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Cataract Controversy

By Miriam Karmel

Is the incidence on the rise?
What’s the best antibiotic to use?
What about prophylaxis?

Cataract surgeons are struggling with too many questions—and not enough answers.

Endophthalmitis following cataract surgery may be on the rise. Or, it may not be. Nobody knows for sure. What is known is that endophthalmitis is a blinding, devastating condition. Outside of that, everything from its cause to its prevention is subject for debate.  

Holes in the Evidence
The dispute was rekindled this past year, with the introduction of a new generation of fluoroquinolones and a meta-analysis of the literature. “It truly is an unsettled area,” said Peter J. McDonnell, MD.

It is unsettled due to what might be called the only good thing about endophthalmitis: The condition is rare, with an incidence historically of 1 in 1,000 or less. Given the 2.8 million cataract surgeries in the United States, there are perhaps only 2,800 new cases per year, a number far too small to conduct the kind of randomized, prospective clinical studies that might put some of the controversy to rest.  

In the absence of such studies, prevention and treatment strategies have been based on clinical impressions and personal experience. But Dr. McDonnell argues that we need to get beyond that. “This is our most common surgical procedure and it looks like there is a growing body of evidence indicating that endophthalmitis may be on the increase, particularly over the last decade.” Dr. McDonnell, who hopes to get funding to conduct a major study, added, “Out of fairness to our profession and our patients, we need to do our best to answer this one way or another.”

Until then, noted David F. Chang, MD, “Without definitive randomized studies, we’re left with using our best judgment in the area of infection prophylaxis.”

Samuel Masket, MD, agrees. “The evidence-based literature may not reflect the best methods for endophthalmitis prophylaxis because studying endophthalmitis is difficult and the appropriate studies have not been performed. So unfortunately, looking at the literature is not always the best way for finding the best methods.”

Even the question of incidence is up in the air. “There are certainly publications that suggest endophthalmitis is on the rise,” said Dr. McDonnell, who was part of the meta-analysis team, which reviewed the literature to determine the incidence of acute endophthalmitis following cataract surgery and penetrating keratoplasty.1 “I happen to believe that it is on the rise,” he said. “But I don’t think there is consensus.”

If it is on the upswing, said Dr. McDonnell, “We’d better figure out how to deal with that. Because if the risk is increased by two to three times, I think most ophthalmologists would say it truly does represent a public health problem of very significant dimension.”

What follows is a look at some of the controversy surrounding endophthalmitis.

Clear Corneal Surgery
Clear corneal cataract extraction is often blamed for the perceived rise in endophthalmitis. The procedure, introduced in the early 1990s, has many advantages, Dr. McDonnell said. It is efficient to perform, cost-effective and allows for rapid visual rehabilitation.

But recent studies, reported in the American Journal of Ophthalmology2 and the Canadian Journal of Ophthalmology,3 found a threefold and a 2.5-fold increased risk of infection with clear corneal incisions, respectively.

The meta-analysis corroborates the risk factor. After examining some 7,000 citations and studies that mentioned endophthalmitis, Dr. McDonnell and his colleagues found some correlation between clear corneal surgery and a higher incidence of endophthalmitis. The literature shows that since the 1990s, the incidence of endophthalmitis following clear corneal surgery was 0.2074 percent, compared with 0.0826 percent for scleral/limbal incisions.

Not everyone, however, accepts the notion that the sutureless surgery leads to more infection. Some attribute the rise to the learning curve, arguing that the numbers are an artifact, reflecting nothing more than the complications that arise as doctors learn a new procedure. When sutureless incisions were introduced, said Dr. Masket, “there was a blip on the screen, an increased number of infections. People had adapted it to their armamentarium, but had not learned the procedure.”

While the retrospective studies suggest a correlation, ophthalmologists must not jump to conclusions that incriminate all clear corneal incisions, Dr. Chang said. As a group, the incisions can vary significantly in terms of size, location and architecture, he noted. Some are less than 3 millimeters wide, while others are wider than 4 mm. “In the cornea, that’s a big difference.” Also, some have greater radial length than others. Some are temporal, and some are superior in location. Some surgeons make a groove, while others do not. Some use diamond blades; others use metal. “Clearly, these incisions are not all equal in terms of the risk of transient leak.”

As Dr. Masket, who has been performing clear corneal surgery exclusively since 1993, put it, “I don’t think that you can condemn the technique. It’s more the technician.” The creation of the incision involves finesse, he said. “If one doesn’t pay attention, it can be associated with a greater likelihood of infection.”

Both Drs. Chang and Masket argue that the technique demands that surgeons pay attention to size and architecture of the incision, because the cornea is less forgiving than the sclera. “The absence of a conjunctival barrier makes the construction of a corneal incision much more important,” Dr. Masket said.

Both caution against making an incision larger than 3.5 mm, because it won’t seal as well, and the larger the incision, the less watertight it’s going to be. Leakage in the early postoperative period could allow organisms to enter the eye. “With any incision, whether it’s corneal or scleral, make sure it’s well apposed and watertight at the end of the case,” Dr. Chang said. “If it’s not, you could put in a suture and reinforce it.”

A study conducted by Dr. McDonnell and his colleagues and published in Ophthalmology4 lends support to suturing. In the study, self-sealing clear corneal incisions were created in rabbit eyes. Then, using an artificial anterior chamber, India ink was applied to the surface of cadaveric human corneas with clear corneal incisions to detect possible flow of surface fluid along the incision. Because this study did not involve in vivo human eyes, the authors did not feel confident making any firm clinical recommendations, Dr. McDonnell said. “We simply suggested that this may, if confirmed in patients, cause surgeons to reconsider use of a stitch or how they use antibiotics postoperatively.”

“The real message,” said Dr. Chang, “is not that clear corneal incisions are inherently risky, but rather that there’s less margin for error. They must be properly sized and constructed.”

Antibiotic Selection and Prophylaxis
Although the FDA has not approved topical antibiotics for surgical prophylaxis to prevent endophthalmitis, and will not allow them to be marketed as such, they are widely used in this way. Despite the absence of any scientific study to say that this practice is effective, physicians administer antibiotic drops pre- and postoperatively to eradicate any conjunctival contamination.

“All cataract surgeons I know use them,” Dr. McDonnell said. “It’s the standard of care in our profession.”

That doesn’t mean their use isn’t controversial. While some lab studies have found antibiotics protective of endophthalmitis in rabbit models, there are no human studies, Dr. Masket noted. “Therein lies the controversy.”

Then there’s the matter of which antibiotic to use. Last year, a fourth generation of fluoroquinolones was introduced, raising the questions of which generation of quinolone to use and whether the newer, more expensive drugs are necessary. Without the proper studies to say that they are necessary or even effective, how do physicians know whether moxifloxacin (Vigamox) and gatifloxacin (Zymar) should become part of their armamentarium?

Deepinder K. Dhaliwal, MD, and her colleagues at the University of Pittsburgh tested moxifloxacin and found that topical application was able to effectively eradicate bacteria in the anterior chamber of rabbits. In a study funded by Alcon, 10 rabbits were injected with bacteria into the anterior chamber and treated with the antibiotic pre- and postinjection, and 10 were injected with bacteria and received placebo drops. None of the moxifloxacin-treated rabbits developed infection; all of the placebo rabbits did. “This is the first study to show that topical application of antibiotic drops could prevent the development of endophthalmitis. The difference in appearance of the eyes in the two groups was very dramatic,” Dr. Dhaliwal said.

So dramatic, in fact, that the decision to switch from second- and third-generation fluoroquinolones to the fourth-generation options is “an obvious choice,” she said. “These antibiotics penetrate better. They’re more potent. Moxifloxacin is preservative free, so surface toxicity should be minimal.”

What’s more, the second- and third-generation drugs, though effective against gram-negative germs, don’t provide the necessary coverage against the predominantly gram-positive strains that cause endophthalmitis.

Another issue is the increase in resistance to the earlier fluoroquinolones. “If we continue to use these less-powerful antibiotics, we’re going to have more organisms that become resistant,” Dr. Dhaliwal said.

The ability of the newer antibiotics to penetrate into the anterior chamber is “something that we have never seen with any ocular topical antibiotic,” Dr. Dhaliwal said. “We need to get the antibiotics to where the bacteria are. The bacteria are in the eye. That’s why intraocular penetration is so critical.”

While she believes there’s no reason not to use the fourth-generation drugs, Dr. Dhaliwal acknowledges that in the absence of a convincing prospective study, some doctors may not want to switch. Cost may be one deterrent, especially as the second-generation fluoroquinolones become available in generic form. What’s more, physicians who have not seen a case of endophthalmitis in 1,000 cases might not see a reason to change a practice pattern when the drug they’ve been prescribing has worked.

Intraoperative Antibiotics 
Another unsettled question is whether to apply antibiotics during surgery and, if so, by what route. And those who do use intracameral antibiotics at the end of a case are divided between those who infuse and those who inject directly into the anterior chamber. Again, there have yet to be well-designed studies to indicate that such use of antibiotics—typically vancomycin (Vancocin)—prevents infection.

Survey results suggest that around 40 percent of physicians use antibiotics at the end of a case, although the CDC, the Academy and academic medical centers have taken a position against prophylactic use of vancomycin, arguing that its systematic use has led to microbial resistance. But Dr. Masket asserts that using it in the eye, in an outpatient setting, is different and “has no likelihood whatsoever of contributing to the problem.”

Whether it contributes to the resistance problem or not, Eric D. Donnenfeld, MD, said that vancomycin is associated with other problems. It can be toxic, and it has been associated with the development of cystoid macular edema. It doesn’t provide gram-negative coverage, and has a very slow kill curve so that the drug drains out of the eye through the trabecular meshwork before it has a chance to be effective.

In a search of a better treatment, Dr. Donnenfeld has been conducting a prospective study of intracameral gatifloxacin injected directly into the anterior chamber at the conclusion of surgery. Injection of gatifloxacin (100 micrograms in 0.1 cc) achieves a 50 times higher level of protection in the aqueous than does topical application, he said. What’s more, treatment may be supplemented with topical gatifloxacin, unlike with vancomycin, which has no topical equivalent.

Although Dr. Donnenfeld uses this treatment in his own practice, he said that for safety reasons he prefers waiting for more data—expected by early summer—before advocating this treatment.

______________________________
1 Taban, M. et al. Presented at the Academy’s Annual Meeting, Nov. 18, 2003, Anaheim, Calif.
2 Cooper, B. A. et al. Am J Ophthalmol 2003:136(2):200–305.
3 Colleaux, K. M. and W. K. Hamilton. Can J Ophthalmol 2000;35:373–378.
4 Ophthalmology 2003;110(12):2342–2348.

______________________________
Points of Discussion

Proper Draping
Dr. Masket: “[Proper draping] is of utmost importance. It prevents microbes on the patient’s lids, lashes and lid margins from getting into the eye and potentiating infection. If that is the source of infection, it behooves us to prevent contamination by isolating lashes and lid margins as well as possible.

“I fashion the drape to curl under the lid margin. And I isolate the ocular margin as much as possible from the lids. Both the lid margins and drape are covered with steristrips. I always double glove and remove the first set of gloves after applying the steristrips, because those gloves may have touched the skin during application.”

The Incision
Dr. Masket: “The architecture must be nearly square in its surface anatomy. The incision must never exceed 3.2 mm in width and the length of the tunnel should be at least 2.5 mm. A 3-mm by 2.5-mm incision is going to be physically very stable, and will not be subjected to deformation by external pressure.

“Do not assume that a smaller incision is a better incision. If it’s too small, the emulsification equipment or the lens can stretch and distort the tissue. A well-constructed 3-mm incision is far better than a stretched 2.5-mm incision.

“It is important to avoid hypotony. If the pressure is low, the incision won’t seal and it will leak. I test IOP with an applanating tonometer [Kratz-Terry, made by Ocular Instruments of Bellevue, Wash.], and perform an intraoperative Seidel test on all incisions. I routinely perform stromal hydration, including the roof of the tunnel, in addition to the sides. If the wound leaks, I rehydrate. If there is leakage after a second Seidel test, I add a suture.”

Which Antibiotic?
Dr. Chang:
“It makes sense to use the fourth-generation fluoroquinolones, moxifloxacin and gatifloxacin. I’m using them. There is less bacterial resistance, good penetration and broad spectrum of activity.”

Dr. Dhaliwal: “I start antibiotic prophylaxis an hour before the case [every 15 minutes for four doses], instill a drop immediately after the surgery, and then four times a day for a week.”

Dr. Masket: “I start them the day before surgery, four times a day, and continue for five days after surgery. Postsurgery every two hours, then four times a day for another five days.”

Administration of the Antibiotic
Dr. Chang:
“If you’ve made a decision that you want to administer some antibiotic at the time of surgery, what makes the most sense to me is to inject it directly into the eye. You know the exact dose that reaches the anterior chamber. With addition to the infusion bottle, you can’t be sure how much is actually getting into the eye at the end of the case.”

Dr. Masket: “I put 20 mg of vancomycin in 500 cc of balanced salt solution. My sense is that injection at the end of surgery is likely to be more efficacious, but I operate in more than one location, and I have concerns that there could be a dilutional error. Because I have to rely on someone else to dilute it, putting 1 mg in 0.1 cc directly into the chamber takes a greater leap of faith [for me].” 

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Meet the Experts

David F. Chang, MD  Clinical professor of ophthalmology at the University of California, San Francisco. Financial interests: None.

Deepinder K. Dhaliwal, MD Director of refractive surgery, director of cornea and external disease and associate professor of ophthalmology at the University of Pittsburgh. Financial interests: Serves on the speakers’ bureau of Alcon.

Eric D. Donnenfeld, MD Cochairman of external disease and cornea at Manhattan Eye Ear and Throat Hospital and in private practice in New York. Financial interests: Is a consultant for Allergan and Alcon.

Samuel Masket, MD In private practice in Los Angeles and clinical professor of ophthalmology at the University of California, Los Angeles. Financial interests: No related interests.

Peter J. McDonnell, MD  Professor of ophthalmology and director of the Wilmer Ophthalmological Institute. Financial interests: No related interests.

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