To Inject or Not to Inject?

Antibiotic delivery method issues in cataract surgery.

BY RENÉ LUTHE, SENIOR ASSOCIATE EDITOR

Use of intracameral antibiotics in cataract surgery to head off infections, particularly endophthalmitis, has grown in recent years, especially since publication of the European Society of Cataract and Refractive Surgeons Endophthalmitis study in 2006. Proponents note the greatly reduced rates of infection in patients who have received antibiotics intracamerally. Infection after cataract surgery is probably the nightmare of every ophthalmic surgeon, notes Terrence O'Brien, MD, of Bascom Palmer's Ocular Microbiology Laboratory. And while endophthalmitis is a rare occurrence, "the pace of inflammation after infection can be so rapid that the eye can be destroyed in a matter of hours," he says.

Thus the results of studies like that of the ESCRS continue to receive a significant amount of attention. Some surgeons remain skeptical, however, noting the persistence of some unresolved issues, as well as the strengths of advanced-generation topical antibiotics available in the United States. Here are the insights of experts and a look at some recent research to help you evaluate your options for staving off endophthalmitis.

Strengthening Intracamerals' Hand

The ESCRS Endophthalmitis Study of 2006 created significant momentum for a shift from a topical delivery of antibiotics to intracameral delivery. The randomized study evaluated 15,971 patients from 23 clinics in nine European countries. Half of patients received 1 mg of intracameral cefuroxime in 0.10 ml of saline solution at the conclusion of surgery, and all patients received a randomized, masked dose of either intensive topical levofloxacin or placebo drops starting 60 minutes before surgery and ending 30 minutes after surgery was completed.¹

The researchers reported distinctly higher rates of endophthalmitis in the group that did not receive the antibiotic perioperatively: 33 per 10,000 patients for presumed cases of endophthalmitis and 23 per 10,000 for proven cases. In contrast, in the group that received intracameral cefuroxime, there were six cases of presumed endophthalmitis per 10,000 patients and four proven cases. Additionally, no patients who received cefuroxime injections had streptococcal infections.

In another 2006 study, Spanish researchers found decreased rates of endophthalmitis following cataract surgery at a hospital in the four years following the addition of a prophylactic 2.5 mg/0.1 ml intracameral bolus of cefazolin at the end of surgery.² A total of 18,579 cases were reviewed for endophthalmitis incidence. Rates of endophthalmitis were 0.047% after the introduction of intracameral cefazolin vs. 0.422% in the pre-cefazolin group.

A study presented at the American Society of Cataract and Refractive Surgeons' 2009 meeting examined the efficacy of prophylactic intracameral moxifloxacin 0.5% solution in 36 patients undergoing cataract surgery. Turkish researchers gave patients one drop of topical moxifloxacin every 15 minutes at least four times before surgery. As the last step in phacoemulsification, 0.1 ml intracameral moxifloxacin 0.5% ophthalmic solution was given to all eyes. After surgery, topical moxifloxacin was given on the day of surgery every two hours while the patient was awake. The dosage was then reduced to q.i.d. until the bottle was empty. There were no infections in any cases.

A poster presented at the 2009 Association for Research in Vision and Ophthalmology Meeting examined the risk factors for postop endophthalmitis in a national sample of Medicare patients and found that in the case-control study, controls were 1.4 times more likely to have received an intracameral antibiotic injection than the endophthalmitis cases (95%; CI: 0.9, 2.3).⁴

In Practice

Steve Arshinoff, MD, of the University of Toronto regards the cumulative weight of the multiple studies as very persuasive. He gives his cataract patients an injection of moxifloxacin, diluting it to 100 mg adding 4 ml BSS to 1 ml taken from the topical Vigamox bottle, and using 0.1 ml of this mixture for each case.

"There have been a number of studies, probably about six altogether. Each shows that pretty much whatever you use — Vigamox, vancomycin, cephalosporin — all resulted in about an 80% reduction in infection, no matter what your baseline rate is," he says.

The intracameral injections somewhat address the problem of leaky incisions, Dr. Arshinoff says, particularly when they are injected into the capsular bag. "It is a vascular, sequestered space and an ideal place for infections to originate. Inject the antibiotic there and you have a much better chance of not having any intraocular infections after surgery."

Dr. Arshinoff finds that surgeons who are reluctant to add intracamerals to their surgical routine typically convert once they experience infections in their patients. He observes that an infection can result from even a minor change in the operating room routine, such as using a different kind of knife than used previously. And then there's always the possibility of an infection resulting from patients who fail to comply with using their topical antibiotic drops once they return home after surgery.

"Not all patients do what we tell them," Dr. Arshinoff notes. "Or some people rub their eyes postop because they are not aware that incisions may leak under pressure. You're always going to have some people who don't come out the way you hope. A surgeon can go a long time and not have any problems, but we all will get problems sooner or later." Giving intracameral antibiotics decreases the risk, he says.

Further, he points out that the intracameral antibiotics are safe and well-tolerated in the eye. He prefers moxifloxacin because it comes in a bottle that is nonpreserved and easy to dilute, so preparation is not complicated.

Dr. Arshinoff believes that other cataract surgeons are increasingly seeing the advantages of intracameral antibiotics, saying that it is his impression that surgeons in his area are increasingly using them.

Eric Donnenfeld, MD, professor of ophthalmology at New York University, reports that he has used both topical and intracameral antibiotics in nearly all his cataract surgeries for the past five years. "I guess it's the 'belt and suspenders theory' of endophthalmitis prevention," he says, explaining that his goal is to simultaneously sterilize the ocular surface to prevent inoculation and have an antibiotic that penetrates into the eye to achieve significant levels of prophylaxis. "I want to give a very high level of antibiotic at the time of surgery — preferably one that's different from the one I've given topically, because there's no single antibiotic that covers all organisms." He achieves better coverage by using two different antibiotics. "And then I want to prevent late wound infections by giving antibiotics postoperatively as well."

Despite his support for intracameral antibiotics, Dr. Donnenfeld says he can understand why they have caught on with only a relatively small number of US cataract surgeons so far. "Approximately 30% of US ophthalmologists use them at the time of cataract surgery, while in Europe, it's much more common," he says.

Surgeons who stick with topical antibiotics are concerned about the possibility of an increased risk of toxicity, as well as the potential for concentration errors and the absence of an FDA-approved injectable antibiotic and the need to formulate it off label. Dr. Donnenfeld also notes that studies have shown that some intracameral antibiotics may increase the risk of cystoid macular edema or toxic anterior segment syndrome. "You have to weigh the risks and benefits and determine what you think is best for your patient," he says.

Should these obstacles one day be surmounted, Dr. Donnenfeld believes most ophthalmologists would quickly adopt intracamerals. "They would adopt it because two is better than one, and because it puts the antibiotic directly into the area at risk for developing endophthalmitis. You get better coverage and you get better concentration into the aqueous."

Dr. Arshinoff is also optimistic about the future of intracameral antibiotics. "Doctors say, 'Well, I don't get infections' — until they get some."

Not So Fast — Maybe

Intracameral antibiotics used prophylactically "could be one of those game-changers that we're always talking about," says Francis Mah, MD, co-medical director of the University of Pittsburgh's Ophthalmic Microbiology Laboratory. But while evidence of their efficacy is growing, he says that some important safety issues leave him reluctant to make the leap.

First, what is the optimal antibiotic to inject? In his view, no studies have yet answered that question.

"There's a lot of data on cefuroxime, and there's some growing information on cefazolin, another beta-lactam, and even fluoroquinolones like moxifloxacin," says Dr. Mah, "but I don't know that we can absolutely say that drug X, Y or Z is the best drug to inject — not only from an efficacy standpoint, but also from a safety standpoint."

The question of the appropriate mechanism for getting the drug from its container into the eye is another issue. "I think that's the big question: How do I do this in a sterile, repeatable, reproducible manner?" he says.

Precisely where to inject the drug is another issue. Dr. Mah notes that some studies added the antibiotic into the infusion fluid, while others have injected it behind the implanted lens or in the anterior chamber; in some peerreviewed case reports, it is injected around the capsular bag through the zonules. Which is best?

"To me," Dr Mah says, "putting the drug in the infusion fluid makes the least amount of sense because we don't even use the entire bottle of infusion fluid on a single phaco, so how much drug is actually getting into the eye? Do we really need to expose all of the tissues for that amount of time — however long it takes you to do phaco?"

Dr. Mah believes that the injection site that makes the most sense is in the capsule, either on top of the implant or behind it. The injection should probably occur at the conclusion of the surgery in order for the maximum amount of drug to remain in the eye as long as possible without dilution. As for injecting by going through the zonules and around the capsule, he concedes that it does make sense since the vitreous is the area to be protected, but mentions that it also features some significant potential for problems.

"If we were to try to distribute this technique to all the different surgeons across the world, I don't think they all would be able to do that repeatedly without causing some complications," Dr. Mah explains. "I think the method would have to be refined a bit in order to reproduce this safely, in all surgeons' hands."

The surgeons who are performing that technique are highly skilled, he points out, with long experience. "It works for them, but I don't know that it would be a safe method for everyone out there."

Unintended consequences over the long term are another concern. In the cases of Celebrex and Vioxx, Dr. Mah points out, no one foresaw that they would increase a patient's chances for heart attack and stroke.

"It took years and millions of patients with experience before we found that link. Similarly, there could be some complication that comes out of left field that we would have never thought of, for example macular degeneration or glaucoma being increased by using X, Y or Z drug intracamerally or at a certain concentration," he says.

Topical antibiotics used alone are vulnerable to the issue of patient noncompliance, but Dr. Mah says he has not found that to be a significant problem thus far. He instructs patients to arrive approximately two hours before surgery. A drop is administered every 15 minutes, for a total of four drops prior to surgery. At the conclusion of the surgery, he instills another drop before removing the speculum.

"I use a collagen shield at the conclusion of surgery; I have ever since my fellowship," Dr. Mah says. The shield is soaked in fortified cefazolin and decadron.

Dr. Mah uses a six-hour collagen shield, so it is nearly always melted away by the next morning. Then the patient uses a fluoroquinolone eyedrop, the same one that was used preoperatively. He instructs patients to use that every couple of hours after surgery while they're awake on the day of the surgery. If the eye looks good the next day, he decreases the dosage to three or four times a day.

Looking Twice at the Data

Dr. O'Brien points out that some of the evidence that has been extrapolated from trials into general recommendations on behalf of intracameral antibiotics might not be completely watertight. The ESCRS study, which he lauds as an ambitious, important undertaking, nevertheless had some design flaws that confound the conclusions and perpetuate lingering questions, he says. One of the most significant was that the topical antibiotic used was an earlier-generation fluroquinolone, rather than the fourth-generation 8-methoxyfluoroquinolones with greater potency and superior penetration that are used widely in the United States.

"Probably the biggest difference in postoperative practice was that the antibiotic eyedrops were not started until 24 hours after surgery in the ESCRS trial," Dr. O'Brien explains, "so the patient went home with the patch and shield over the eye and didn't even start the drops until one day later."

This, Dr. O'Brien says, may have been a reason why those eyes might have been at higher risk for infection. "It's hard to say whether it was just the intracameral injection alone in the eye, or the way the eyedrops were used or which eyedrops were used that accounted for the significant difference in reduction of endophthalmitis in the intracameral cefuroxime group and for the high overall rate of endophthalmitis observed in this study, including high rates of Streptococcal infection at particular centers."

However, Dr. O'Brien says that the ESCRS study did provide some compelling evidence that intracameral drug delivery during cataract surgery can have a very protective effect against endophthalmitis. The data have led him to use intracameral antibiotics for his high-risk cataract cases. Otherwise, he uses a combination of topical antiseptics and antibiotics both pre- and postoperatively.

"The key is starting the antibiotic prior to the surgery. We have the patient get four doses of an advanced-generation fluoroquinolone beginning about one hour prior to the surgery," Dr. O'Brien explains. He then uses an antiseptic povidoneiodine solution directly onto the eye immediately before beginning surgery; it is not rinsed away until it can exert a microbicidal effect.

At the conclusion of the surgery, the patient is given a pulse of advanced-generation fluoroquinolones. Upon returning home, the patient begins the drops almost immediately. They instill the fluoroquinolone six to eight times a day for the first 48 hours and then decrease dosing to four times a day for five days.

"It's a total of seven days postoperative dosing, but the first 48 hours, when there might be a window of opportunity for an infection, we dose more frequently: every two hours or so during that first vulnerable period where organisms might have gained entrance to the eye or there may be a higher risk for infection," Dr. O'Brien says.

For Those Still on the Fence

Edward J. Holland, MD, professor of ophthalmology at the University of Cincinnati and director of cornea service at the Cincinnati Eye Institute, has not yet incorporated intracameral drug delivery into his cataract surgeries, though he says the practice makes sense. Like Dr. Mah, he thinks the method of injecting the antibiotic into the eye requires some refinement to be trusted, among other things.

"But there's a prospective trial ongoing looking at putting moxifloxacin directly in the eye," he says. "If those data end up being quite strong, that might sway surgeons."

Unlike vancomycin, an antibiotic commonly used intracamerally, moxifloxacin does not have to be mixed before being injected into the eye. "It can be taken directly from the bottle and injected directly into the eye because it's preservative-free," Dr. Holland explains.

Still, he says, the penetration of the fourth-generation fluoroquinolone applied topically is so high that some surgeons question whether intracameral antibiotics are necessary. Thus far, the jury is still out. OM

References

1. ESCRS Endophthalmitis Study Group. Prophylaxis of postoperative endophthalmitis following cataract surgery: Results of the ESCRS multicentre study and identification of risk factors. J of Cataract Refract Surg. 2006;32:407-410.
2. Romero P, Mendez I, Salvat M, Fernandez J, Matias A. Intracameral cefazolin as prophylaxis against endophthalmitis in cataract surgery J of Cataract Refract Surg. 2006;32:438-441.
3. Arslan OS, Toker MI, Ozdamar A, Polat N, Arici C. Preliminary results of prophylactic intracameral moxifloxacin 0.5% ophthalmic solution in cataract surgery patients. American Society of Cataract and Refractive Surgeons Meeting 2009. San Francisco. April 3-7 2009.
4. Gower EW, Keay L, Cassard S, Tielsch J, Behrens A, Stare D, Schein O. Risk factors for Post-cataract surgery endophthalmitis among a nationally representative sample of Medicare patients. Poster presented at: Association for Research in Vision and Ophthalmology 2009 Meeting. Fort Lauderdale, Fla. May 3-7 2009.