A review and discussion of the ESCRS endophthalmitis study

ByRandall J. Olson, MD

Intracameral injection of antibiotics as endophthalmitis prophylaxis in cataract surgery has been much discussed since the publication of a major study funded by the European Society of Cataract and Refractive Surgeons. That study concluded an intracameral injection of cefuroxime at the time of cataract surgery reduced the risk for developing endophthalmitis postoperatively. ¹

The results of this study, conducted with 13,698 patients in 24 centers across Europe, seem impressive due to the large-scale efforts of the researchers, but, to properly interpret these results, it is necessary to examine the study design.

The ESCRS Endophthalmitis Prophylaxis Study was a prospective, randomized, partially masked, placebo- controlled trial in which patients were randomly assigned to one of four groups: Groups received either a topical placebo and no intracameral antibiotic; intracameral cefuroxime 1 mg and topical placebo; perioperative topical levofloxacin 0.5% and no intracameral injection; or both intracameral cefuroxime and topical levofloxacin. Patients receiving topical levofloxacin or placebo received one drop at 1 hour and 30 minutes before surgery, and three drops at 5-minute intervals after surgery.

Patients in all groups were treated with topical povidone-iodine perioperatively and received topical levofloxacin beginning the day after surgery.

Because of a concern that opening the lid to apply antibiotics might cause wound leaks, the study design specified drops would be administered immediately following surgery, but no later on the day of surgery.

The group of patients receiving intracameral plus topical antibiotics had the lowest rate of postoperative endophthalmitis; the highest rate was seen in the control group that received neither (Figure 1).

The difference between the group receiving no antibiotics and the group receiving topical levofloxacin was not statistically significant, nor was the difference between the group receiving intracameral cefuroxime only and the group receiving intracameral cefuroxime plus levofloxacin. However, the difference in the rate of endophthalmitis between all patients receiving intracameral cefuroxime (0.073%) and all patients not receiving intracameral cefuroxime (0.335%) was statistically significant (P = .002). Patients not treated with intracameral cefuroxime had a nearly fivefold greater risk for developing endophthalmitis than those who received intracameral cefuroxime.

Figure 1
Postoperative endophthalmitis rates:
ESCRS study

In the ESCRS study, the group of patients receiving intracameral and topical antibiotics had the lowest rate of endophthalmitis.¹

Comparison to other studies

The incidence of endophthalmitis in patients who did not receive intracameral antibiotics was high in the ESCRS study compared to other recent studies (Figure 2).^1-3

In the ESCRS study, patients did not receive the topical antibiotic other than those administered immediately following surgery until the next day, approximately 18 to 24 hours after cataract surgery. In a retrospective study of endophthalmitis cases at the John A. Moran Eye Center by Wallin and colleagues,⁴ data indicate that starting topical antibiotics on the day after surgery rather than the day of surgery increased the risk for endophthalmitis significantly (odds ratio 13.7; P = .005).

The multivariate analysis indicates that starting an antibiotic on the first postoperative day was a significant risk factor for endophthalmitis. If contamination occurs at the time of surgery, then the time for antibiosis is in the immediate perioperative period.

In the Wallin study of topical antibiotic prophylaxis using a second-generation fluoroquinolone, the rate of endophthalmitis was similar to that in the ESCRS study with both intracameral and topical administration of the antibiotic. ^1,4 The difference between these studies may be due to the more aggressive use of topical antibiotics in the United States or to surgical technique.

More study is needed to adequately address the question of whether intracameral administration is more beneficial than aggressive use of topical antibiotics.

Figure 2
Postoperative endophthalmitis rates

Data from recent studies show lower incidence of endophthalmitis in patients who did not receive intracameral antibiotics vs. the rate shown in the ESCRS study.^1-3

Risks with intracameral administration

Before widespread adoption of intracameral antibiotic prophylaxis, the potential risks and benefits should be weighed. A decrease in the incidence of postoperative endophthalmitis is one benefit.

However, a risk of intracameral antibiotic administration is inducing toxic anterior segment syndrome (TASS) due to a lack of a commercially prepared antibiotic product. TASS can be caused by improper dosing or mixing of the intracameral antibiotic.⁵ Other risks include cystoid macular edema, which has been reported after cataract surgery with intracameral use of vancomycin.⁶ In addition, the aminoglycoside antibiotics have been reported to be toxic to the retina and should be used intracamerally with great caution.⁷

In addition to a composition error, concentration and osmolarity errors are also a possibility. No antibiotic is approved by the Food and Drug Administration specifically for intracameral use, so no ready-made formulation is available.

This risk also exists with the current practice of using the topical preparation of moxifloxacin for intracameral administration. The intravenous formulation of moxifloxacin would be more appropriate than the topical preparation. Contamination can occur from the bottle tip or the bottle itself. Medicolegally, complications that result from the use of these preparations can be difficult to defend.

Endophthalmitis caused by organisms resistant to current antibiotics is an increasing concern for ophthalmologists. In a recent evaluation of bacterial sensitivity to organisms isolated from the vitreous of individuals with postoperative endophthalmitis,⁸ the most frequently isolated organism was coagulase-negative Staphylococcus. Of four isolates tested, three (75%) were resistant to the current generation of ophthalmic fluoroquinolones. Five staphylococcal isolates out of seven (71%) tested were resistant to both current generation ophthalmic fluoroquinolones, moxifloxacin and gatifloxacin, with a minimum inhibitory concentration of 8 µg/mL or greater. All sensitivities were the same for the two current generation fluoroquinolones.

No evidence exists of a clear benefit for intracameral antibiotic use over appropriate topical current generation fluoroquinolone prophylaxis.
— Randall J. Olson, MD

Researchers note that endophthalmitis selects resistant organisms; results of a study by Deramo and colleagues indicate resistance is not high among all staphylococcal organisms.⁸ However, resistance to these antibiotic agents is occurring faster than anticipated, and past experience predicts that intermediate resistance will be followed by profound resistance.

In the future, intracameral antibiotic administration may be the only way to achieve levels as high as 8 µg/mL in the anterior chamber, or perhaps multiple antibiotics administered by different routes will be needed to defend against resistant organisms.

Conclusion

No evidence exists of a clear benefit for intracameral antibiotic use over appropriate topical current generation fluoroquinolone prophylaxis. With no commercially available product, TASS and contamination concerns with intracameral administration of antibiotics exist. More studies are needed to determine the best, most effective antibiotic prophylaxis, although to show statistically significant results, a large number of participants would be necessary. Intracameral antibiotics may be an important part of prophylaxis and may eventually become the standard of care, but these issues must be resolved before their use is widely adopted.

References

Barry P, Seal DV, Gettinby G, et al; ESCRS Endophthalmitis Study Group. ESCRS study of prophylaxis of postoperative endophthalmitis after cataract surgery: Preliminary report of principal results from a European multicenter study. J Cataract Refract Surg. 2006;32:407-410.
West ES, Behrens A, McDonnell PJ, et al. The incidence of endophthalmitis after cataract surgery among the U.S. Medicare population increased between 1994 and 2001. Ophthalmology. 2005;112:1388-1394.
Moshirfar M, Feiz V, Vitale AT, et al. Endophthalmitis after uncomplicated cataract surgery with the use of fourth-generation fluoroquinolones: A retrospective observational case series. Ophthalmology. 2007;114:686-691 (Epub ahead of print 2006 Dec 20).
Wallin T, Parker J, Jin Y, et al. Cohort study of 27 cases of endophthalmitis at a single institution. J Cataract Refract Surg. 2005;31:735-741.
Mamalis N, Edelhauser H, Hellinger W, et al. Toxic anterior segment syndrome (TASS) outbreak final report – September 22, 2006. Available at http://www.ascrs.org/press_releases/Final-TASS-Report.cfm. Last accessed April 10, 2007.
Axer-Siegel R, Stiebel-Kalish H, Rosenblatt I, et al. Cystoid macular edema after cataract surgery with intraocular vancomycin. Ophthalmology. 1999;106:1660-1664.
Campochiaro PA, Conway BP. Aminoglycoside toxicity – a survey of retinal specialists. Implications for ocular use. Arch Ophthalmol. 1991;109:946-950.
Deramo VA, Lai JC, Fastenberg DM, Udell IJ. Acute endophthalmitis in eyes treated prophylactically with gatifloxacin and moxifloxacin. Am J Ophthalmol. 2006;142:721-725.