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