Bleb-related ocular infections can occur months to years after the initial surgery. An infected bleb can soon become a dire situation, since the fluid within the bleb is continuous with the anterior chamber, and the infection can rapidly spread posteriorly. In this article, we provide a run down of risk factors for infection and discuss how you can prevent and treat it.

Clinical Findings
A bleb infection can involve the subconjunctival space, the anterior segment and the vitreous cavity. Usually the spread of infection proceeds in that order, with an infected bleb (blebitis) progressing to anterior chamber and then vitreous involvement, also called bleb-related endophthalmitis.

Figure 1. Blebitis with tremendous conjunctival injection three days after intensive topical and oral antibiotics.

When a patient presents at your office, common subjective complaints include ocular pain, foreign body sensation, blurred vision and tearing. The patient may recall a history of a red eye with a discharge. Examination will reveal conjunctival and ciliary injection, most intense around the bleb edge, and purulent discharge. The bleb typically has a milky-white appearance with loss of clarity, and you may observe a pseudohypopyon within the bleb.¹ A positive Seidel's test is common. Some pa-tients may have hypotony, and even a flat anterior chamber. Alternatively, an in-creased intraocular pressure is possible due to internal closure of the sclerostomy site with purulence and debris. If there is an anterior chamber reaction, corneal edema, keratic precipitates and hypopyon may occur. Vitreous cells are diagnostic of posterior segment involvement. If the media are not clear, B-scan ultrasound can help diagnose infection of the posterior segment.

Risk Factors
The incidence of late endophthalmitis after guarded filtration procedures depends on several factors, such as: 

 • The use of 5-fluorouracil and mitomycin-C during glaucoma surgery probably increases the incidence of late infectious complications.^2,3,4 While antifibrotic agents produce thinner blebs that enhance filtration, they also lead to an increased incidence of bleb-related infections. One study reported an incidence of endophthalmitis after trabeculectomy with 5-fluorouracil (mean follow-up of 23.7±16.3 months) of 3 percent in cases performed superiorly.⁴
 
A 2.1-percent incidence of bleb-associated endophthalmitis after trabeculectomy supplemented with mitomycin was reported in another study after a mean follow-up of 16 months.⁵ Other researchers found an incidence of endophthalmitis after mitomycin filtering procedures performed superiorly of 1.1 percent after 18.5 months of follow-up.⁶ A 2002 study reported a 1-percent incidence of endophthalmitis after trabeculectomy with mitomycin.⁷
Antifibrosis agents are likely to in-duce a hypocellular or acellular bleb with less fibrovascular proliferation.^8,9,10 Mitomycin produces filtering blebs that have a thinner and irregular epithelium, with fewer goblet cells and a more atrophic and avascular stroma. Full-thickness procedures are also more frequently complicated with late endophthalmitis than non-augmented trabeculectomies.¹¹

Figure 2. Blebitis with decreased vision and pain prior to antibiotic therapy.

• Inferior filtering procedures are more likely to lead to endophthalmitis than superior ones.^12,7,6,4  An inferior filtering bleb is more exposed and more likely to suffer accidental minor trauma, epithelial drying and accumulation of infectious agents in the tear lake than superior blebs.

 • Bleb leaks are a predisposing factor for infection.^7,13,14 The use of antifibrotic agents increases the incidence of bleb leaks after trabeculectomy. A thin bleb wall is probably associated with a higher risk of infection because of the transconjunctival spread of organisms and development of bleb leaks. 

 • Bacterial conjunctivitis and blepharitis have been associated with bleb-related endophthalmitis.¹⁵ A previous episode of blebitis is an important risk factor for post-trabeculectomy endophthalmitis.² Releasable sutures have been linked to intraocular infection in sporadic cases.¹⁶ 

 • Systemic diseases such us diabetes mellitus can make the patient more vulnerable to bleb-related ocular infections.²

Microbiology
The bacteria that cause bleb-related endophthalmitis almost certainly arise from the ocular flora, be they transient or permanent. Certain microorganisms such us Streptococcal species can spread through the intact conjunctiva^17,14  and then enter the eye through the sclerostomy.

The most commonly involved organisms are the Streptococcal and staphylococcal species.^{18,19,15,20,14,4}

There may be regional differences or changing patterns of infecting organisms responsible for blebitis.¹⁴ It's important to point out that organisms isolated from the ocular surface in patients with bleb-related endophthalmitis may differ from those responsible for an intraocular infection.¹⁵

Treatment
A recent survey among glaucoma specialists in the American Glaucoma Society reported different approaches to the treatment of blebitis, reflecting the lack of scientific evidence to guide our practice patterns.²¹

Figure 3. Anterior chamber of eye in Figure 2 with acute blebitis. Subsequent evaluation of vitreous cells confirmed the diagnosis as endophthalmitis.

Here's our recommended approach: When a bleb-related infection is diagnosed, the physician collects, stains and cultures a conjunctival exudate. If there's a substantial anterior chamber reaction, he may also obtain an aqueous humor sample. A vitreous tap and/or vitrectomy with injection of intraocular antibiotics should be done in cases of vitreous involvement. Specimens are stained with Gram and Giemsa stains and cultured in blood agar, chocolate agar, enriched broth and Sabouraud's medium. However, you should keep in mind the relatively limited value of conjunctival culture in the diagnosis of blebitis and bleb-related endophthalmitis. A 1985 study found that only five of 18 eyes showed the same organism in the conjunctiva and vitreous.¹⁵

In patients with blebitis (i.e., infection limited to the filtration bleb, without anterior chamber reaction), you can prescribe frequent topical application of a broad-spectrum antibiotic, with close supervision; for example, ofloxacin given every half hour to every hour. The patient can apply bacitracin ointment, which provides good coverage of gram-positive organisms, at bedtime. Oral antibiotics with high penetration into the eye (fluroquinolones: ofloxacin, moxifloxacin, or levofloxacin) is one current recommendation.²² Admission may not be necessary if you can see the patient daily.

If there is mild-to-moderate anterior segment reaction, treatment with fortified topical antibiotics around the clock and admission seems advisable. Combination of topical fortified cefazoline (50 mg/ml) or topical fortified vancomycin (25 mg/ml), and amikacin (50 mg/ml) or tobramycin
(14 mg/ml), would properly cover gram-positive and gram-negative microorganisms, respectively.

In patients with moderate-to-severe anterior chamber reaction, hypopyon and/or cellular reaction in the vitreous cavity (i.e., bleb-related ndophthalmitis), vitreous biopsy and intravitreal antibiotics are required, either through a pars plana injection or associated with a vitrectomy. A possible intravitreal antibiotic choice is 1 mg of vancomycin (10 mg/ml) and 400 mg of amikacin (5 mg/ml). Add oral antibiotics and hourly fortified topical eye-drops.

Vitrectomy, Corticosteroids and Bleb Revision
The role of pars plana vitrectomy and systemic antibiotics in the management of late endophthalmitis after glaucoma filtering surgery is not clear. A prospective, randomized clinical trial evaluating the treatment of postoperative bacterial endophthalmitis after cataract surgery showed that immediate vitrectomy wasn't necessary in patients with better than light-perception vision at presentation, but was of substantial help for those who had light-perception-only vision. Systemic intravenous antibiotic treatment wasn't helpful.²³ However, it's unclear whether the preceding re-sults are applicable to bleb-related intraocular infections.

The effect of corticosteroids is unknown, and their use might be harmful. Therefore, we recommend starting topical steroids after the infection shows signs of improvement. The goal is to reduce the intense inflammation and prevent scarring of the bleb.

After resolution of the infection, the function of the filtration bleb may be impaired, requiring additional medication or surgical intervention, such as the implantation of a drainage device, for adequate pressure control.
The visual outcome is usually good in cases with blebitis and poor when the vitreous is involved, especially with virulent bacteria such as streptococcus, coagulase-positive staphylococci or gram-negative organisms. Coagulase-negative staphylococcal organisms (S. epidermidis) tend to have a more benign course.^24,14,4

Prevention
Long-term antibiotic prophylaxis isn't recommended, as it seems to have no effect on the resident flora of the conjunctiva, may induce antibiotic resistance and may increase the risk of endophthalmitis.²⁵ Another AGS survey showed that only a minority of the members (6 percent) routinely prescribed long-term antibiotic prophylaxis in filtered eyes.²⁶ 

It seems reasonable, however, to use intermittent long-term therapy in some patients with high risk of bleb-related infection. Intermittent and alternating use of antibiotics with different spectra of coverage might minimize the development of drug-resistant organisms. Promptly treat conjunctivitis and blepharitis, and have the patient avoid soft contact lens wear.

Related ocular infection is essential to an early diagnosis and management. Previous bleb-related infection and monocular patients with bleb leaks may require more decisive treatment (e.g, surgical bleb revision).¹  
Current research is evaluating the role of novel anti-scarring agents that would improve the outcome of filtration surgery without the severe alteration of bleb morphology.²⁷ One such agent is transforming growth factor beta2. Subconjunctival application of antihuman TGF-beta2 has been associated with a favorable outcome of filtration surgery, and is currently being evaluated in large randomized clinical trials.²⁸  

Marlene R. Moster, MD, is professor of Clinical Ophthalmology at Thomas Jefferson School of Medicine and is an attending surgeon on the Glaucoma Service, Wills Eye Hospital, Philadelphia. Contact her at (610) 949-9788; moster@willsglaucoma.org.
Augusto Azuara-Blanco, MD, PhD, is a consultant ophthalmic surgeon and Honorary Clinical Senior Lecturer at the Department of Oph-thalmology, Aberdeen Royal Infirmary, University of Aberdeen in Aberdeen, United Kingdom. Contact him at +44 12 24 55 32 17; or  aazblanco@aol.com.

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