of inflammatory material under the internal limiting membrane of the retina) is not uncommon in cases of endogenous Aspergillus infection.²⁵

The management of endogenous endophthalmitis depends on the clinical features (fungal vs. bacterial), the specific organism isolated, and the severity of infection.^24–27 Once a diagnosis of endogenous endophthalmitis is suspected, evidence for other organ involvement must be sought. This is usually accomplished in consultation with an infectious disease specialist or internist. The presumptive clinical diagnosis is made by positive blood or urine cultures or by focal active infection of nonocular tissues.

The management approach in cases of suspected endogenous Candida endophthalmitis is generally tailored to the clinical situation. When chorioretinal infiltrates are present with no or minimal vitreous involvement, systemic therapy alone is recommended. With moderate-to-severe vitreous involvement (Fig. 14) or in cases with a worsening course in spite of systemic therapy, vitrectomy and intraocular amphotericin B are generally recommended. Although many antifungal agents are not available for intravitreal administration, voriconazole and miconazole are treatment options for amphotericin-resistant fungi (Table 9).

TABLE 9. Antifungal Agents

The choice of systemic antifungal agents is based on several factors.^27,114 For example, if there is no evidence of disseminated disease or if patients are too ill to tolerate the toxicity associated with systemic amphotericin B, other less toxic systemic oral antifungal medications can be used. This is usually administered in conjunction with an infectious disease consultant.

When Aspergillus infection is suspected, aggressive local ocular therapy including vitrectomy and intravitreal amphotericin B is usually indicated.²⁵ Successful treatment in Aspergillus endophthalmitis cases can be accomplished, but the occurrence of a macular abscess may reduce central vision on a permanent basis (Fig. 15). Because an intraocular Aspergillus infection is frequently associated with other organ involvement, particularly cardiac valve vegetation, a comprehensive systemic evaluation is mandatory, and systemic therapy is indicated in most cases.

Endogenous bacterial endophthalmitis is felt to be less common than fungal endophthalmitis. In a 10-year retrospective study of 28 bacterial cases at the Massachusetts Eye and Ear Infirmary,²⁶ the fol1owing organisms were most frequently isolated: S. aureus 25%, Escherichia coli, 18%, and Streptococcus species 30%. Sources of infection were identified in 90% of cases. Endocarditis and the gastrointestinal tract were the most common sources.

In a retrospective review of 72 cases of endogenous endophthalmitis from multiple sources, one report reviewed the spectrum of causative bacteria and showed B. cereus as the most frequently reported bacterial agent.²³ This high incidence of endogenous Bacillus endophthalmitis was due to its association with intravenous drug abuse. This report also showed an increasing incidence of infections by organisms of low pathogenicity in immune-compromised hosts. The authors of this series proposed a classification scheme for endogenous endophthalmitis based on the location (anterior or posterior segment) and extent (focal or diffuse) of the primary intraocular infection. Focal and anterior cases appear to have a better visual prognosis, while posterior diffuse disease nearly always leads to significant loss of vision.²³

To diagnose endogenous bacterial endophthalmitis, a high index of suspicion is important. All patients with visual loss and progressive intraocular inflammation should undergo indirect ophthalmoscopy looking for evidence of septic foci in the posterior segment. In some cases, the established intraocular inflammation is the initial finding leading to the diagnosis of bacterial endocarditis and sepsis. As with endogenous fungal endophthalmitis, an internist or infectious disease specialist should be involved in both the systemic workup and medical therapy. Some patients will present with a known site of infection. In these cases, the intraocular organism is almost always the same as that cultured from the other organ site. These findings will help guide the selection of appropriate antibiotic therapy for both the systemic and ocular infection. In cases without a known site of infection other than the eye, a systemic laboratory workup that includes cultures of blood, urine, sputum, and other suspicious sites should be obtained.

Systemic antibiotics are often used to treat of endogenous endophthalmitis. In cases with focal chorioretinitis but without marked vitreous infiltrates, systemic therapy alone may achieve involution of the lesions. In eyes that fail to respond to systemic antibiotic therapy alone, intraocular therapy may be beneficial. When severe vitritis or marked vitreous infiltrates are present, a vitrectomy and intraocular antibiotic injection are usually recommended.¹¹⁴

To reduce the incidence of postoperative endophthalmitis, each of the factors implicated in the pathogenesis should be addressed. First, an attempt should be made to decrease or eliminate eyelid and conjunctival microflora both preoperatively and intraoperatively. This goal may be accomplished by using preoperative topical antibiotics and topical antiseptic agents. Second, administering subconjunctival antibiotic at the time of surgery should be considered.

Studies evaluating the effectiveness of preoperative administration of antibiotics and povidone-iodine have reported a significant decrease in conjunctival bacterial colony counts.^122–125 Topical antibiotics were reported to be most effective in decreasing conjunctival bacterial colony counts when administered 2 hours before surgery rather than one or more days before surgery.¹²³ The combination of topical antibiotics and povidone-iodine was found to sterilize the conjunctiva in more than 80% of treated patients.¹²²

Subconjunctival antibiotics are commonly administered after intraocular surgery. The rationale for subconjunctival antibiotic administration at the completion of the ocular procedure is to inhibit growth of bacteria that may gain entry into the eye during the operative procedure. Studies performed evaluating the effectiveness of prophylactic subconjunctival antibiotics in reducing the incidence of postoperative endophthalmitis reported conflicting results.^119–121

Administering antibiotics in the irrigating fluid for cataract surgery has become a common technique for infection prophylaxis. This technique carries the risks of antibiotic toxicity, cost, and the possibility of emergence of resistant bacteria.^126–127 One study showed a higher risk of postoperative cystoid macular edema with prophylactic instillation of vancomycin in irrigating fluid.¹²⁸ At least 10 patients in the EVS developed endophthalmitis in spite of receiving antibiotics in the irrigating fluid for cataract surgery. The non–peer-reviewed literature contains reports of extremely low infection rates, but statistical support has been lacking. Thus, the risk-to-benefit ratio of this approach is not known. The American Academy of Ophthalmology (2000) has issued a Policy Statement discouraging the routine use of antibiotics in the irrigating fluid for cataract surgery.

The various strategies to prevent postoperative endophthalmitis are based on current knowledge regarding the pathogenic mechanisms of postoperative endophthalmitis. Perhaps of greatest importance, the preoperative ocular examination will help to identify the high-risk patient as previously described. In these patients, eyelid and conjunctival cultures can be performed before performing intraocular surgery. Based on the culture results and the overall clinical evaluation, preoperative topical antibiotic treatment may be considered. In patients with eye diseases requiring chronic administration of topical medications, new sterile medications should be provided to the patient before and after intraocular surgery.

On the day of cataract surgery, treating patients with prophylactic topical antibiotics that have activity against organisms commonly causing endophthalmitis can be considered. A thorough surgical prep, which includes lid margins, is performed. Instillation of 5% povidone-iodine on the conjunctiva followed by irrigation with saline is part of the surgical prep.¹²⁹ The eyelids and eyelashes can be draped out of the surgical field with a plastic eye drape. A dry surgical field can be maintained when instruments are passed in and out of the eye. Attention to watertight wound closure is a priority, particularly in complicated surgical procedures or in reoperations that tend to have a higher incidence of postoperative wound leak. Vitreous incarceration in the wound should be eliminated by anterior vitrectomy techniques. At the conclusion of surgery, subconjunctival antibiotic injection using a combination of agents effective against the majority of causative gram-positive and gram-negative organisms can be considered.

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