Late Bleb-related Endophthalmitis after Trabeculectomy with Adjunctive 5-Fluorouracil

Late Bleb-related Endophthalmitis after Trabeculectomy with Adjunctive 5-Fluorouracil BARBARA WOLNER, MD,l JEFFREY M. LIEBMANN, MD/ JOSEPH W. SASSANI, MD/,2 ROBERT RITCH, MD,l MARK SPEAKER, MD, PhD/ MICHAEL MARMOR, PhD3

Abstract: The incidence of late-onset bleb-related endophthalmitis was evaluated retrospectively in 229 consecutive trabeculectomies performed with adjunctive 5-fluorouracil (5-FU) therapy. Mean follow-up was 23.7 ± 16.3 months (range, 3 to 60 months). Thirteen eyes (5.7%) of 11 patients developed blebrelated endophthalmitis an average of 25.9 ± 17.4 months (range, 5 to 58 months) after surgery. Infection occurred in 9 of 96 (9.4%) procedures performed from below and in 4 of 133 (3.0%) procedures performed superiorly (P = 0.05, Fisher's exact test). The relative risk of bleb-related endophthalmitis in trabeculectomy from below versus above is 4.0 after adjustment for age and sex (95% confidence interval = 1.1, 14.8). Trabeculectomy with adjunctive 5-FU performed from below carries an increased risk of late bleb-related infection. The incidence of late bleb-related endophthalmitis after 5-FU trabeculectomy appears to be higher than that for trabeculectomy without adjunctive 5-FU injections. Ophthalmology 1991; 98: 1053-1 060

Endophthalmitis may occur months to years after filtration surgery. The route of infection is believed to involve transconjunctival migration of bacteria, as opposed Originally received: September 26. 1990. Revision accepted: March 25. 1991. Department of Ophthalmology, New York Eye and Ear Infirmary, New York City. 2 Department of Ophthalmology, The Milton S. Hershey Medical Center, Hershey. 3 Laboratory of Biostatistics and Epidemiology, Department of Environmental Medicine, New York University School of Medicine, New York. 1

Presented in part at the American Academy of Ophthalmology Annual Meeting, Atlanta, October/November 1990. Supported by The Glaucoma Foundation, New York, New York. The authors have no proprietary interest in any material or device described in this article. Reprint requests to Jeffrey M. liebmann, MD, Clinical Assistant Professor of Ophthalmology, The New York Eye and Ear Infirmary, 310 E 14th St, New York, NY 10003.

to early postoperative endophthalmitis, which results from introduction of the infectious agent at the time of surgery. Clinically, the spectrum of late bleb-related endophthalmitis may vary_ Early in the course of disease, infection may be limited to the region of the filtering bleb (Brown R, unpublished data, presented at the 1989 AAO annual meeting). Spread of infection is characterized by progressive anterior segment inflammation and/or vitreal involvement. Cystic, thin-walled blebs, more common after fullthickness filtration surgery than trabeculectomy, are believed to be more susceptible to infection than thicker, more spongy blebs. 1- 6 Adjunctive 5-fluorouracil (5-FU) therapy, which increases the success of glaucoma filtration surgery in patients with poor surgical prognoses, is associated both clinically and histologically with a cystic and thin-walled bleb. 7 We evaluated the incidence, clinical findings and course, and risk factors for late bleb-related endophthalmitis in a consecutive series of 229 eyes undergoing trabeculectomy with adjunctive 5-FU injections. 1053

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Table 1. Indications for Adjunctive 5-FU Therapy Indication

No. of Eyes

Aphakia/pseudophakia Neovascular glaucoma Prior failed filter Age <40 years Secondary glaucoma Initial trabeculectomy Black race

65 12

52

50 100

52 51

* Some eyes had more than one indication for the use of 5-FU.

PATIENTS AND METHODS We reviewed the records of all patients undergoing 5FU trabeculectomy between June 1, 1984 and June 30, 1989. Surgery was performed by two of us (RR, JL). Data recorded included patient age, sex, race, site of filtration surgery, total dose of 5-FU administered, and the presence of early bleb leaks (within the first 6 postoperative weeks) or leaks present at the time of infection. Each referring primary ophthalmologist was contacted for all patients no longer undergoing periodic follow-up at our institution. Of the patients who remained endophthalmitis-free, data could not be obtained for 22.7% (49 of 216) during the final year of data collection (1989), and were considered lost to follow-up. Two or more years of follow-up were attained by 39% of all eyes (90 of229), including patients with endophthalmitis whose follow-up was terminated at the time of infection. Surgery was performed using a standardized technique. If the patient had undergone prior intraocular surgery involving manipulation of the conjunctiva, the quadrant with the least amount of conjunctival scarring was chosen as the surgical site. All initial surgeries were performed superiorly. After regional anesthesia was achieved, a limbus-based conjunctival flap was created and hemostasis maintained with a monopolar diathermy. A one half thickness, rectangular scleral flap (3 mm radially, 4 mm circumferentially) was dissected. A clear corneal paracentesis track was made at least 90 0 from the filtration site. An internal section of clear cornea and trabecular meshwork (1 mm radially, 3 mm circumferentially) was removed. A basal iridectomy was performed and the scleral flap was reapposed with two to five 9-0 or 10-0 monofilament nylon sutures. From 1984 to 1986, the conjunctival incision was closed with interrupted 10-0 polypropylene on a cardiovascular needle (Ethicon, Somerville, NJ). Since 1986, the incision has been closed with a 9-0 monofilament polyglactin suture on a cardiovascular needle (Ethicon). The anterior chamber was reformed and the bleb expanded with balanced salt solution or sodium hyaluronate irrigated through the corneal paracentesis site. The conjunctival closure was demonstrated to be watertight. Five-fluorouracil injections were begun 180 0 from the operative site at the time of surgery or on the first postoperative day. The total dose of5-FU varied according to patient diagnosis and postoperative complications. A diagnosis of bleb-related endophthalmitis was made 1054

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based on the presence of characteristic white material within the bleb, associated surrounding conjunctival injection, and intraocular inflammation. A generalized conjunctivitis or blepharoconjunctivitis was not deemed an adequate finding for a presumed clinical diagnosis of bleb-related endophthalmitis. Patients presenting with bleb-related endophthalmitis were hospitalized and treated with therapy deemed appropriate for the extent of infection. Cultures of the bleb were obtained in all eyes by vigorously rubbing a brothmoistened swab over the conjunctival surface of the bleb. The swabs were then directly innoculated onto aerobic and anaerobic sheep's blood agar, chocolate and Sabouraud's agar, and thioglycolate broth. A culture was considered positive if the same organism grew on two or more media. 8 If mild anterior chamber inflammation associated with a purulent bleb was present, intensive topical, subconjunctival, and systemic antibiotics were used and the patient was closely monitored for progression of the infection. Eyes with vitreal involvement noted on direct examination or on B-scan ultrasonography underwent diagnostic aqueous and vitreous cultures and were additionally treated with intravitreal antibiotics and systemic steroids. The cumulative incidence of bleb-related endophthalmitis and the incidence rate per patient-year were calculated for the entire group. Separate incidences for surgery performed from above and from below and endophthalmitis-free survival by Kaplan-Meier estimation also were determined. 9 The relative risk of bleb-related endophthalmitis for surgery performed from below versus above was calculated with Cox regression analyses. 10 Duration of observation in months in Kaplan-Meier and Cox regression analyses were calculated from the date of surgery to the date of bleb-related endophthalmitis for those persons experiencing this event or to the date of rightcensoring (i.e., date of last contact for those remaining endophthalmitis-free). Right-censoring refers to the fact that we do not know if subjects who remained endophthalmitis-free to their last contact would later develop blebrelated endophthalmitis if they were followed longer or "further to the right" in a graphical analysis of survival endophthalmitis-free versus time. Data obtained when there were less than five patients at risk in each of the primary subgroups (inferior and superior trabeculectomy) were deleted from Cox regression analysis. Additional statistical analyses were performed using Fisher's exact test and the two-tailed t test.

RESULTS Five-fluorouracil trabeculectomy was performed on 229 eyes of200 patients (93 females, 107 males) between June 1, 1985 and June 30, 1989. There were 132 white patients, 55 black patients, 10 Hispanic patients, and 3 Asian patients. Mean age was 56.7 ± 20.2 years (range, 3 to 87 years). Indications for 5-FU therapy included aphakia or pseudophakia, neovascular glaucoma, prior failed filtering procedure(s), patient age less than 40 years, various secondary glaucomas, and black race (Table 1). Patients were

WOLNER et at

•

BLEB ENDOPHTHALMITIS

Table 2. Patient Data All Patients

Bleb-Related Endophthalmitis

Endophthalmitis-free

Superior Site

Inferior Site

Age (yrs) (range)

56.7 ± 20.2 (3-87)

45.0 ± 19.9 (18-85)

57.4 ± 20.0 (3-87)

54.5 ± 20.3 (7-87)

59.8 ± 19.6 (3-87)

Eyes (no)

229

13

216

133

96

Sex Male Female

107 93

9 2

98 91

64 55

49 42

5-FU dose (mg) (range)

30.3 ± 12.8 (5- 80)

30.0 ± 10.6 (10-50)

30.3 ± 13.0 (5-80)

29.4 ± 12.9 (5-75)

31 .6 ± 12.8 (10-80)

Follow-up (mos) (range)

23.3 ± 16.0 (3-60)

25.9 ± 17.4 (5-58)

23.1 ± 16.0 (3-60)

20.9 ± 14.6 (3-60)

26.6 ± 17.3 (3-60)

Not applicable

25.9 ± 17.4 (5-58)

Not applicable

20.2 ± 12.9 (8-39)

27.1 ± 19.7 (5-58)

Months to infection (range)

followed for a mean of 23.7 ± 16.3 months (range, 3 to 60 months). The mean total dose of 5-FU administered was 30.3 ± 12.8 mg (range, 5 to 80 mg). Ninety-six procedures were performed inferonasally or inferotemporally and 133 were performed superonasally or superotemporally (Table 2). Thirteen eyes of 11 patients (5.7%) developed bleb-related endophthalmitis. Two of these presented with hypopyon and vitreous involvement and required anterior chamber and vitreous aspiration. The other 11 (85%) presented with bleb and anterior segment involvement only. Our overall incidence of bleb-related endophthalmitis after 5-FU trabeculectomy is 5.7%. Bleb-related endophthai mitis developed in 9.4% (9 of 96) of procedures performed from below and in 3.0% (4 of 133) of procedures performed from above during the follow-up period (P = 0.05, Fisher's exact test). The incidence rate of blebrelated endophthalmitis in surgery performed from above was 1.7% per patient-year and in procedures performed from below was 4.2% per patient-year. The average time to the onset of infection was 25.9 ± 17.4 months (range, 5 to 58 months). The mean age of patients in whom bleb-related endophthalmitis developed was less than those patients in whom it did not (45.0 ± 19.9 years versus 57.4 ± 20.0 years, P = 0.03, l test) (Table 2). The mean total dose of 5-FU did not differ significantly between the two groups (mean total dose of 5-FU was 30.0 ± 10.6 mg in 13 eyes developing bleb-related endophthalmitis and 30.3 ± 13.0 mg in 216 eyes without bleb-related endophthalmitis, P = 0.9, l test). As shown in Table 3, univariate analysis showed significantly increased relative risk for bleb-related endophthalmitis among males and among patients younger than 60 years of age. Increased but nonsignificant relative risks also were found for trabeculectomy from below compared with above and, when evaluated on a per-year basis, for surgery conducted between 1988 and 1989 compared with

Table 3. Univariate Estimates of Relative Risks of Bleb-related Endophthalmitis by Various Risk Factors

Risk Factor Sex Male Female Age <60 yr >60 yr Trabeculectomy site Inferior Superior

No. of Cases/ Patient-Years Follow-up

Incidence Rate (%)

Relative Risk

PValue (95%) CI)'

11/232 2/207

5.2 0.97

4.9

0.03 (1.1,45.5)

11/186.9 2/233

5.9 0.86

6.9

0.004 (1.5, 63.6)

9/212.5 4/232

4.2 1.7

2.4

0.17 (0.7, 10.9)

, P value calculated from the binomial distribution ; 95% confidence interval for relative risk.

surgery performed between 1984 and 1987 (data not shown). The sex distribution of patients, however, varied significantly over time; 31.9% (30 of 94) of patients operated on between 1988 and 1989 were female, compared with 53.3% (72 of 135) operated on between 1984 and 1987 (P = 0.03, chi-square analysis). The percentage of surgeries performed from above also varied with time; 74.5% (70 of 94) were performed from above between 1988 and 1989 compared with 46.7% (63 of 135) performed between 1984 and 1987. In consequence, foUowup of patients with surgeries performed from below was significantly longer than patients with surgeries performed from above (26.6 ± 17.3 months versus 20.9 ± 14.6 months, respectively, P = 0.01, l test). Results of Kaplan-Meier estimation of survival endophthalmitis-free are shown in Figure 1. These two survival distributions were not significantly different (P>0.15).

1055

OPHTHALMOLOGY

Survival

•

JULY 1991

Endophthalmitis-free

..

1_ _ _

. c

___ ,

- r lfT"'!1f t1J1l-'"j

-; O.IS

i

o 0.7

.. "o

, 0

20

Mo ·n t h.

I OW

i ng

.pal'.nll

al r Ilk

Sup. r nf.

1 '3 ••

eo

7.

.,

33

$8

55

8 Ur g e r

.,.

80

50

40

30

f0I

y

e

"

Fig 1. Kaplan-Meier estimation of survival without bleb-related endophthalmitis.

Table 4. Multivariate Estimates of Relative Risks of Bleb-related Endophthalmitis from Gox Regression Analysis Risk Factor Inferior trabeculectomy site (versus superior site) Age <60 years (versus age >60 years) Male (versus female) >

PValue

Relative Risk

(95% GI»

0.04

4.0

(1.1 , 14.8)

0.004 0.05

13.02 4.5

(2.2, 75.5) (0.97, 20.0)

95% confidence interval for relative risk.

Because of the several changes with time noted above and possible unrecognized differences in technique or other unidentified factors, Cox regression analyses were conducted with stratification by year of surgery (1988 to 1989 versus 1984 to 1987). Cox regression analyses considered age, sex, total5-FU dose, glaucoma diagnosis, race, and trabeculectomy site as possible covariates. The final multivariate model, shown in Table 4, found independent significant effects of age, sex, and trabeculectomy site. The relative risk for trabeculectomy performed from below compared with that from above (adjusted for age and sex) after a mean follow-up of23.7 months was 4.0 (95% confidence interval = 1.1 , 14.8). The incidence of chronic bleb leaks for the entire group of patients could not be accurately determined from the available data because of the retrospective nature of the study. However, patients with bleb-related endophthalmitis were evaluated at the time of presentation for the presence of a bleb leak. Bleb leaks were noted at the time of presentation in 55.6% (5 of9) of cases performed from below and in 75.0% (3 of 4) of cases performed from above. Chronic or intermittent bleb leaks were known to be present in 61.5% (8 of 13) of these eyes before the development of bleb-related endophthalmitis. Microbiologic results are presented in Table 5. External cultures were obtained by vigorously rubbing a broth1056

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moistened cotton swab over the bleb in 11 of 13 eyes. Anterior chamber and vitreous aspirates were obtained from the remaining two eyes. Organisms isolated from the external surface ofthe blebs included Staphylococcus aureus (7 eyes, 1 of which was methicillin resistant), Hemophilus hemolyticus (1 eye), and Pseudomonas aeruginosa (1 eye). Another grew both Serratia marcescens and methicillin-resistant S. aureus. Vitreous cultures of the two patients with vitreous involvement grew Hemophilus irifluenzae in one patient and no growth in the other. A patient treated at another hospital showed no growth on conjunctival culture. Two patients developed nonsimultaneous bleb-related endophthalmitis in both eyes. S. aureus was cultured from both infections in one patient, while S. aureus and H. hemolyticus were cultured in the second patient. Possible risk factors predisposing to infection, such as chronic blepharitis or poor hygiene, were not present in these two patients and no etiology for bilateral infection could be identified. Visual acuity decreased by two or more lines in 35.5% (5 of 13) ofinfected eyes (Table 5), three of which worsened by more than five lines. The latter included the two eyes presenting with vitreous involvement. For all patients, mean intraocular pressure was 10.1 mmHg (range 5 to 16 mmHg) before development of blebrelated endophthalmitis and 12.5 mmHg (range, 8 to 20 mmHg) after bleb-related endophthalmitis. Scarred, nonfunctional blebs developed in the two eyes requiring vitrectomy, one of which became phthisical. Another eye developed progressive bleb failure over several months.

DISCUSSION The diagnosis of bleb-related endophthalmitis is a clinical one based on the sudden onset of pain and the findings of inflammation localized to the filtering bleb, purulent material within the bleb and associated intraocular inflammation (Fig 2). Late endophthalmitis occurring after filtration surgery differs in its presentation from endophthalmitis occurring in the early postoperative period after intraocular surgery. The latter usually presents with diffuse pain, loss of vision, and involvement of the anterior chamber and vitreous. Because the route oflate infection after filtration surgery begins with the filtering bleb, endophthalmitis may be detected at an earlier stage if patients are alerted to present immediately upon development of possible signs or symptoms. When ocular involvement is limited to the anterior segment, treatment with topical, periocular, and systemic antibiotics is possible. If the vitreous is involved, more aggressive therapy is necessary. The cumulative incidence (number of patients with a certain condition found in a group of patients) of blebrelated endophthalmitis after filtering surgery has been reported to range from 0.2% to 9.6%.1,4,5,11,12 These numbers do not accurately reflect the true incidence of infection, however, because the length of follow-up or rates per patient-year were not reported in these series. The true incidence rate per patient-year of bleb-related endophthalmitis is unknown.

-..J

oVl

.-

Bleb surface

BA, AC RX

BA, AC RX

BA, AC RX

BA, AC RX

BA, AC RX

BA, AC RX

INF

INF

INF

INF

00 POAG, Prior FFP

00 Uveitic glacuoma, prior FFP

00 Uveitic glaucoma, prior FFP

OS Angle-recession glaucoma, INF prior FFP INF 00 Post keratoplasty glaucoma INF OS Aphakic glaucoma

INF

00 Aphakic glaucoma

4

5

6

7

8

9

11

Topical (Fortified)

BA, hypopyon, Vitreous Bleb surface vitritis

Tobramycin Carbenicillin

H. innuenza

NG

NG

Tobramycin Bacitracin

Vancomycin Tobramycin Cefazolin Gentamicin Cefazolin

S. aureus (MR) Tobramycin

P. aeruginosa

S. aureus

=

20/80

20/80

20/80

= bleb abscess; AC RX

Gentamicin Clindamycin Dexamethazone Gentamicin Clindamycin Dexamethazone

None

superior; BA

Cefazolin

Cefazolin

Gentamicin Cefazolin Gentamicin Cefazolin

Unknown

20/50

=

Cystic

Cystic

Cystic, leak NA

Cystic

Scarred, failed

Scarred, failed

Cystic, leak NA

Flat

Cystic, leak

Cystic, leak

Cystic

Cystic, leak Scarred, failed Cystic

Cystic, leak Cystic, leak Flat

Cystic

Post-BRE

Cystic, leak Cystic

Cystic, leak Cystic, leak Cystic

Cystic

Pre-BRE

Bleb Appearance

10

16

10

5

13

7

=

no growth;

13

Phthisis

8

10

11

18

16

10

20

11 12

18

11

8

11

19

Post-BRE

12

8

10

15

12

Pre-BRE

Intraocular Pressure

cells and flare in the anterior chamber; NG

NLP

HM

20/100

20/40

20/160

20/50

20/40 20/40

20/50

20/30

20/50

20/30

20/50

20/40

20/20

Post-BRE

20/50

20/30

None

Ceftriaxone None Ciprofloxicin Oxacillin None Gentamicin Ciprofloxicin Ceftriaxone None Gentamicin Ciprofloxicin Ciprofloxicin None

20/40

None

20/40

20/40

Gentamicin Cefazolin Ceftazidine

None

Ciprofloxicin

20/25

None

None

Ciprofloxicin

20/25

Pre-BRE

Visual Acuity

Ciprofloxicin

None

Intracameral

Cefazolin

Systemic

Unknown

None

Gentamicin Carbenicillin

Gentamicin Cefazolin Gentamicin Cefazolin Gentamicin Vancomycin Gentamicin Vancomycin Gentamycin Vancomycin

Gentamicin Cefazolin Gentamicin Vancomycin None

Subconjunctival

Antibiotic Therapy

BRE = bleb-related endophthalmitis; POAG = primary open-angle glaucoma; FFP = failed filtering procedure; INF = inferior; SUP MR = methicillin resistant; NA = not available; Leak = bleb leak present; HM = hand motions; NLP = no light perception .

10

00 POAG, Prior FFP

Bleb surface

BA, AC RX BA, AC RX

SUP SUP

3 3

BA, hypopyon, Vitreous vitritis

Bleb surface Lids

BA, AC RX

INF

Bleb surface

BA, AC RX

2

Results

Gentamicin Cefazolin Gentamicin Bleb surface S. aureus Cefazolin Tobramycin Bleb surface S. aureus Vancomycin Gentamicin Bleb surface S. aureus Bleb surface H. hemolyticus Cefazolin Gentamicin Cefazolin Bleb surface S. aureus Gentamicin Vancomycin Bleb surface S. marcesans Tobramycin S. aureus (MR) Carbenicillin Tobramycin Bleb surface S. aureus Vancomycin

Source

SUP

2

BA, AC RX

Presenting Findings

OS Juvenile open-angle glaucoma 00 Juvenile open-angle glaucoma, prior FFP OS Rieger's anomaly 00 Rieger's anomaly

Site

SUP

Glaucoma Diagnosis

OS POAG, Prior FFP

Patient Eye No.

Bacterial Cultures

Table 5. Eyes Developing Bleb-related Endophthalmitis: Clinical Findings, Culture Data, and Outcome

OPHTHALMOLOGY

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JULY 1991

Table 6. Previous Reports of Bleb-related Endophthalmitis Procedure

No. of No. of Patients Cases

121 46 Iridencleisis 66 86 35 157 Scheie procedure 302 Posterior lip 182 sclere'ctomy 120 Trabeculectomy 1100 435 133 5-FU trabeculectomy 133' 96t Trephination

11 4 1 3 1 2

.7

3 4 2 2 2 4 9

Follow-up Incidence (mo) (%) Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported Not reported 20.9 ± 146 26.6 ± 17.3

9.6 8.3 1.5 3.4 3.0 1.2 1.5 1.6 3.3 0.2 0.45 1.5 3.0 9.4

Author, Year Tabbara, 1976 Sugar, 1958 Sugar 1958 Tabbara, 1976 Hattenhauer, 1971 Tabbara, 1976 Hattenhauer, 1971 Hattenhauer 1971 Lamping, 1986 Katz, 1985 Mills, 1981 Freedman, 1978 Wainer, 1991 Wainer, 1991

, Performed from above. t Performed from below.

The incidence of bleb-related endophthalmitis appears to be related to the particular characteristics of filtration blebs produced by various procedures. Full-thickness procedures tend to result in cystic, thin-walled blebs, and these are believed to be more susceptible to late infection than the thicker, more spongy blebs associated with trabeculectomyl-6 (Table 6). Bellows and McCulley l3 reported on four cases of bleb-related endophthalmitis associated with contact lens wear in patients with inadvertent filtering blebs after cataract surgery. Recently, adjunctive 5-FU therapy has been used after trabeculectomy in those patients with a relatively high risk of failure from standard filtration surgery. By inhibiting fibroblast proliferation, 5-FU improves the effectiveness of glaucoma filtration surgery and decreases conjunctival scarring. 7,14-l8 Rockwood et ailS reported blebrelated endophthalmitis in 3 of 155 (1.9%) eyes undergoing 5-FU filtration surgery with adjunctive 5-FU, both with trabeculectomy and full-thickness procedures. For our patients, we calculated both the cumulative incidence and the incidence rate. Relative risks were de-

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rived from Cox regression analyses and controlled for potential confounding variables. Stratification of the data, based upon year of surgery, helped to minimize the effects of other possible confounding variables such as minor changes in surgical technique, patient characteristics, or other unidentified factors over time. Bleb-related endophthalmitis occurred in 3.0% of eyes with superonasal or superotemporal 5-FU trabeculectomies. The incidence rate was 1.7% per year. This number more closely resembles the rate of bleb-related endophthalmitis after full-thickness procedures than after trabeculectomyl.2.4,S.II.12.IS.l9 (Table 6). Infection occurred in 9.4% of patients who had surgery from below (incidence rate of 4.2% per year). The relative risk for the development of bleb-related endophthalmitis after 5-FU trabeculectomy from below versus above after adjusting for sex and age was 4.0 (95% confidence interval = 1.1, 14.8). There was no increased risk associated with glaucoma diagnosis, race, or total dose of 5-FU. The cumulative incidence of bleb-related endophthalmitis was higher than that reported for trabeculectomy without adjunctive 5FU for surgeries performed both from above and from below (Table 6). Several explanations can be entertained for the increased risk when surgery is performed from below. Blebs created superiorly tend to be covered by the upper lid and are not subjected to continual mechanical irritation by the lid margin, while those in the inferior position undergo mechanical trauma from the lower lid margin during eye movement. This mechanical irritation may cause a breakdown in bleb wall integrity. The bacterial flora present in the tear lake and lid margin may contribute to an increased incidence of infection. Inferior blebs tend to change shape over time to become more loculated and to lie above the resting position of the lower lid (Fig 3). Exposure of the bleb in the interpalpebral fissure may lead to drying and epithelial breakdown. Other risk factors for the development of bleb-related endophthalmitis included male sex and younger age. Eighty-two percent of our patients who developed blebrelated endophthalmitis were male, although males were

Fig 2. Left. purulent material within a superonasal conjunctival filtering bleb. Fig 3. Right, inferotemporal filtering bleb in a patient with iris-nevus syndrome.

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only slightly more numerous than females in the overall study population (P = 0.03, t test). Others have found no sexual preponderance. IO,20,21 The mean age of our patients developing bleb-related endophthalmitis was more than 10 years younger than those who did not develop the disease (45.0 years versus 57.4 years). Young, male patients are perhaps more likely to be physically active, have an occupational exposure to airborne pathogens, or other routes of exposure to infectious organisms. However, we lack a clear explanation for these associations. Chronic bleb leaks have been suggested as a risk factor in the development of bleb-related endophthalmitis. 1,2,4,20 Mandelbaum et al20 noted 5 of 36 of their patients to have leaking or ruptured blebs at the time of presentation. Hattenhauer and Lipsich 1 reported 90.9% (10 of 11) of their patients who developed endophthalmitis to have thinwalled blebs. All of our patients had thin, cystic blebs at the time of presentation. We found a bleb leak in 55.6% (5 of9) of our bleb-related endophthalmitis patients who had blebs located inferiorly and in 75.0% (3 of 4) of those patients with blebs located superiorly. Because we did not follow all these patients ourselves, many patients without bleb-related endophthalmitis could have had undetected bleb leaks. It is our impression, however, that late bleb leaks are a risk factor for the development of bleb-related endophthalmitis. The treatment of late, chronic bleb leaks after 5-FU trabeculectomy is unrewarding. We have used a variety of therapies, alone and in combination, in the treatment of asymptomatic chronic leaks (Table 7). The value of chronic antibiotic prophylaxis also remains to be determined. In one series, three of four patients developing bleb-related endophthalmitis were receiving antibiotic prophylaxis at the time. 2 A variety of organisms were cultured. However, the relationship of conjunctival culture results to the organism causing infection is not clear. Mandelbaum et al20 reported that in 8 of 18 untreated patients with bleb-related endophthalmitis, the organism isolated from external and intraocular sources was distinct. It is possible that the organism cultured from the bleb surface was not the same as the organism responsible for the infection. The experience of one of the authors (MS) with five other cases of bleb-related endophthalmitis in which aqueous and vitreous cultures were obtained, in addition to the one case of H. influenzae reported here, suggests that external cultures of the bleb yield the same organism as that obtained from intraocular cultures. In a recent molecular epidemiologic study22 of acute postoperative endophthalmitis performed at our institution by one of us (MS), an organism was isolated from the patient's eyelid, conjunctiva, or nose that was genetically indistinguishable from the organism isolated from the vitreous in 82% of the cases examined. Our microbiological findings cannot be directly compared with those of Mandelbaum et al20 because most of our patients presented with a lesser degree of intraocular involvement than did their patients and, accordingly, did not require the cultures of intraocular fluids that would have allowed a direct comparison. Therefore, although

Table 7. Treatment Alternatives for Chronic, Late Bleb Leaks Patching Aqueous suppressants Therapeutic contact lens Collagen shield Simmons shell Symblepharon ring Trichloracetic acid External conjunctival cryopexy Tissue adhesive Thermal coagulation (laser or cautery) Surgical revision

the clinical picture and the response to intensive antibiotic therapy were characteristic of early bleb-related endophthai mitis, we cannot definitively categorize and compare them microbiologically with other series. The less severe intraocular involvement observed in our patients compared with those in other series may reflect infection with less virulent organisms or earlier presentation for treatment. The microbiologic results may have been affected by other unique characteristics of our patients, such as the high incidence of bleb leaks in patients treated with 5-FU, compared with the patients treated by Mandelbaum et al,20 most of whom did not have bleb leaks. The majority of organisms isolated from the external surface were S. aureus and all patients responded to an antibiotic regimen that would be expected to cover most staphylococci and streptococci adequately. Visual outcome and bleb function in most of our patients was good in contrast with other reports. 1.4.12.20 The favorable outcome in our series may be attributed to the characteristics of our patient population. Eleven eyes presented with purulent blebs without evidence of vitreous involvement. In a similar group of patients with early bleb-related endophthalmitis, Brown (unpublished data; presented at the 1989 AAO annual meeting) reported 11 of 15 eyes retaining good visual function. Kanski21 reported good vision in 16 of 20 patients treated for blebrelated endophthalmitis. Favorable visual outcome also may reflect the less virulent staphylococci in our series compared with the more virulent streptococci in another series. 20 While our experience suggests that in the absence of clinical signs of vitreous involvement, intraocular antibiotics are unnecessary, we do recommend prompt vitrectomy and intraocular antibiotics if any signs of progression of the infection or vitreous involvement are present. Vitreous surgery, however, was associated with bleb failure in our series. In conclusion, adjunctive 5-FU injections at the time of trabeculectomy may result in incidences of late blebrelated endophthalmitis comparable with those reported for full-thickness filtering procedures. This may be due to the physical characteristics of the bleb, which resemble the thin, cystic appearance of full-thickness procedures more closely than the diffuse, thicker, low bleb seen more commonly with trabeculectomy. Patients undergoing 5FU trabeculectomy need to be informed of the possible increased possibility oflate bleb-related endophthalmitis, 1059

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especially if surgery is to be performed from below. The increased risk of late bleb-related endophthalmitis may be acceptable if the surgical success rate is improved and intraocular pressure better controlled. Finally, patients having filtration surgery should be carefully instructed on the early signs and symptoms of bleb-related endophthalmitis and told to report immediately if these occur, as early treatment appears to be associated with an improved prognosis for visual recovery and bleb function.

REFERENCES 1. Hattenhauer JM, Lipsich MP. Late endophthalmitis after filtering surgery. Am J Ophthalmol1971; 72:1097-101. 2. Lamping KA, Bellows AR, Hutchinson BT, Afran SI. Long-term evaluation of initial filtration surgery. Ophthalmology 1986; 93:91-101. 3. Blondeau p, Phelps CD. Trabeculectomy vs thermosclerostomy: a randomized prospective clinical trial. Arch Ophthalmol 1981 ; 99:81016. 4. Sugar HS, Zekman T. Late infection of filtering conjunctival scars. Am J Ophthalmol1958; 46:155-70. 5. Tabbara KF. Late infections following filtering procedures. Ann Ophthalmol1976; 8:1228-31. 6. Leopold IH, Apt L. Postoperative intraocular infections. Am J Ophthalmol 1960; 50:1225-47. 7. Gressel MG, Parrish RK II, Folberg R. 5-Fluorouracil and glaucoma filtering surgery: I. An animal model. Ophthalmology 1984; 91 :37883. 8. Foster RK. Endophthalmitis.ln: Tasman W, Jaeger EA, eds., Duane's Clinical Ophthalmology, rev. ed. Philadelphia: JB Lippincott, 1990, vol 4, ch 24. 9. Matthews DE, Farewell VT. Using and Understanding Medical Statistics. Basel: Karger, 1985; 67-86, 148-57.

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10. Lee ET. Statistical Methods for Survival Data Analysis. Belmont, CA: Lifetime LeaminQ Publications, 1980; 306-24. 11. Katz LJ, Cantor LB, Spaeth GL. Complications of surgery in glaucoma. Early and late bacterial endophthalmitis following glaucoma filtering surgery. Ophthalmology 1985; 92:959-63. 12. Freedman J, Gupta M, Bunke A. Endophthalmitis after trabeculectomy. Arch Ophthalmol1978; 96:1017-8. 13. Bellows AR, McCulley JP. Endophthalmitis in aphakic patients with unplanned filtering blebs wearing contact lenses. Ophthalmology 1981; 88:839-43. 14. The Fluorouracil Filtering Surgery Study Group. Fluorouracil Filtering Surgery Study one-year follow-up. Am J Ophthalmol 1989; 108:62535. 15. Rockwood EJ, Parrish RK II, Heuer OK, et al. Glaucoma filtering surgery with 5-fluorouracil. Ophthalmology 1987; 94:1071-8. 16. Heuer OK, Parrish RK II, Gressel MG, et aI. 5-Fluorouracil and glaucoma filtering surgery. III Intermediate follow-up of a pilot study. Ophthalmology 1986; 93: 1537-46. 17. Taniguchi T, Kitazawa Y, Shimizu U. Long-term results of 5-fluorouracil trabeculectomy for primary open-angle glaucoma. Intemational Ophthalmol1989; 13:145-9. 18. Ruderman JM, Welch DB, Smith MF, Shoch DE. A randomized study of 5-fluorouracil and filtration surgery. Am J Ophthalmol 1987; 104: 218-24. 19. Mills KB. Trabeculectomy: a retrospective long-term follow-up of 444 cases. Br J Ophthalmol1981; 65:790-5. 20. Mandelbaum S, Forster RK, Gelender H, Culbertson W. Late onset endophthalmitis associated with filtering blebs. Ophthalmology 1985; 92:964-72. 21. Kanski JJ. Treatment of late endophthalmitis associated with filtering blebs. Arch Ophthalmol 1974; 91 :339-43. 22. Speaker MG, Milch FA, Shah MK, et al. Role of extemal bacterial flora in the pathogenesis of acute postoperative endophthalmitis. Ophthalmology 1991; 98:639-50.