Skepticism over use of intracameral antibiotic prophylaxis may be waning in US

Seven years after publication of the European Society of Cataract and Refractive Surgeons endophthalmitis study, intracameral antibiotic prophylaxis has gained wide acceptance in many countries as the most effective way to prevent postoperative endophthalmitis in cataract surgery. A fivefold reduction in the incidence of this complication was shown at the time, and since then, other large studies have been performed, leading to comparable results.

As reported in the recent ESCRS Guidelines for Prevention and Treatment of Endophthalmitis Following Cataract Surgery, “a striking drop from rates near 0.3% – 1.2% prior to the institution of intracameral cefuroxime, to rates of only 0.014% – 0.08% after institution of intracameral cefuroxime” was shown in areas of France, Spain and South Africa, as well as by the Swedish cataract registry, which now has 500,000 cases. A study in Singapore, conducted on 50,000 patients, showed a decrease from the previous already low rate of 0.06% to 0.01% with intracameral cefazolin.

The growing body of evidence is gradually reducing the initial skepticism of the U.S. ophthalmic community, and this manner of prophylaxis is beginning to be considered a potential and possibly better alternative to the popular regimen of topical fourth-generation fluoroquinolones.

American Academy of Ophthalmology Preferred Practice Patterns state that “there is mounting evidence that injecting intracameral antibiotics as a bolus at the conclusion of surgery is an efficacious method of endophthalmitis prophylaxis,” and a 2011 American Society of Cataract and Refractive Surgery Cataract Clinical Committee white paper on the subject acknowledged the evidence in support of the use of intracameral injection as well as perioperative topical use.

“Neither of the documents dictates a universal protocol,” David F. Chang, MD, OSN Cataract Surgery Board Member, said. “They appropriately leave room for individual physician judgment and decision making.”

As chairman of the ASCRS Cataract Clinical Committee, Chang was also involved in the survey published in 2007, in which, following disclosure of the ESCRS study results, more than two-thirds of U.S. respondents stated that they did not plan to start injecting intracameral antibiotics. Undemonstrated superiority of intracameral antibiotics over perioperative topical prophylaxis with latest-generation fluoroquinolones was one of the reasons, but the survey also revealed concerns over mixing errors and toxic anterior segment syndrome because of the lack of a commercially available intracameral formulation.

“In the 2007 ASCRS survey, 82% of respondents said that they would use such a product assuming reasonable cost. Following many additional studies published subsequently, the percentage would probably be even higher today,” Chang said.

Large study in U.S.

“A manufactured drug [for intracameral antibiotic prophylaxis] would have to go through FDA approval process, and this is a hurdle in this country at this point,” Neal H. Shorstein, MD, said.

Shorstein’s experience with intracameral antibiotic prophylaxis became the first large study in the U.S. on the topic and allowed comparison with ESCRS study results.

The study was started as a way to address the increased rate of endophthalmitis reported in 2007 at the Kaiser Permanente Walnut Creek Medical Center and included 16,264 cataract surgery patients operated between 2007 and 2011.

“Initially, we used intracameral cefuroxime as in the ESCRS study but excluded patients with allergy to penicillin and cephalosporins and patients with posterior capsule rupture. We managed in this way to cut our endophthalmitis rate by half,” Shorstein said.

The observation that two-thirds of the cases of endophthalmitis in this period were in eyes that had not received intracameral cefuroxime led to the decision of extending intracameral prophylaxis to all patients, substituting moxifloxacin or vancomycin as alternative options to overcome the problem of allergies and injecting even in cases of posterior capsule rupture.

“The subsequent endophthalmitis rate turned out to be 10 times lower — a significant drop, which induced us to use this protocol routinely. In 2007, we had one case in 300 cataract operations; now, we have 1 in 7,000,” Shorstein said.

“Evidence is overwhelming, but the lack of a manufactured product, and the potential risks of compounding the drug, still restrains ophthalmologists in the U.S. from a complete shift towards intracameral injection. The off-label use of intracameral agents isn’t itself a problem since every form of antibiotic prophylaxis, including topical, is, after all, off label here,” he said.

At Shorstein’s institution, extemporaneous compounding could be performed under the best safety conditions.

“We are an integrated system with a licensed compounding pharmacy that is a part of our surgical center, and our pharmacist, Ellen T. Nguyen, has a lot of experience in compounding,” he said. “Once she developed a protocol that conformed to U.S. Pharmacopeial Convention, it was relatively easy to put this into routine practice.”

The protocol was published as a short report in the Journal of Cataract and Refractive Surgery.

According to Peter Barry, FRCS, FRCOphth, FRCSI, ESCRS study chairman, Shorstein’s study is of particular relevance to American ophthalmology.

“Hopefully, this study represents the chink in the armor that will help open the door to intracameral prophylaxis in the U.S.,” he said.

Single-dose preparation

The European Medicines Agency recently approved Aprokam (Laboratoires Théa), a single-dose preparation of cefuroxime specifically designed for intracameral administration in Europe.

“Aprokam has given further impulse to the uptake of intracameral cefuroxime as prophylaxis. A recent survey conducted across Europe showed that 74% of surgeons now use intracameral antibiotics, and there is a steady growing trend,” Barry said.

Currently available in 17 countries, Aprokam should be introduced in at least five more this year.

Price variations, as well as various regulatory processes and reimbursement policies, account for different penetration rates of Aprokam across countries. In some cases, health policy regulations establish that whenever an approved product is available, it must be used over the non-approved product.

“The problem with Aprokam is that it turns out to be 20-fold more expensive than extemporaneous cefuroxime compounding,” Oliver Findl, MD, said.

He estimated that intracameral antibiotic prophylaxis is now used by approximately 80% of the surgeons in Austria, but the individual doses are mostly prepared by hospital pharmacies.

“Contamination is not my concern, since our pharmacies work under stringent sterile compounding rules,” he said.

In other countries, Aprokam has turned out to be more convenient than a compounding pharmacy.

“The cost in Ireland is €110 for a box of 10, which accounts for €11 per patient. In our university hospital, we have chemotherapeutic facilities, and cefuroxime is prepared in single doses once a week for all cataract patients under absolute sterile conditions. However, other hospitals find it is easier, safer and even cheaper to use Aprokam,” Barry said.

Antibiotics for intracameral prophylaxis

The use of other antibiotics for intracameral prophylaxis is described in the literature and considered as a preferred alternative to cefuroxime by some surgeons for various reasons.

Chang has used direct intracameral injection of vancomycin for 12 years and had no cases of bacterial endophthalmitis with phaco during this time.

“For many years, a common criticism of vancomycin was that it would clear the anterior chamber too quickly for the bacteriostatic drug to be effective. However, in 2007, a unique human pharmacokinetics study from Liverpool demonstrated surprisingly high and prolonged aqueous levels of vancomycin following intracameral injection at the conclusion of cataract surgery, likely exceeding most gram-positive [minimum inhibitory concentrations] for up to 30 hours,” he said.

Moxifloxacin, used directly from the 2.5 mL bottle of the topical preparation Vigamox (Alcon Laboratories), is becoming a popular choice in the U.S.

“I use moxifloxacin as Vigamox directly from the bottle; it requires no dilution, is isotonic, non-preserved and has a pH near neutral. As a result, in limited doses it is safe for the intraocular environment. I deliver 50 µL via a cannula through the paracentesis at the close of surgery after I have tested the incisions, at physiologic IOP, for a watertight seal. I have used it in this same fashion, originally as part of a multicenter safety study, for all intraocular surgery for nearly 8 years, and I have not witnessed any significant complications or side effects,” Samuel Masket, MD, said. However, he noted that there have been reports of systemic moxifloxacin inducing iris pigment dispersion.

In his opinion, the risks related to compounding by “kitchen pharmacies” represent significant concerns and are better avoided.

“A compounding error, most typically a dilution mistake, is potentially problematic as it can induce TASS and cause significant ocular damage,” Masket said.

A large study in Japan evaluated the results of 19 centers that switched to intracameral moxifloxacin. In more than 18,000 cataract cases, a threefold decrease in the rate of endophthalmitis was found.

“Moxifloxacin has been used previously in small studies with no more than 200 patients. The Japanese study is going to be a help to those that believe that moxifloxacin should be a preferred agent because it comes preservative free,” Barry said. “I personally would have anxiety that it is the commercial eye drop preparation that is being injected in the eye because the manufacturing standards for quality and sterility of agents for intrathecal use is a lot stricter than for topical drop use. I would be very reluctant to give an intravenous injection of moxifloxacin from a drop bottle.”

However, moxifloxacin might have a role in preventing infection with Enterococcus, which is a relatively more common cause of endophthalmitis in Japan compared with Europe and North America, he said.

Topical antibiotics

The use of topical antibiotics in addition to intracameral prophylaxis is a current controversy. Several reports quoted by the recently released ESCRS guidelines led to the conclusion that no clear benefit has been established. In addition, concerns have been raised by the steadily growing bacterial resistance to antibiotic agents, including fluoroquinolones.

Although no topical antibiotic is approved by the FDA for this use, the majority of ophthalmologists in the U.S. administer topical antibiotics as a stand-alone prophylaxis or in combination with intracameral agents.

“There may be about 35% of U.S. ophthalmologists who use intracameral agents, but typically not as monotherapy. Without doubt, roughly 90% of U.S. ophthalmologists employ topical antibiotics pre- and postop, even though the data have not established efficacy for this purpose. Some do so as common practice, and there are concerns about medicolegal ramifications should infection occur. But some also feel, as I do, that there is a place for topical as well as intracameral antibiotics,” Masket said.

Topical antibiotics reduce the surface flora, so there are fewer bacteria available for contamination at surgery. But, as Masket sees it, their most important role, even in combination with intracameral prophylaxis, is for protection over the first few days that follow surgery.

“Postoperatively the eye is still potentially subject to contamination until such time as the epithelium is sealed over the incisions, which may take 2 to 4 days,” Masket said.

Fourth-generation fluoroquinolones are still the most commonly used agents in the U.S., but several studies, including recent ones from Bascom Palmer Eye Institute, found specific high resistance to this class of antibiotics in isolates of bacteria from human endophthalmitis cases.

“These agents have likely lost much of their prophylactic benefit at standard doses,” Masket said. “There has been increasing use of alternatives such as Polytrim (Allergan), a combination of polymyxin B sulfate and trimethoprim.”

The issue of resistance is alarming, he said, but it is unlikely that ophthalmic use contributes significantly to the problem.

“Ophthalmology accounts for about 0.2% of the total antibiotic use in the world, which includes veterinary, agricultural, as well as human consumption,” he said.

Substantial evidence that postoperative topical antibiotic drops confer no added benefit over intracameral cefuroxime injection comes from the 2013 report of the Swedish National Cataract Register.

“Sweden has been on the forefront in the use of intracameral injection. In the last decade, they have scaled back their use of topical antibiotics significantly. Throughout the country, the use of topical is around 5% or less, and the endophthalmitis rate is extremely low,” Shorstein said.

His personal experience, with three surgeons only using intracameral injection in uncomplicated cataract surgery and a rate of infection that is very close to the Swedish experience, led him to conclude that “intracameral as a sole method of prophylaxis is probably sufficient.”

According to Findl, no additional antibiotics are required unless the patient presents with specific conditions. All that is needed in addition to intracameral prophylaxis is a strict antisepsis protocol, giving povidone-iodine a sufficient time of at least 5 minutes to be effective against infectious agents, he said.

The type and presence of resistant bacteria tend to vary in relation to specific areas and even times, and physicians should be alert to local bacterial susceptibility and resistance trends, Barry said.

Methicillin-resistant Staphylococcus aureus (MRSA) is a growing problem, he said.

“Patients considered at risk for MRSA, who were hospitalized in the 6 months previous to surgery or live in residential care, are mandatorily screened before they are allowed to come in for the cataract operation. If they are found positive, they are treated first and then rescreened. This still leaves us with the problem of community MRSA, where you don’t screen the population but have an anxiety that it might be there. It is a different problem depending on where you live, an issue that needs to be addressed,” he said.

Intravitreal injections

Prevention of endophthalmitis with intravitreal injections is a new challenge, and no uniform agreement exists among vitreoretinal surgeons, Barry said.

“There is very little data, an awful lot of confusion, no guidelines and huge variability in the way prevention is done,” he said. “Serious anxieties exist on the use of topical antibiotics, which, used routinely after injection, might select out and create the environment for the development of resistant bacteria, ready to invade the eye when the next injection is scheduled 1 month later.”

Large studies recently published in the literature found that the rate of endophthalmitis after intravitreal injections is low when topical povidone-iodine, a sterile eyelid speculum and topical anesthetic are used. In a total of 8,027 intravitreal injections from single-use vials administered across four DRCR.net randomized trials, seven cases of endophthalmitis occurred, six of which involved the use of topical antibiotics. In a study carried out by the Post-Injection Endophthalmitis Study Team on 117,171 intravitreal injections, topical antibiotic use was associated with a trend toward increased risk of suspected endophthalmitis. In a study carried out in Canada, nine cases of endophthalmitis were reported in 15,895 injections. The overall rate was greater with the use of topical antibiotics compared with no antibiotics. A Swiss study found three cases in 40,011 injections, yielding an incidence of 0.0075% per injection. Two of the three cases occurred in patients using post-injection antibiotics.

“The data in the literature clearly show that routine use of topical antibiotics only serves to promote the selection of antibiotic-resistant organisms. Most people I know do not advocate the routine use of antibiotics. Special consideration may be given for patients with significant ocular surface disease, where a course of pre-injection lid hygiene and topical antibiotics might be warranted,” David N. Zacks, MD, PhD, said.

His impression from the literature and conversations with colleagues is that most physicians in the U.S. are using Betadine prep (Purdue Products) and a lid speculum as a means to prevent infection. The use of sterile gloves and masks varies among practitioners.

“Cataract happens twice, once right and once left. But patients who receive intravitreal injections might receive 40 or more over a few years, and this definitely poses a hazard,” Findl said.

In his department, about 4,000 injections are performed per year in the OR with a strict disinfection and sterilization protocol. No antibiotics are used, but the infection rate is near zero.

“There have been infections in people receiving intravitreal injections, and in fact, I personally had to do surgery in patients who had mature cataract following infection with intravitreal. Most surgeons I know use antibiotics as well as povidone,” Masket said.

Consensus on a protocol for asepsis and antisepsis and an acceptable prophylactic regimen are necessary, Barry said.

“We are talking about an elderly, frail population, where numbers are now overwhelming and on the increase,” he said.

The joint forces of ESCRS and Euretina are currently planning a registry of cases. Based on the information collected, a study and a plan for the future will be designed.

“Infectious endophthalmitis after intravitreal injection, as most of us are currently performing them, is a very rare occurrence. I think the community has done an excellent job of making intravitreal injection a safe and accessible procedure for our patients,” Zacks said. “It is my impression that there is already a consensus in the community, but this would have to be explored more carefully through surveys and communication with practitioners.” – by Michela Cimberle