Looking back at the 2006

Intracameral cefuroxime: the debate continues

In this article, originally published in the Journal of Cataract & Refractive Surgery as a guest editorial, David F Chang MD, reflects on the impact of the landmark ESCRS intracameral cefuroxime trial

Published 15 years ago in March 2006, the landmark ESCRS intracameral (IC) cefuroxime trial remains the single most important study of antibiotic prophylaxis for ophthalmic surgery. Encouraged by Swedish national registry studies suggesting the efficacy of IC cefuroxime prophylaxis, ESCRS undertook the bold challenge of conducting a multi-centre, prospective randomised clinical trial. The study objective was to determine whether perioperative antibiotics prevent endophthalmitis and, if so, whether they should be administered topically or through IC injection. The audacious goal was to enrol up to 35,000 cataract surgical patients to demonstrate statistical efficacy of either topical fluoroquinolone or IC cefuroxime. Patients were randomised to one of four treatment groups. The four groups received placebo drops only, topical levofloxacin, IC injection of 1mg cefuroxime and a combination of topical levofloxacin plus IC cefuroxime.

From September 2003 to January 2006, approximately 16,000 patients had been enrolled at 24 sites in nine European countries. When an interim analysis showed clear superiority of one treatment group, the data-monitoring committee recommended unmasking of the study. This revealed such a clear benefit to IC cefuroxime that study recruitment was ended, and the decision was made to publish a preliminary report as quickly as possible. The full study analysis was published one year later and demonstrated a nearly five-fold reduction in the

endophthalmitis rate with IC cefuroxime. that did not plan on adopting routine Publication and announcement of the IC antibiotic prophylaxis was concerned preliminary findings was a significant and about the risk for mixing solutions (45%) thought-provoking event in ophthalmology. and felt that more study was needed In 2006, topical antibiotic prophylaxis was (89%). However, if a reasonably priced the community standard in North America IC antibiotic were to be commercially and Europe. However, a small percentage approved, then 82% were likely to use it. of surgeons were combining intraocular These survey results seemed to indicate antibiotic administration, either by that absent an approved intraocular direct IC injection or adding the product, most surgeons were antibiotic to the irrigating bottle. not convinced of enough For these surgeons, the ESCRS benefit to offset the risks for study offered validation of mixing or compounding their approach. Others were antibiotic solutions. emboldened to adopt IC In 2012, based largely antibiotic prophylaxis based on on the ESCRS study, the study results. However, most the European Medicines believed that study weaknesses and Agency (EMA) approved the lack of a commercially approved David F Chang MD Aprokam (Laboratoires Théa), intraocular antibiotic argued against the first premixed IC cefuroxime adopting this practice routinely. formulation for endophthalmitis To better understand the immediate prophylaxis. Aprokam soon became impact and implications of the ESCRS available in many European countries study, the ASCRS Cataract Clinical and was effectively endorsed by ESCRS in Committee surveyed the global their 2013 Guidelines for Prevention and membership of ASCRS in January 2007. Treatment of Endophthalmitis. In a small This was nine months after publication ESCRS survey, 74% of 193 respondents of the preliminary findings but six reported regularly using IC antibiotics, months prior to publication of the full and its adoption generally reflected study analysis. Of the more than 1,300 whether a commercial formulation respondents, 30% were using intraocular was available to them or not. Several antibiotic prophylaxis. Half of them large retrospective studies subsequently directly injected the antibiotic, and half reported reduced endophthalmitis rates placed the antibiotic in the irrigation after adoption of IC cefuroxime, adding bottle. Vancomycin was preferred by 60% further support to the 2006 ESCRS study of these surgeons and a cephalosporin by conclusions. This included the first 23%. Sixteen percent of surgeons were large retrospective study of IC antibiotic already injecting IC antibiotic prior to the prophylaxis in the United States. ESCRS study, and 7% started or planned When the ASCRS member survey was to do so because of the study. The 77% repeated in 2014, a substantial shift in opinion and practice pattern was revealed according to the 1,147 respondents. The percentage of surgeons using IC Publication and announcement of the antibiotic prophylaxis increased from 30% to 50%, and most were now using preliminary findings was a significant direct IC injection compared with placing and thought-provoking event in antibiotic in the irrigating solution (84% vs 16% in 2014; 52% vs 48% in 2007). ophthalmology Antibiotic preference was evenly divided between moxifloxacin (33%), cefuroxime David F Chang MD EUROTIMES | APRIL 2021

(26%) and vancomycin (37%); however, vancomycin (52%) was still the leading preference in the United States. Most (75%) believed that it was important to have an approved commercial formulation for IC injection (up from 54% in 2007), and this would increase adoption of IC antibiotic to nearly 84%. Risks for non-commercially prepared solutions were a concern for half of those not using IC antibiotic.

The question of which IC antibiotic is preferable for endophthalmitis prophylaxis was not addressed by the ESCRS study. Large retrospective studies from the Aravind Eye Care System have provided strong support for the safety and efficacy of IC moxifloxacin prophylaxis using a preparation that is commercially available in India. Meanwhile, the emergence of haemorrhagic occlusive retinal vasculitis associated with vancomycin has caused a precipitous decline in its use worldwide.

In the ESCRS trial, the 0.25% endophthalmitis rate in patients receiving topical levofloxacin alone was unusually high compared with historical benchmarks. This and concerns that the trial was terminated prematurely were the most significant criticisms of the study. Largely for these reasons, the ESCRS study does not qualify as a valid efficacy study for the US Food and Drug Administration (FDA). A manufacturer would, therefore, need to conduct a new prospective randomised trial to obtain FDA approval. Until then, surgeons with endophthalmitis rates much lower than 0.25% while using topical prophylaxis alone are left to ponder whether adding an IC antibiotic would be significantly better. Would the risk for toxicity from mixing or compounding errors outweigh the small, theoretical benefit?

Although the ESCRS study did enable EMA approval of an affordable commercial product, it fell short of leading

The question of which IC antibiotic is preferable for endophthalmitis prophylaxis was not addressed by the ESCRS study

David F Chang MD to the US FDA approval of intraocular cefuroxime. With inconsistent global availability of commercial intraocular antibiotics, the ESCRS study also failed to establish a definitive standard of care for antibiotic prophylaxis. However, thanks to multiple big data and registry studies, the preponderance of evidence now supports the original conclusions from this groundbreaking study. That no other prospective, randomised trial of this size or quality has since been conducted speaks to the foresight, audacity, and determination of the ESCRS study organisers under Peter Barry’s leadership. In a review and analysis of the published literature, the 2017 Cochrane review concluded that the ESCRS study “provides the best evidence for antibiotic prophylaxis against postcataract surgery endophthalmitis”. It was the only study to be rated “moderate to high-certainty evidence”. For this reason, the 2006 ESCRS clinical trial continues to rank as one of the most important and influential studies of the past two decades in cataract surgery. This article originally appeared in the Journal of Cataract & Refractive Surgery: February 2021 - Volume 47 - Issue 2 - p 150-152 and is reprinted with the permission of the author

References on request.

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