An eye with endophthalmitis
Source: Andrzej Grzybowski, MD
Although evidence of the benefits of intracameral antibiotics continues to mount, some say additional steps are needed before widespread adoption occurs among U.S. surgeons
Research evidence of the anti-endophthalmitis benefits of intracameral antibiotics continues to accumulate, but questions continue over whether it is clearly time for U.S. cataract surgeons to move to the prophylactic, say observers.
“I think it is up to the individual surgeon to make a decision on whether or not they feel it is the time to start incorporating intracameral antibiotics,” said Nick Mamalis, MD, professor of ophthalmology, John Moran Eye Center, University of Utah, Salt Lake City.
Dr. Mamalis noted that the incidence of postoperative endophthalmitis in the first world has dropped markedly over the last 30 years to about one in 1,500 cases—even without intracameral antibiotics—due to the use of preoperative povidone iodine, a fourth-generation fluoroquinolone topically, proper wound construction, and intactness of the lens capsular bag at the completion of cataract surgery.
“Endophthalmitis has markedly decreased as our surgeries have gotten better, as our techniques have gotten better, as our sterile techniques have improved, and I do think using careful techniques, preop betadine on the eye, sealing the wound, and then immediate postop topical fourth-generation fluoroquinolones have been very efficacious in preventing endophthalmitis,” Dr. Mamalis said.
But in recent years a growing share of ophthalmologists have become convinced of the additional protective benefits of intracameral antibiotics.
“Intracameral antibiotics were viewed with skepticism when first introduced,” said Bonnie Henderson, MD, clinical professor of ophthalmology, Tufts University School of Medicine, Boston. “However, the body of evidence that it is effective and safe is so overwhelming that most physicians accept it as a viable method to prevent infection. The biggest obstacle for using intracameral antibiotics in the U.S. is not because of a question of its efficacy but rather the lack of availability of a U.S. [Food and Drug Administration] approved product.”
Widespread European use of a trial-tested formulation of cefuroxime (Aprokam, Thea Pharmaceuticals, Clermont-Ferrand, France)—about 75% of surgeons in ESCRS use intracameral antibiotics—demonstrated the appeal of such a treatment option.¹
In the 3 years since release of the ASCRS 2014 Intracameral Antibiotic Review and Position Paper,2 additional U.S. and international studies have been published that demonstrated intracameral antibiotics’ ability to reduce postop endophthalmitis, Dr. Mamalis noted.
The largest U.S. study was done by a Kaiser Permanente group using either cefuroxime or moxifloxacin and found a significantly decreased incidence of postop endophthalmitis and no association with increased postop adverse events.3 Another large study in India found a 0.02% endophthalmitis rate among 38,160 eyes of charity patients who received intracameral moxifloxacin prophylaxis, which was one-fourth the rate of the 37,777 eyes that did not receive intracameral moxifloxacin.4
“I believe there have been sufficient published reports in peer-reviewed journals to support the use intracameral antibiotics, even before there is a commercially available FDA-approved product,” Dr. Henderson said. “U.S. surgeons have the benefit of learning from the experience of our European colleagues. The high acceptance rate and proven efficacy in Europe substantiate the move toward intracameral antibiotics.”
Not everyone is convinced that a broad shift to intracameral antibiotics is prudent.
Andrzej Grzybowski, MD, professor and chair of ophthalmology, University of Warmia and Mazury, Olsztyn, Poland, said that among the unanswered questions about intracameral antibiotics are why some studies do not show a protective effect from them, why many studies show similar effects from topical antibiotics, and most importantly, which intracameral antibiotics should be used.
Dr. Grzybowski noted “there are many arguments against cefuroxime, vancomycin, and moxifloxacin.” He added that “none of them can be treated as ideal for IC prophylaxis.”
Dr. Mamalis noted that multiple studies published since the original ESCRS endophthalmitis study using cefuroxime have shown it is effective in preventing postop endophthalmitis. Cefuroxime has been approved by European regulators and is available for easy mixing for use in intracameral injections. However, Dr. Grzybowski noted that “MRS, penicillin-resistant Streptococcus pneumoniae, and Pseudomonas spp are resistant to cefuroxime” and the increase in endophthalmitic cases caused by resistant bacteria was reported in Europe.5
“Cefuroxime must be mixed by compounding pharmacies or mixed by the operating room staff for U.S. surgeons who wish to use it,” said Dr. Mamalis, who is chair of the ASCRS Toxic Anterior Segment Syndrome (TASS) Task Force.
Among surgeons who have used moxifloxacin, the greatest experience has been with Vigamox (moxifloxacin, Alcon, Fort Worth, Texas), which is preservative-free, and used for injection intracamerally at the conclusion of the surgery—either diluted 50-50 with balanced salt solution or undiluted.
“We’ve actually run into problems with TASS occurring in intracameral antibiotic when the antibiotic is mixed at an incorrect dosage,” Dr. Mamalis said. “When you are trying to mix, especially the cefuroxime, that’s a multistep procedure, and if that is done wrong in the operating room you can end up getting doses 10 times the recommended dose and that can cause toxicity.”
Toxicity problems also have stemmed from mistaken use by compounding pharmacies of non-preservative-free moxifloxacin for intracameral injections.
“So, the features that we are looking for is that the compounding pharmacy or whoever is mixing these is extremely accurate and that you get the proper dosage that you need to inject intracamerally,” Dr. Mamalis said.
Vancomycin has been used at several large surgery centers for 20 years, but recent evidence has emerged that it can be associated with postop hemorrhagic occlusive retinal vasculitis (HORV).
“Although this is extremely rare, this is a very serious, devastating condition and as a result, surgeons have had to reconsider in the use of intracameral vancomycin for the prevention of endophthalmitis,” Dr. Mamalis said.
The problems that have arisen from intracameral use of some antibiotics and concerns over increasing antibiotic resistance led Dr. Grzybowski to urge moving away from antibiotic-based endophthalmitis prophylaxis to antisepsis-based endophthalmitis prophylaxis—mostly with povidone–iodine (PVI).
“It was recently shown that PVI can be safely and effectively used in the treatment of keratitis and conjunctivitis,” Dr. Grzybowski said, adding that the recent European study by Freiberg et al. based on 134,701 intravitreal injections reported an exceptionally low rate of endophthalmitis (0.0074% per injection with no antibiotics and only PVI used in the peri-injection period).6
Dr. Grzybowski noted that in the U.S., intracameral antibiotics are given supplementary to topical antibiotics causing an increase in unnecessary consumption of antibiotics. Whereas, in many European countries, topical antibiotics are eliminated with the use of intracameral antibiotics.
Among the newer initiatives focused on intracameral antibiotic use is that of the ASCRS Research Council, which is putting together a large group of ophthalmologists and ophthalmic centers that can perform large-scale studies.
“And one of the first topics that this council is going to look into is trying to put together a large study to look at intracameral antibiotics with the idea that we would get enough patents in the study to show that there is a difference that would be significant enough to allow submission to the FDA for an eventual approval of intracameral antibiotics for prevention of endophthalmitis,” Dr. Mamalis said.
Pharmaceutical companies could use such research to seek FDA approval.
“And that would allow the manufacturer of single-use doses of intracameral antibiotics that surgeons can use in an approved manner directly from the company,” Dr. Mamalis said. “That’s going to be a big step going in that direction.”
ASCRS also is checking whether the FDA would consider data from previous studies, such as the ESCRS endophthalmitis study, as evidence of the efficacy of the antibiotics.
“The ASCRS is being proactive to try to set up the study, which will hopefully allow the approval of these agents to be used in the U.S. in a similar way to how they are used in Europe,” Dr. Mamalis said.
1. Barry P, et al. 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;32:407–10.
2. Braga-Mele R, et al. Intracameral antibiotics: Safety, efficacy, and preparation. http://www.ascrs.org/sites/default/files/resources/JCRS_December_2014.pdf
3. Shorstein NH, et al. Decreased postoperative endophthalmitis rate after institution of intracameral antibiotics in a Northern California eye department. J. Cataract Refract Surg. 2013;39:8–14.
4. Haripriya A, et al. Efficacy of intracameral moxifloxacin endophthalmitis prophylaxis at Aravind Eye Hospital. Ophthalmology. 2016; 123:302–8.
5. Grzybowski A, et al. Microbial flora and resistance in ophthalmology: A review. Graefe’s Archive for Clinical and Experimental Ophthalmology. 2017; DOI 10.1007/s00417-017-3608-y.
6. Freiberg FJ, et al. Low endophthalmitis rates after intravitreal anti-vascular endothelial growth factor injections in an operation room: A Retrospective Multicenter Study. Retina. 2017; ePub ahead of print.
Editors’ note: The surgeons interviewed for this article have no financial interests related to their comments.