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Intraocular antibiotic prophylaxis in best interests of patients
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During my residency and fellowship training in the 1970s, the two most dreaded complications of cataract surgery were expulsive choroidal hemorrhage and endophthalmitis. In advanced countries, expulsive choroidal hemorrhage has been nearly eliminated as a blinding complication by phacoemulsification with its small self-sealing incision. The incidence of infectious endophthalmitis has been reduced from as many as one per 400 during my training to about one per 1,000 through the use of povidone-iodine antiseptic prophylaxis, careful draping of lids and lashes, and surgeon care in assuring a well-sealed incision, but there is still room for improvement in preventing this serious sight-threatening complication.
In the U.S., topical antibiotics are used nearly routinely, started a few hours to days before the surgery, given again in the operating room immediately after surgery and then continued for 1 or more weeks, depending on the surgeon. Unfortunately, data to support the use of topical antibiotics in an advanced country operating suite where povidone-iodine prep and good draping are utilized are lacking. Nonetheless, more than $500 million worth of off-label antibiotic drops (because the antibiotic drops utilized are only approved by the FDA for the treatment of bacterial conjunctivitis or keratitis) are prescribed each year in the U.S. and universally reimbursed by third-party payers, including CMS, for endophthalmitis prophylaxis.
If one examines the literature in other surgical specialties regarding antibiotic use for infection prophylaxis, the critical elements are a high concentration of a bactericidal antibiotic effective against the most likely infectious agents given perioperatively in the operating suite that reaches therapeutic concentrations in the target tissue or space. For ophthalmology, the infectious agents are primarily gram-positive staphylococcal and streptococcal species, many of which may express some level of methicillin resistance. The tissue or space is the anterior chamber and vitreous. The antibiotics most commonly selected for infectious prophylaxis in ophthalmology by those expert in the field include vancomycin, a so-called fourth-generation fluoroquinolone, cefuroxime or tobramycin, alone or in combination.
While reduction of surface pathogen load with preoperative antibiotic drops is of potential value, there is no good supporting literature for this approach, and the povidone-iodine antisepsis now routinely placed onto the ocular surface and into the conjunctival fornices puts the value of this approach in question.
The target perioperative area for the eye is intraocular contamination of the anterior chamber and vitreous with surface pathogens during surgery. This naturally led cataract surgeons to consider intraocular antibiotics at the time of surgery. Following the lead of Jim Gills, MD, and others, nearly 20 years ago I adopted vancomycin and tobramycin placed in the irrigating bottle and delivered during surgery. My clinical experience, and that from other surgeons, suggested this was an effective approach, but laboratory studies suggested that the antibiotic concentrations achieved were subtherapeutic. The next approach evaluated by pioneering surgeons was to inject antibiotics directly into the anterior chamber and later into the vitreous following the completion of surgery. Laboratory studies confirmed that an effective antibiotic concentration could be reached using this method. In addition, studies confirmed effective doses of the preferred antibiotics could be used safely without damaging the corneal or trabecular meshwork endothelium or retina. Fortunately, effective bactericidal concentrations of several antibiotic drugs were found to be safe according to laboratory and clinical studies. This led a significant number of the world’s ophthalmologists to adopt the clinical application of intraocular antibiotics for prophylaxis against infectious endophthalmitis.
In my opinion, the clinical evidence is now very convincing that intraocular antibiotics injected after the completion of cataract surgery are a superior method of reducing the risk of infectious endophthalmitis when compared with topical antibiotic drops. The early studies in the Scandinavian countries followed by the landmark ESCRS-sponsored clinical trial in Europe were so convincing that intracameral cefuroxime is now the standard of care in Europe. Topical antibiotics in the European trial were not shown to add any benefit, and for most European countries and surgeons, they have been eliminated from the regimen, saving European third-party payers hundreds of millions of dollars while simplifying the postoperative regimen for the patient and enhancing compliance with the still prescribed anti-inflammatory drop regimen.
Other large and convincing clinical trials with intraocular moxifloxacin, cefuroxime and/or vancomycin from India, the United States and Japan affirm at least a fourfold reduction in infectious endophthalmitis when an intraocular injection of an effective antibiotic in a safe concentration is placed into the eye after the completion of cataract surgery. Most surgeons in the U.S. who have adopted a non-FDA-approved off-label injection of antibiotic are utilizing moxifloxacin, vancomycin or a combination of the two. These injections are either derived from a high-quality compounding pharmacy or prepared by the surgeon or the nursing staff in the operating room.
After several years of preparing a moxifloxacin intracameral injection myself in the operating room, I am now a user of a compounded formulation of moxifloxacin and triamcinolone (TriMoxi, Imprimis) that I inject transzonularly into the vitreous. This approach is a topic for another extended commentary, and I will disclose that I am a consultant to this company. For me, efficacy and safety as well as patient compliance, convenience and satisfaction have driven the adoption of this approach, which also saves each patient and third-party payers significant money because the once-required topical antibiotic and steroid are no longer necessary. I have personally avoided the use of intraocular vancomycin after reports of a possible association with hemorrhagic occlusive retinal vasculitis, a potentially bilateral blinding complication. I still personally use a topical NSAID and, as appropriate, a topical lubricant.
Along with every other U.S. surgeon, I would love to have an FDA-approved intraocular antibiotic for endophthalmitis prophylaxis. ASCRS surveys confirm that this is a strong desire of its members and a major unmet need for American ophthalmology. So, why don’t we have one? Unfortunately, the cost to achieve FDA approval for an intraocular antibiotic in the U.S. would be expected to reach at least $100 million. With several large quality pharmaceutical companies in the U.S. and a market that currently represents 4 million cataracts a year, this is an easily overcome barrier except for one major “catch-22.” Our third-party reimbursement policies currently have bundled the cost of the intraocular antibiotic injection into the procedure fee and also made it illegal for the surgeon who uses an intraocular antibiotic injection for endophthalmitis prophylaxis to bill the patient directly. Sadly, in addition to penalizing the patient in need of an alternative to drops and reducing choice for U.S. ophthalmologists and their patients, this ruling by CMS has made it impossible for a pharmaceutical manufacturer to expect a return on the investment required to get an intraocular antibiotic FDA approved.
I personally believe that the intraocular antibiotic should not be considered a part of the standard cataract operation and bundled into the surgical fee. The classical steps of the cataract operation defined in every textbook do not include an intraocular antibiotic injection given after the completion of surgery as a standard part of the surgical procedure. The cataract operation is complete before the antibiotic injection is given. The surgeon can place one of the patient’s prescribed topical antibiotic drops on the eye, and this less effective method does have a reimbursement pathway, or inject an antibiotic into the eye. The intraocular injection, also done after the cataract surgery is complete, like the application of a topical drop, is simply a more effective approach that is also likely to cost less, saving the patient and system money.
Because this is to me a very important point, I will say it again. Antibiotic drops have always been reimbursed. They are not part of the surgical procedure and are not bundled into the surgical facility fee. They are used to prevent a postoperative complication. Alternatives for endophthalmitis prophylaxis applied after the cataract surgery is completed include topical drops, intraocular injections of antibiotics and in the future many other innovative therapies, including punctal plugs, conjunctival rings, extended-release deposits and the like. They are all alternatives to drops and are not part of the standard cataract surgery procedure. They are all applied after the standard cataract surgery is complete. In my opinion, they all should be reimbursed just like drops. This is a clear example of an innovation that is totally consistent with the so-called “triple aim” of our federal government: improved outcomes, high patient satisfaction and reduced cost. Unfortunately, one branch of government is calling for innovation while another is penalizing it.
I am hoping over time a pathway to FDA approval and third-party reimbursement for intraocular antibiotic prophylaxis against infectious endophthalmitis can be found. I am hoping that a coalition of likeminded surgeons and the organizations that represent them along with patient advocacy groups and perhaps some congressional support can help us find a pathway to a safe and effective FDA-approved CMS- and private insurance-reimbursed intraocular antibiotic for endophthalmitis prophylaxis. This effort is important, in the best interests of our patients, and deserving of every ophthalmologist’s support.
Disclosure: Lindstrom reports he is a consultant to Imprimis Pharmaceuticals.