Controversies in Endophthalmitis Management

Do the EVS guidelines still hold up in 2012? A look at the questions that remain unanswered.

Raj R. Rathod, MD • William F. Mieler, MD

The treatment of endophthalmitis has evolved significantly over the last several decades. As the number of surgical procedures has risen, so has the concern for the prevention of, and prophylaxis against, infection, along with improved treatment of infection when it does occur (Figure 1).

Figure 1. A devastating outcome after endophthalmitis, following an intravitreal injection for AMD.

THE EVS

The Endophthalmitis Vitrectomy Study (EVS) of the late 1980s paved the way for the evolution of the treatment of acute postoperative endophthalmitis. Soon after intravitreal antibiotics became a viable option for treatment, the EVS group sought to refine the use of antibiotics by comparing outcomes of vitrectomy vs vitreous tap.

The study found that in patients with hand motion or better vision, there was no difference in outcomes between just a vitreous tap and the more complete vitrectomy (both groups used intravitreal antibiotics). However, there was significant benefit for employing immediate vitrectomy when vision at presentation was light perception. Intravenous antibiotics did not seem to play a role in affecting outcomes,¹ although the antibiotics that were available at that time offered limited intraocular penetration.

Although the EVS provided valuable information, many questions remained unanswered. For instance, the study was limited to bacterial infection following cataract extraction or secondary lens implantation and did not address infection following other intraocular procedures or trauma, nor did it discuss fungal infections or endogenous infections.

The use of intravitreal corticosteroids was also not studied, as the issue was quite controversial at that time, and it remains so even today (see below). Moreover, the choice of antibiotics for treatment has expanded since the study concluded.

POSTOPERATIVE BACTERIAL ENDOPHTHALMITIS

Acute postoperative endophthalmitis is generally defined as an infection occurring within six weeks of intraocular surgery, and it is most often caused by a bacterial culprit. The current treatment approach in general follows the findings of the EVS study, with initial vitreous tap and antibiotic injection for most cases, and early vitrectomy for cases in which the vision is LP.

More recently, there has been a trend for a more aggressive vitrectomy approach, especially with the advent of small-gauge vitrectomy surgery. The theoretical advantage of vitrectomy is the ability to clear out significant inflammatory debris that often accompanies endophthalmitis, to wash out the microbes, and potentially to treat or prevent some of the complications that can arise.

Treatment has also evolved in terms of types of the antibiotics employed. Currently employed intravitreal antibiotics include ceftazidime 2.25 mg/0.1 mL and vancomycin 1 mg/0.1 mL. Patients are then sent home on topical fourth-generation fluoroquinolones (moxifloxacin, gatifloxacin or besifloxacin) every two hours and oral moxifloxacin 400 mg daily.

These newer-generation antibiotics have been shown to have broad-spectrum activity against the major pathogens involved in postoperative endophthalmitis.² Studies have also shown that moxifloxacin can reach adequate aqueous and vitreous levels when given orally³ and when administered topically every two hours.⁴

Although oral gatifloxacin also was shown to have significant intraocular penetration, the medication was pulled off the market due to concerns over blood sugar regulation. If medication cost is an issue, ciprofloxacin administered orally may also reach significant intraocular levels,⁵ although the coverage profile is not as broad as fourth-generation agents.

After initial treatment, close monitoring is essential, as the clinical course and outcomes are variable. Depending on clinical response, repeat treatment with intravitreal injections remains an option, although it is rarely required. Vitrectomy may also be employed at any time to address lack of response or to treat any number of complications that may arise.

Delayed-onset (or indolent) endophthalmitis occurs generally more than six weeks after surgery and can present a diagnostic challenge, given the more delayed presentation and confusion with other entities. The causative organisms may include Propionibacterium acnes (which often has a granulomatous inflammation and capsular plaque) or fungal pathogens.

Initial treatment is often with the same approach, with vitreous tap and injection of intravitreal antibiotics. If clinical features are suggestive of or if cultures show the presence of a specific organism, directed treatment is often necessary. For P. acnes infection, the treatment strategies range from intravitreal vancomycin to vitrectomy with subtotal capsulectomy to vitrectomy with IOL explant and complete capsulectomy. Several studies have shown that the last option may be the only completely curative approach.^6,7 Treatment of fungal infection is described below.

Bleb-associated infections present another challenge in the management of postoperative infections. The treatment can vary depending on the severity of the infection. Grade 1 (infection limited to bleb) and grade 2 (involvement of anterior chamber) blebitis can be initially managed with intense topical treatment (either topical fluoroquinolone every two hours or hourly fortified vancomycin and tobramycin) and oral moxifloxacin. Grade 3 infections, which involve the vitreous cavity, are treated as any other postoperative infection.⁸

PROPHYLAXIS

There is debate over the most appropriate strategy for preventing infection around the time of intraocular surgery. Most ophthalmologists agree that several steps are important in reducing the rate of infection, including minimizing the ocular surface flora with 5% povidone-iodine, keeping the eyelashes covered, and a careful and aseptic surgical technique with appropriate wound closure.

Some surgeons advocate the addition of broad-spectrum topical antibiotics for three days prior to surgery to reduce surface pathogens, although this recommendation remains contentious. A large European study found that intracameral cefuroxime given at the time of cataract surgery reduced the rate of postoperative endophthalmitis.⁹ The results must be viewed with caution, as the study had an overall higher rate of infection than has been recently quoted in the literature.

Several other studies have since shown reduced rates of endophthalmitis when intracameral antibiotics are given at the end of cataract surgery (either cefuroxime or cefazolin).^10-14 Although the use of postoperative topical antibiotics has not been shown to reduce the rate of infection, most practitioners prescribe an agent to be used following surgery. This practice seems to differ, however, regarding prophylaxis following an intravitreal injection.

INTRAVITREAL INJECTIONS

With the exponential rise in the number of intravitreal injections over the last several years, much interest exists in determining the most effective technique for prophylaxis against infection in this setting. Although practices can vary widely among physicians, an expert panel published recommendations based on areas of strong agreement and areas in which consensus was not achieved.¹⁵

The areas of strong agreement are as follows:

• Povidone-iodine for ocular surface, eyelids and eyelashes.
• Use of a speculum and avoiding contamination of the needle with eyelashes or eyelid margin.
• Avoidance of extensive massage of the eyelids either pre- or postinjection (to avoid expressing meibomian glands).
• Avoidance of injecting patients who have active eyelid or ocular adnexal infection.
• Using adequate anesthetic for each patient (topical drops and/or subconjunctival injection).
• Dilating the eye.
• Avoiding prophylactic or postinjection anterior-chamber paracentesis.

Consensus was not found on the following points:

• Most did not want to use a povidone iodine flush and preferred drops; no benefits were attributed to drying.
• Most did not use a sterile drape.
• Most advocated the use of gloves.
• Regarding the use of pre- or postinjection antibiotics, there is a paucity of published scientific data to support a reduction in endophthalmitis.
• Regarding an IOP check following injection, there is no consensus on the IOP level at which physicians are comfortable discharging patients.
• No consensus was reached about patient competency to self-report signs and symptoms of endophthalmitis or other adverse events.
• No consensus was reached on the need for clinical follow-up exams vs telephone exchanges with a physician or nurse.

At the present time, most ophthalmologists no longer employ pre- or postinjection prophylactic antibiotics, and care is taken regarding potential contamination of the surgical field from the mouth or nose (the ophthalmologist and the patient do not speak during the procedure).

If infection develops after an intravitreal injection, most follow the treatment guidelines of postoperative endophthalmitis as described above. If the eye is eventually stabilized, a greater challenge remains in determining whether or not to continue intravitreal injections in that eye if the underling condition warrants treatment.

Great concern exists over the development of resistance to commonly used antimicrobials, especially when used repeatedly/intermittently after ocular procedures. Recent studies have shown rapid emergence of resistance of ocular surface flora following topical antibiotics^16-18 and a significant prevalence of resistance in the patients being treated.^19,20

ENDOGENOUS ENDOPHTHALMITIS

Infections that spread to the eye hematogenously usually occur in patients who are hospitalized with known systemic infections, and these infections tend to be fungal in origin. In cases in which a bacterial source is more likely, treatment is tailored to the specific presentation (Figure 2).

Figure 2. Endogenous endophthalmitis caused by Klebsiella from a liver abscess presenting with a fibrinous anterior-chamber reaction and hypopyon. Ultrasound showed dense vitritis and a subretinal abscess. The patient was treated with vitrectomy surgery and intravitreal antibiotics.

The patients who develop these infections are often acutely ill, and surgical intervention may need to be delayed until the patient has been stabilized. Intravitreal antibiotic injections are a reasonable starting point.

FUNGAL ENDOPHTHALMITIS

Endophthalmitis can be caused by fungal agents through endogenous sources, after intraocular surgery or from penetrating trauma. Although fungal infections remain rare overall, they are often difficult to treat and can have significant morbidity (Figure 3).

Figure 3. Chronic postoperative fungal endophthalmitis with capsular/IOL deposits in a patient with a multifocal lens implant.

A relative paucity of therapeutic agents has added to the challenge, as amphotericin-B has traditionally been the mainstay of treatment. Fluconazole, voriconazole and caspofungin are all agents that may have a role in current treatment schemes. Voriconazole, specifically, has a broad spectrum of activity against common fungal pathogens and has been shown to achieve significant aqueous and vitreous levels when administered orally.^21-23

TRAUMATIC ENDOPHTHALMITIS

Infection after open-globe and intraocular foreign body (IOFB) injuries can be devastating, and anatomic and visual outcomes are often quite guarded. Although the spectrum of causative agents and their toxicity are different than the above scenarios, the treatment approach, in terms of antibiotics implemented, remains essentially the same.

Bacillus species are often identified and tend to be quite virulent, yet in most cases, Bacillus is sensitive to vancomycin. Encouraging data came out of a study from the Iraq war, in which patients that sustained IOFB injuries remained free of endophthalmitis when they were maintained on oral and topical antibiotics, even when IOFB removal was delayed beyond one year (the globe injury itself was repaired as soon as possible).²⁴

CORTICOSTEROIDS

The role of corticosteroids in the acute management of endophthalmitis remains controversial. Corticosteroids were not studied in the EVS, and there are limited data that show either a benefit or a disadvantage.²⁵ Most experts believe that in certain situations, depending on the pathogen and the timing of administration, they may be beneficial.

At the present time, the use of corticosteroids in managing endophthalmitis is at the discretion of the treating physician. When employed, an intravitreal dose of dexamethasone 400 µg/0.1 mL is typically given.

CONCLUSION

Although much progress has been made over the last several decades in the treatment of endophthalmitis, starting with the seminal EVS data, many challenges remain. The field will continue to evolve as the pathogens and antimicrobials themselves further evolve. RP

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