Cystoid macular edema after cataract surgery with intraocular vancomycin

Cystoid Macular Edema after Cataract Surgery with Intraocular Vancomycin Ruth Axer–Siegel, MD, Hadas Stiebel–Kalish, MD, Irit Rosenblatt, MD, Eyal Strassmann, MD, Yuval Yassur, MD, Dov Weinberger, MD Objective: To determine whether the use of supplemental prophylactic vancomycin in the irrigating solution during extracapsular lens extraction is associated with increased incidence of cystoid macular edema. Design: Prospective, randomized, double-masked clinical study. Participants: Consecutive series of 118 patients 60 years of age or older undergoing cataract surgery. Intervention: The study group received an irrigating balanced salt solution supplemented with vancomycin (10 ␮g/ml), and the control group received the salt solution only. Fluorescein angiography was performed 1 and 4 months after surgery. Main Outcome Measures: Evidence of angiographic and clinical cystoid macular edema, and visual acuity at 1 and 4 months after surgery. Results: The rate of postoperative angiographic cystoid macular edema was significantly higher in the study patients than in the control group at 1 month (55% vs. 19%, P ⫽ 0.0006) and 4 months (26% vs. 4%, P ⫽ 0.0099). The rates of clinical macular edema were 23% and 7%, respectively, at 1 month (P ⫽ 0.011) and 20% versus 0% at 4 months (P ⫽ 0.006). Visual acuity of 20/30 or better was noted at 4 months after surgery in 76% of the study group compared to 95.5% of the control group. Conclusions: The role of preventive intracameral vancomycin during intraocular surgery should be reassessed in view of the associated increase in the incidence of angiographic cystoid macular edema. Ophthalmology 1999;106:1660 –1664 Endophthalmitis is a devastating complication of intraocular surgery. Although its incidence in the developed world has declined to 0.072% to 0.092% after extracapsular cataract surgery (ECCE),1,2 it still constitutes a major clinical hazard, owing to its deleterious effect on postoperative visual acuity. The prophylactic use of antibiotics for postoperative endophthalmitis is controversial. Originally, the antibiotic was delivered topically, subconjunctivally, or periocularly.3,4 The clinical use of intraocular antibiotics for prophylaxis of endophthalmitis dates back at least 26 years, but it has always been tempered by concerns of toxicity.5 Recently, the intraocular supplementation of antibiotics to the infusion fluids during anterior segment surgery has been gaining popularity. Gills6,7 reported 1 infection in 20,000 cases of cataract surgery in which gentamicin 8 ␮g/ml was used, 1 infection in 9928 cases with vancomycin 20 ␮g/ml, and no infections in 25,000 cases with both antibiotics. The author also suggested the use of a filter for all irrigation fluids.

Originally received: October 18, 1998. Revision accepted: May 26, 1999. Manuscript no. 98689. From the Department of Ophthalmology, Rabin Medical Center, Beilinson Campus, Petah Tiqva, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Address correspondence to Ruth Axer–Siegel, MD, Department of Ophthalmology, Rabin Medical Center (Beilinson Campus), Petah Tiqva 49100, Israel.

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There is, however, a paucity of antibiotic toxicity studies in humans. The few small reports in the literature have reported no significant toxicity.7,8 In a more extensive study by Wood et al,9 108 consecutive patients undergoing penetrating keratoplasty received vancomycin 1000 ␮g/ml in balanced salt solution (BSS), both as the irrigation fluid during surgery and by instillation to fill the anterior chamber at the conclusion of surgery. Again, no corneal toxicity was noted. Finally, Gimbel et al10 retrospectively reviewed 4684 patients who received intracameral gentamicin (8 ␮g/ml) and vancomycin (2.3 mg/ml) during cataract surgery. No case of endophthalmitis was observed, and the average amount of endothelial cell loss in 50 randomly selected eyes was similar to other reported series of cataract surgery without supplemental antibiotics. In 1995, vancomycin (10 ␮g/ml) was added routinely to the BSS delivered to the anterior chamber in all ECCE operations performed in our department. During the same period, one of the authors (I.R.) noted clinically that there had been an increase in the rate of cystoid macular edema (CME), raising the suspicion that it was associated with the use of intracameral vancomycin. This clinical observation prompted us to conduct a prospective, randomized clinical trial to evaluate the possible influence of supplemental vancomycin in the irrigation solution during ECCE on the incidence of postoperative CME. To the best of our knowledge, the potential retinal toxicity of supplemental intracameral vancomycin during cataract surgery in humans has not been studied in a controlled fashion.

Axer–Siegel et al 䡠 Cystoid Macular Edema and Intraocular Vancomycin Table 2. Comorbidity of the Groups: No. (%)

Posterior capsular rupture Diabetes Myopia or drusen

Figure 1. Fluorescein angiogram demonstrating the minimal amount of leakage that was determined as equal to grade I of the Miyake classification.

Patients and Methods The study population included all consecutive patients 60 years of age or older who underwent ECCE with posterior chamber intraocular lens (IOL) implantation in our ophthalmology department, from May 1, 1996, to June 30, 1996, and who agreed to participate in the study. The patients signed an informed consent form. Exclusion criteria were diabetic retinopathy; retinal vascular disease; uveitis; pre-existing macular pathology such as age-related macular degeneration, epiretinal membrane, macular hole, prior ocular surgical intervention, severe cardiac, renal, or liver dysfunction; and preoperative use of anti-inflammatory drugs. The study was approved by the institutional review committee. To prevent errors in randomization of patients for operations with and without vancomycin, the randomization process was simplified for the operating room staff, by first randomizing all the patients who were scheduled for ECCE during this period into the two groups and then excluding those who were ineligible for the study. The operations were performed by the departmental senior physicians and residents. The surgical technique was identical in all patients and consisted of planned ECCE through a corneoscleral tunnel with an anterior chamber maintainer and implantation of an IOL in the posterior chamber. In the study group, supplemental vancomycin 10 ␮g/ml was added to the BSS, which was delivered to the anterior chamber by the anterior chamber maintainer Table 1. Data on Patients and Operating Physician: No. (%)

Age (yrs) Gender Male Female Preoperative VA ⬎6/12 6/12–6/60 ⬍6/60 Patients operated by senior physicians VA ⫽ visual acuity.

Vancomycinⴙ (n ⴝ 60)

Control (n ⴝ 58)

74 (⫾10)

72 (⫾8)

21 (35) 39 (65)

20 (35) 38 (65)

2 (3.3) 35 (58.3) 23 (38.3) 48 (80)

2 (3) 36 (62) 20 (35) 46 (79)

Vancomycinⴙ (n ⴝ 60)

Control (n ⴝ 58)

3 (5) 7 (11) 6 (10)

3 (5) 4 (7) 6 (10)

throughout the operation; the control group received BSS without any supplementation. At the conclusion of the operation, chloramphenicol and dexamethasone drops were instilled into the conjunctival sac. All patients received a subconjunctival injection of gentamycin and dexamethasone, and the eyes were patched with neomycin 5% ointment. Dexamethasone and chloramphenicol drops were prescribed four times daily during the first postoperative month and twice daily thereafter until the 6-week visit. Complete ocular examination was performed by masked observers (H.S.K. and E.S.) 1 day before surgery and 1 day, 1 week, 3 weeks, 6 weeks, and 4 months after surgery. The examination included visual acuity testing, slit-lamp biomicroscopy, intraocular pressure measurement, and ophthalmoscopic evaluation with the ⫹90-diopter lens. The flare and cells in the anterior chamber were assessed clinically and graded on a scale of ⫹1 to ⫹3. Clinical CME was defined as the presence of macular edema with at least one cyst, as identified by two observers (H.S.K. and E.S.) through the dilated pupil with the ⫹90-diopter lens. Whenever the two observers did not agree, a third observer (D.W.) examined the patient and the majority opinion was accepted. Fluorescein angiography (FA) was performed at the 1-month and 4-month visits, and the angiograms were examined by two masked observers. Angiographic CME (ACME) was defined as a perifoveal leakage of grade I or more according to the Miyake classification (slight fluorescein retention is seen on the angiogram, the area of the retention is ⱕ1 mm2, and the lesion does not show a complete circle around the fovea)11 (Fig 1); there was no further grading of the CME. In the event of a disagreement between the observers (R.A.S. and I.R.), a third observer (D.W.) was consulted and the majority opinion was accepted. Patients with a clinical diagnosis of CME were treated with sub-Tenon steroid injection and dexamethasone and Voltaren drops (Geigy, Summit, NJ). The statistical analysis was performed with the SPSS WIN statistical software (SAS Institute, Cary, NC). Chi-square test and Fisher’s exact test were used as necessary. Probability values of less than 0.05 were considered statistically significant.

Results Of the original 144 patients (74 study, 70 control), 26 were excluded (14 and 12, respectively) because of ocular or systemic pathology. Data regarding age, gender, patients’ preoperative visual acuity, and percentage of surgery performed by senior physicians are presented in Table 1. The final analysis included 60 vancomycin patients (39 female, 21 male) of mean age 74 (⫾10) years and 58 control subjects (38 female, 20 male) aged 72 (⫾8) years; there were no significant intergroup differences in gender, age, preoperative visual acuity, or percentage of surgery performed by senior physicians. Table 2 lists the incidence of rupture of the posterior capsule, diabetes, drusen, or myopia in the two groups. None of these differences were significant. The duration of the operation was 20 to 50 minutes in both groups. Table 3 lists the patient compliance data at 1 and 4 months after surgery. At 1 month, in the vancomycin group, 60 patients (100%) were examined and 40 (67%) underwent FA; in the control group,

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Ophthalmology Volume 106, Number 9, September 1999 Table 3. Patient Compliance: No. (%)

1 mo Clinical examination Fluorescein angiography 4 mos Clinical examination Fluorescein angiography

Table 5. Visual Acuity: No. (%)

Vancomycinⴙ (n ⴝ60)

Control (n ⴝ 58)

60 (100) 40 (67)

58 (100) 43 (74)

45 (75) 35 (58)

44 (76) 24 (55)

1 mo 20/40 20/30 4 mos 20/40 20/30

Vancomycinⴙ

Control

P

or worse or better

31/60 (52) 29/60 (48)

20/58 (35) 38/58 (66)

0.052

or worse or better

11/45 (24) 34/45 (76)

2/44 (5) 42/44 (96)

0.0079

* Fisher’s exact test.

58 patients (100%) were examined and 43 (74%) underwent FA. After 4 months, 45 (75%) study patients and 44 (76%) control patients were examined and 35 (58%) and 24 (55%), respectively, had FA. The decreased percentage of patients appearing for FA at the 4-month visit was attributed to noncompliance because of nausea or the unpleasant nature of the procedure, and others failed to complete follow-up for reasons of illness or inconvenience. Nevertheless, there was no significant between-group difference in percentage of completers, nor was there a significant difference between the completers and those who did not complete the follow-up and the angiograms in age (t test), baseline and 1-month postoperative visual acuity, ACME at 1 month, rates of hypertension or insulin-dependent diabetes mellitus, surgeon (staff or resident), and incidence of posterior capsular tear (Pearson chi-square test). Although the grading of the anterior chamber flare and cells was subjective, no major differences were found between the groups. Table 4 lists the incidence of angiographic and clinical CME in the study and control groups. ACME was detected by FA at 1 month in 22 (55%) of the 40 patients in the study group and in 8 (19%) of the 43 patients in the control group (P ⫽ 0.0006, Pearson’s chi-square test), and in 9 (26%) of 35 and 1 (4%) of 24 patients, respectively, at 4 months (P ⫽ 0.0099, Fisher’s exact test). Figures for clinical CME were 14 (23%) of 60 vancomycin patients and 4 (7%) of 58 control subjects (P ⫽ 0.011, Pearson’s chi-square test) at 1 month, and 9 (20%) of 45 vancomycin patients and no control subjects at 4 months (P ⫽ 0.006, Fisher’s exact test). All these differences remained significant when the patients with posterior capsular rupture and diabetes were excluded. Table 5 lists the visual acuity results. At 1 month after surgery, there was no significant difference in visual acuity between the groups, whereas at 4 months, a visual acuity of 20/40 or less was noted in 11 (24%) of 45 vancomycin patients, but only 2 (5%) of 44 control subjects (P ⫽ 0.0079, Fisher’s exact test). However, when the patients with posterior capsular tear and diabetes were excluded (9 vancomycin patients, 7 control subjects), this difference diminished. A visual acuity of 20/40 or less was noted in 7 (19%) of 36 vancomycin patients versus 2 (5%) of 37 control subjects (P ⫽ 0.089, Fisher’s exact test). Table 4. Cystoid Macular Edema: No. (%)

Angiographic 1 mo 4 mos Clinical 1 mo 4 mos

Vancomycinⴙ

Control

P

22/40 (55) 9/35 (26)

8/43 (19) 1/24 (4)

0.0006* 0.0099†

14/60 (23) 9/45 (20)

4/58 (7) 0/44 (0)

0.011* 0.006†

* Pearson’s chi-square test. † Fisher’s exact test.

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Discussion The use of perioperative prophylactic antibiotics is still controversial. Studies have demonstrated that even with preoperative topical antibiotics, anterior chamber aspirate cultures show bacterial contamination rates as high as 43%.12 In a recent survey of nosocomial postoperative endophthalmitis, the cultured endophthalmitis organisms proved to be sensitive to the preoperative topical prophylactic antibiotics that were applied. Moreover, 61% of the culture-positive patients known to have received prophylactic subconjunctival antibiotics at the conclusion of surgery were sensitive to the antibiotics used, and 39% were resistant.2 Theoretically, the most effective method for reaching the bactericidal level in the eye is intracameral administration at the time of surgery. However, there are no large, randomized, prospective studies comparing the effect of antibiotics in the irrigating fluid versus a placebo in reducing the incidence of postoperative endophthalmitis. Moreover, endophthalmitis can still occur despite the use of antibiotics in the irrigating fluid.13 In an in vitro model, Gritz et al14 showed that exposure to antibiotics for up to 2½ hours generally has no effect on organisms commonly responsible for endophthalmitis. Therefore, they suggested that the use of antibiotics in this manner should be critically reassessed. Another significant point against using vancomycin on a prophylactic basis is the risk of the emergence of vancomycin-resistant organisms.15,16 In the study by Miyake et al,11 51% of patients had ACME at 1 to 2 months after intracapsular cataract extraction and 25% did so after 4 to 7 months. The Miami Study Group found an ACME incidence of 11% at 4 months after ECCE with a Binkhorst IOL implant,17 and Rosetti et al,18 in a prospective, randomized study of ECCE with IOL implantation, noted a rate of 15% (7 of 46 patients) at 1 month after surgery with a decrease to 9% and 4% after 3 and 6 months, respectively. In their review of 90 studies of cataract surgery, Powe et al19 found an overall incidence of ACME of 8.9% (range, 2.7%–11.3%) of ECCE cases. In our study, the incidence of ACME in the control group at 1 and 4 months after surgery was 19% and 4%, respectively, rates comparable with those found in the abovementioned series,11,17–19 although ACME was more prevalent in the vancomycin group at both timepoints (55% and 26%, respectively). Gills,6,7 Peyman and Daun,20 and Gimbell et al10 all reported on thousands of patients who un-

Axer–Siegel et al 䡠 Cystoid Macular Edema and Intraocular Vancomycin derwent cataract surgery with vancomycin in the irrigating solution without retinal sequelae. However, none of these authors performed FA. Additionally, in all three series, surgery was performed by a single expert surgeon, whereas our patients were operated on in a teaching hospital by many surgeons. Therefore, we may assume that the surgical procedures performed in our hospital were of longer duration, dictating a longer period of vancomycin administration. The shorter exposure time in the earlier studies may have contributed to their lack of retinal sequelae. Cystoid macular edema is a nonspecific pathologic response to a variety of ocular diseases. Any condition inducing intraocular inflammation, retinal vascular occlusion, retinal traction, as well as toxic effect caused by nicotinic acid and epinephrine may be associated with CME.21 Cystoid macular edema after cataract surgery was characterized by Gass and Norton22 in 1996. Theories have proposed a role for vitreous traction on the macula as well as inflammatory factors in the development of CME. The role of light exposure either intraoperatively or postoperatively in the production of CME is unclear.23 Jampol et al23 reported a series of cataract extraction with and without a filter in the operating microscope that eliminated radiation below 400 nm. They found no difference in the incidence of CME between the two groups. However, in another series in which posterior chamber lenses with or without near-ultraviolet filtration were implanted, there was significantly less CME after surgery when the lens material contained filtration of wavelengths below 400 nm. Tso and Shih24 developed an experimental model for macular edema in adult rhesus monkeys undergoing cataract extraction. Although CME was not demonstrated in any of the animals in the histopathologic studies, horseradish peroxidase showed, in all eyes, disruption of the blood–retinal barrier at the retinal pigment epithelium (RPE). The eyes with vitreous loss also showed disruption of the blood– retinal barrier at the retinal capillaries. This study suggested that the blood–retinal barrier at the RPE is more vulnerable than at the retinal capillaries. Using a rabbit model of intravitreous vancomycin, Pflugfelder et al25 found that doses of up to 2 mg were nontoxic in both phakic and aphakic vitrectomized eyes, whereas doses of 5 mg caused irreversible damage to the retina and the RPE. The pathologic alterations occurred in the photoreceptor outer segments, in the outer retinal layers, and in the RPE. An accumulation of cellular debris in the subretinal space was noted, but there was no CME. The damage was not related to the duration of the contact of the antibiotic with the retina. An investigation of the retinal toxicity of vancomycin in the infusion solution in vitrectomy and lensectomy in rabbit eyes revealed that concentrations of 8, 16, and 32 ␮g/ml caused no abnormal electroretinographic findings or histologic changes, but 100 ␮g/ml caused ERG amplitude depression and abnormal histologic changes, unrelated to CME.26 The mechanism of the increased incidence of ACME in the vancomycin-treated group in our study is unknown. The experimental histopathologic studies performed to date demonstrated retinal toxicity unrelated to CME caused by tenfold higher doses of vancomycin.25,26 We may speculate

that the link between the above-mentioned histopathologic studies and the experimental model of Tso and Shih24 may be possible damage to the RPE, which disrupts the outer blood–retinal barrier, thus causing ACME. The 1995 study of the Endophthalmitis Vitrectomy Study Group27 did not report retinal toxicity with 1 mg of intravitreous vancomycin. In this study, the most common cause of impaired vision was macular abnormalities, with clinical macular edema occurring in 6% to 17% of patients in the different subgroups. Owing to the presence of severe inflammation, it was impossible to distinguish the role of the intraocular antibiotic treatment from the influence of the infection, the inflammation, or the multiple surgical interventions. In our series, there was a significant between-group difference in the percentage of patients with a visual acuity of 20/40 or less (24% in the vancomycin group vs. 5% in the control group) at 4 months after surgery. This difference diminished to 19% versus 5%, respectively, when the patients with posterior capsular tear and diabetes were excluded. However, the small number of patients with capsular tear and diabetes prevented us from drawing conclusions about possible mechanisms that may have rendered them more susceptible to the influence of intracameral vancomycin. Our data should be analyzed with caution because of the relatively small size of the series and the partial compliance of the patients, some of whom refused to undergo FA. However, despite the considerably lower compliance for FA and for the 4-month visit, there was no significant betweengroup difference in the percentage of patients completing the follow-up and no difference between the completers and the noncompleters of the follow-up visits and the angiograms with regard to baseline factors, including vision and 1-month postoperative angiographic data, or other characteristics (surgeon, hypertension, diabetes, and posterior capsular rupture). Although the lack of between-group differences in numeric and baseline factors cannot absolutely rule out any bias, in view of the increased incidence of ACME in the patients receiving vancomycin in the irrigating fluid, we suggest that this mode of prophylactic treatment be re-evaluated. Acknowledgments. The authors thank Mrs. Gloria Ginzach and Mrs. Marian Propp for their editorial and secretarial assistance.

References 1. Kattan HM, Flynn HW Jr, Pflugfelder SC, et al. Nosocomial endophthalmitis survey. Current incidence of infection after intraocular surgery. Ophthalmology 1991;98:227–38. 2. Aaberg TM, Jr. Flynn HW Jr, Schiffman J, Newton J. Nosocomial acute-onset postoperative survey. A 10-year review of incidence and outcomes. Ophthalmology 1998;105:1004 –10. 3. Allen HF, Mangiaracine AB. Bacterial endophthalmitis after cataract extraction. II. Incidence in 36,000 consecutive operations with special reference to preoperative topical antibiotics. Arch Ophthalmol 1974;91:3–7. 4. Barza M. Use of quinolones for treatment of ear and eye infections. Eur J Clin Microbiol Infect Dis 1991;10:296 –303.

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17. Cystoid macular edema in aphakic and pseudophakic eyes. Am J Ophthalmol 1979;88:45– 8. 18. Rossetti L, Bujtar E, Castoldi D, et al. Effectiveness of diclofenac eyedrops in reducing inflammation and the incidence of cystoid macular edema after cataract surgery. J Cataract Refract Surg 1996;22 Suppl 1:794 –9. 19. Powe NR, Schein OD, Gieser SC, et al. Synthesis of the literature on visual acuity and complications following cataract extraction with intraocular lens implantation. Cataract Patient Outcome Research Team. Arch Ophthalmol 1994;112: 239 –52. 20. Peyman GA, Daun M. Prophylaxis of endophthalmitis. Ophthalmic Surg 1994;25:671– 4. 21. McDonald HR, Schatz H, Johnson RN, Madeira D. Acquired macular disease. In: Tasman W, Jaeger EA, eds. Duane’s Clinical Ophthalmology, rev. ed. Hagerstown, MD: Lippincott, Williams & Wilkins, 1998; v. 3, Chap. 23. 22. Gass JDM, Norton EWD. Cystoid macular edema and papilledema following cataract extraction. A fluorescein fundoscopic and angiographic study. Arch Ophthalmol 1966;76: 646 – 61. 23. Jampol LM, Sanders D, Kraft M. Ultraviolet light and pseudophakic cystoid macular edema. Invest Ophthalmol Vis Sci 1982(Suppl):129. 24. Tso MO, Shih CY. Experimental macular edema after lens extraction. Invest Ophthalmol Vis Sci 1977;16:381–92. 25. Pflugfelder SC, Hernandez E, Fliesler SJ, et al. Intravitreal vancomycin. Retinal toxicity, clearance, and interaction with gentamicin. Arch Ophthalmol 1987;105:831–7. 26. Borhani H, Peyman GA, Wafapoor H. Use of vancomycin in vitrectomy infusion solution and evaluation of retinal toxicity. Int Ophthalmol 1993;17:85– 8. 27. Results of the Endophthalmitis Vitrectomy Study. A randomized trial at immediate vitrectomy and of intravenous antibiotics for the treatment of postoperative bacterial endophthalmitis. Arch Ophthalmol 1995;113:1479 –96.