Surgeons make their own rules for endophthalmitis prevention, treatment

For all the debates, panel discussions and published studies surrounding endophthalmitis infections, little is being done in the United States to uniformly track infection rates or develop specifically indicated medications.

David F. Chang, MD, is chair of the American Society of Cataract and Refractive Surgery Cataract Clinical Committee. Source: Chang DF

With the growing elderly population, the number of cataract surgeries performed yearly is expected to increase, and with it, the number of endophthalmitis cases will likely rise. Many ophthalmologists are waiting for answers regarding growing antibiotic resistance, the safety of intracameral prophylactic injections and the best standard of care for treating endophthalmitis. Meanwhile, individual clinicians proceed with the surgical techniques, prophylactic measures and treatment options that have worked for them in the past.

Although no national tracking system follows endophthalmitis, the overall rate of infection appears low, according to published studies and anecdotal information. But any clinician who has had even one patient develop endophthalmitis can speak to the devastating visual consequences.

Endophthalmitis rates after cataract surgery

In a study published in the April 2007 issue of Ophthalmology, Moshirfar and colleagues reported a rate of endophthalmitis after cataract surgery of 0.07%. The study looked at 20,013 patients who underwent surgery at one of nine centers and had received topical fluoroquinolones preoperatively and postoperatively.

Theodore Eickhoff

In 2007, the American Society of Cataract and Refractive Surgery Cataract Clinical Committee conducted an online survey of ASCRS members; the results were published by the committee and its chair, David F. Chang, MD, in the October 2007 issue of the Journal of Cataract and Refractive Surgery. According to Dr. Chang, a total of 1,312 members responded, of which 90% reported an infection rate of one or less than one case per every 1,000 cataract surgeries.

Francis S. Mah

Francis S. Mah, MD, put these numbers into perspective. “An extremely low rate of surgical site infections outside of ophthalmology is 1% or 2%,” he said. “We’re significantly lower than the 1% to 2% that is really good in general surgery.”

Theodore Eickhoff, MD, an infectious disease expert, agreed. “In experienced hands, bacterial endophthalmitis following ophthalmologic surgery is usually down under a tenth of a percent so you’re looking at something less than one in 1,000, and that’s pretty good,” he said.

The biggest concern

Endophthalmitis infections can develop after any intraocular procedure, including glaucoma surgery and intravitreal injections. As the number of intravitreal injections being performed has increased since anti-VEGFs became available, many calls for increased prophylactic vigilance have gone out.

At the 2007 American Society of Retina Specialists meeting, Andrew A. Moshfeghi, MD, reported a low rate of endophthalmitis after intravitreal injections among Bascom Palmer clinicians. As of April 1, 2008, approximately 25,000 injections performed since Jan. 1, 2005, had resulted in five culture-proven cases of endophthalmitis, or a rate of 0.02%.

The rate presented by Dr. Moshfeghi is similar to that published by Pilli and colleagues in the May issue of American Journal of Ophthalmology. Among 10,254 anti-VEGF infections performed over about a 2-year period, three cases of suspected endophthalmitis developed, all of which were culture-negative.

“We believe inoculation occurs at the time of the injection, so optimizing the injection protocol is important to minimize the risk of infection,” Dr. Moshfeghi said.

“With retina specialists who are very comfortable with this approach and are very cognizant of the risk performing these injections, I feel like, if anything, the rate will either stabilize or lower,” he said.

Therefore, anterior segment surgeons who perform cataract procedures may have the most reason to be concerned about endophthalmitis.

“There were 3 million cataracts done in the U.S. last year; it’s the most common surgery in the U.S. period, and as a result of that, even if you have an incidence that’s very low, much less than 1%, it still equates to many, many patients every year having a very devastating problem,” Uday Devgan, MD, FACS, said.

Outcomes

The severity of vision loss that endophthalmitis can cause is a major concern.

“Those rare patients that do get into trouble really don’t do well at all, and that’s why you hear about it because they can be devastating and often are devastating infections,” Dr. Eickhoff said.

“It’s one of the most severe complications we have of cataract surgery,” Dr. Devgan said, noting that as long as the infection goes unchecked, ocular structures can incur massive damage.

The effects can range from mild to total vision loss.

“It’s real and everybody’s scared of it because it is so terribly destructive,” Dr. Eickhoff said. “With a nasty bacterium like Staph aureus or Pseudomonas aeruginosa, it is, I think, unusual to have useful vision after, even if it’s cured.”

A range of surgical techniques

Still, no major action against endophthalmitis is currently under way. Endophthalmitis rates are difficult to quantify due to the wide variety of surgical techniques, prophylactic measures and treatments used. Most published rates today reflect the experience of a single ophthalmic surgery center or hospital, which can ensure procedural uniformity to avoid confounding variables.

Samuel Masket

“You talk to 10 different surgeons, and they’re all doing something a little bit different,” Dr. Mah said.

“Most of us are going to go based on our own personal experience,” Kerry D. Solomon, MD, said.

Regarding surgical preparation, Samuel Masket, MD, said that endophthalmitis prevention depends on reducing the number of microbes on the ocular surface and the opportunity those microbes have to enter the eye. Most ophthalmologists advocate adequate eyelash and eyelid draping and the use of povidone iodine prep.

Clear corneal vs. scleral tunnel

More controversial is the surgical technique employed.

In 2007, the European Society of Cataract and Refractive Surgeons Endophthalmitis Study Group reported the results of its multinational investigation into risk factors and prophylactic measures for post-cataract surgery endophthalmitis. The prospective study, published in the June 2007 issue of the Journal of Cataract and Refractive Surgery, included 16,603 patients from 24 centers in Austria, Belgium, Germany, Italy, Poland, Portugal, Spain, Turkey and the United Kingdom.

A total of 29 patients developed endophthalmitis; 20 cases were culture-proven. The investigators reported that patients who underwent cataract surgery with a clear corneal incision had a 5.88 times greater risk of developing endophthalmitis than patients who received a scleral tunnel incision.

Additionally, in a literature review published in the May 2005 issue of Archives of Ophthalmology, Taban and colleagues showed that endophthalmitis rates appeared to have increased over the previous decade. They said the increase may have been due to the use of clear corneal incisions, which were associated with a 0.189% rate of infection, compared with 0.074% for scleral incision surgery and 0.062% for limbal incision surgery.

“There’s a learning curve in how to make a well-sealing clear corneal incision,” Dr. Devgan said. “I think as we’ve gotten better at making our clear corneal incisions, we’ve become more vigilant about things.”

“What’s probably caused the differences between the rates of endophthalmitis between clear cornea and scleral tunnel is the fact that clear cornea incisions are not as forgiving,” Dr. Mah said.

Dr. Devgan recommended using a sterile fluorescein strip to test the integrity of incisions, while Dr. Solomon noted that smaller incisions can be more effective at reducing the gap of opportunity for microbes to enter the eye.

Tracking system

Without a more concrete standard of care for preparation and surgical measures, endophthalmitis rates remain unknown. Implementing a national tracking system does not appear to be on the radar of any of the major groups in ophthalmology.

Dr. Mah said that his group, the Charles T. Campbell Ophthalmic Microbiology Laboratory in Pittsburgh, approached the National Eye Institute about 5 years ago with the idea of establishing a systematic, nationwide ocular infection tracking system, which would start with endophthalmitis.

“Eye infections really are kind of like the stepchild in the [Centers for Disease Control and Prevention],” he said. “If you look at the CDC, they’ve got various specialties, but they really don’t have a dedicated eye specialty epidemiologist.”

Dr. Mah, who serves as medical director of the Campbell Laboratory, proposed a tracking system to be coordinated with similar labs across the country. The NEI estimated a $5 million infrastructure cost for such a program and suggested the group approach the Department of Defense or industry for financial backing.

“So that was kind of where we were stuck,” Dr. Mah said, although he remains supportive of the idea.

“I think this is a perfect time to look into some type of consortium or some type of group to prospectively follow endophthalmitis,” he said.

As director of the ASCRS Task Force on infectious disease, Dr. Mah said that the organization has no immediate plans to address endophthalmitis tracking. Dr. Masket, chair of the cataract panel of the American Academy of Ophthalmology’s Preferred Practice Patterns Committee, said the same of that organization.

“Cataract surgery and endophthalmitis are definitely very important to ASCRS and our committee, but there are other things that need to be looked at,” Dr. Mah said.

“ASCRS definitely does want to get involved and try to look at these issues,” he said.

Research made complicated

Not only is tracking made difficult by the differences in procedures, but studying and approving medications can also be problematic.

“The variables in surgical technique are huge, and therefore, unless you had a very consistent operation, particularly incision, there are just so many confounding factors in having a good study,” Dr. Masket said.

As a result, physicians continue to use a variety of treatments because no specific medication is indicated for the prevention or treatment of endophthalmitis.

Another problem is the low rate of infection seen in most study populations. “It’s good that we have low rates, but it makes for difficult study,” Dr. Masket said.

“FDA labeling requires demonstration of efficacy through well-designed clinical trials, typically placebo-controlled,” Dr. Chang said. “Because of the low incidence of endophthalmitis, sufficiently large, placebo-controlled trials are too expensive and difficult to conduct.”

Such a study would necessitate either industry backing or the support of a large national ophthalmic organization. Industry is going to want to see profit, which is problematic when most surgeons are already using the newer-generation topical fluoroquinolones produced by the nation’s largest ophthalmic product companies: Vigamox (moxifloxacin 0.5%, Alcon), Zymar (gatifloxacin 0.3%, Allergan) and Iquix (levofloxacin 1.5%, Vistakon).

“I don’t know if the companies see an appropriate market that’s available to them,” Dr. Devgan said.

Rising resistance

“To make it even worse, when we want to look at specific antibiotics, now we’re looking at moving targets because the microbes continue to change their sensitivity to different antibacterials,” Dr. Masket said. “So if we were to study an antibiotic today, in 3 years or even less, that information could be very much obsolete.”

At the forefront of growing concerns about resistance is methicillin-resistant Staphylococcus aureus (MRSA).

“The percent of patients who end up with an endophthalmitis from MRSA is much, much higher now than it was in years past, and it looks like it’s on an upward trend,” Dr. Devgan said.

Additionally, whereas MRSA used to be considered primarily a hospital-acquired infection, more cases are showing community origins.

Investigations

Even though MRSA resistance to antibiotics appears to be increasing, most surgeons continue to use the newer-generation topical fluoroquinolones off-label for cataract surgery prophylaxis. Thus, potential studies could investigate their efficacy because they have not been proven in a prospective study.

“There are no good studies available yet that demonstrate that the use of topical antibiotics in fact reduces the rates of infection,” Dr. Masket said. “However, we know that the use of topical antibiotics do reduce the available microorganisms on the ocular surface. The reason we have chosen to use the fluoroquinolones is low toxicity profile, comfort, ease of administration and good broad-spectrum coverage.”

Other physicians advocate studying formulations for intracameral injection.

“Intracameral [injections have] some attractive potential advantages by virtue of actually directly delivering the drug into the compartment that we would like,” Terrence P. O’Brien, MD, said. Topical medications have to cross the epithelium and stroma before getting into the aqueous humor, he noted.

For some, a combination of topical and intracameral fluoroquinolones may be the answer. “I think fluoroquinolones in general are very intriguing because if we’re dosing someone pre- and postop, the idea that you can have an intracameral dose of the same medicine is helpful and appealing,” Dr. Solomon said.

The ESCRS study

The ESCRS Endophthalmitis Study Group looked at one specific option for intracameral injection: cefuroxime. The study found that patients who had not received intracameral cefuroxime as a prophylactic had a 4.92 times greater chance of developing endophthalmitis after cataract surgery.

Despite the study’s size and scale, these results have not led to widespread use of intracameral cefuroxime in the United States. The major issue is that cefuroxime is not approved or packaged for use as an intracameral medication.

Dr. Chang said that some ASCRS members who responded to the 2007 online survey expressed concern about mixing antibiotic preparations for intracameral injection. “The possible risks of administering ‘homemade’ intracameral antibiotic mixtures were a significant concern to 45% of surgeons not currently using them,” Dr. Chang said.

“Many ophthalmologists are reluctant to ask their operating room nurses to mix solutions for direct intracameral injection,” Dr. Masket said. “There’s a legitimate concern that a dilutional error will either cause significant toxicity and damage to the eye or might expose the patient to [toxic anterior segment syndrome].”

“I think that trial raised maybe more questions than it answered,” Dr. O’Brien said. He noted that the rate of endophthalmitis among controls in the ESCRS study population was three to four times higher than the rates typically quoted in the United States and that certain variables, including incision type and additional pharmaceuticals used, were not controlled. Additionally, the study was halted at about half enrollment because the investigators felt their goals had been met.

Intracameral use in the U.S.

Still, the ASCRS survey showed that members are not completely opposed to the idea of using intracameral injections. “Eighty-two percent of respondents overall said that they would likely inject an intracameral antibiotic if it were commercially available at a reasonable cost,” Dr. Chang said.

“It certainly makes sense to place an antibiotic directly into the surgical site of potential infection, namely the anterior chamber at the conclusion of cataract surgery,” he said.

The question then becomes, which formulation would be best for intracameral injections?

Cefuroxime is a generic drug, which translates into low financial value for any potential industry backer.

Additionally, in a study published in the October 2007 issue of the Journal of Cataract and Refractive Surgery, Dr. O’Brien and colleagues conducted a review of available data on potential formulations for intracameral injections. Gram positive organisms carried a high rate of resistance to cefuroxime, and the drug can take 8 to 12 hours to kill bacteria.

Vancomycin is another possible candidate for intracameral use. It continues to show good activity against MRSA isolates, but again, it is a generic drug.

“There’s not much incentive for a company to get that generic and then do all the work behind it, get it FDA-approved as a label indication for intracameral use,” Dr. Devgan said.

The future

Intracameral prophylactic injections for endophthalmitis may not be approved any time in the near future.

“In my capacity of ASCRS president 2 years ago, I approached the FDA on the subject, and it was made very clear to me that unit doses for intracameral administration of antibiotics would not be approved until studies demonstrated their safety and efficacy,” Dr. Masket said.

“I would hope that we would be able to organize similar studies in this country testing intracameral agents with a design that could be accepted by the FDA so that the pharmaceutical manufacturers could provide unit doses of antibiotic to the ophthalmic surgeon,” he said.

But no plans appear to be in the works. ASCRS has no proposed studies, and Alcon officials told OSN that the company has no plans to pursue an intracameral formulation of moxifloxacin for use as a prophylactic.

Evan so, Dr. Mah believes that “eventually an intracameral antibiotic method will probably become standard.”

In the meantime, physicians will continue to use a patchwork of tried-and-true methods for prophylaxis and treatment. While some may not encounter a case of endophthalmitis, others who have seen a patient go from 20/40 vision before cataract surgery to no light perception after a post-surgical endophthalmitis infection will follow the debate with particular interest. – by Jessica Loughery

Considering the incidence of endophthalmitis after cataract surgery, what technique do you use and why?

References:

• Chang DF, Braga-Mele R, Mamalis N, et al; ASCRS Cataract Clinical Committee. Prophylaxis of postoperative endophthalmitis after cataract surgery: results of the 2007 ASCRS member survey. J Cataract Refract Surg. 2007;33(10):1801-1805.
• Endophthalmitis Study Group, European Society of Cataract and Refractive Surgeons. Prophylaxis of postoperative endophthalmitis following cataract surgery: results of the ESCRS multicenter study and identification of risk factors. J Cataract Refract Surg. 2007;33(6):978-988.
• Moshirfar M, Feiz V, Vitale AT, Wegelin JA, Basavanthappa S, Wolsey DH. Endophthalmitis after uncomplicated cataract surgery with the use of fourth-generation fluoroquinolones: a retrospective observational case series. Ophthalmology. 2007;114(4):686-691.
• O’Brien TP, Arshinoff SA, Mah FS. Perspectives on antibiotics for postoperative endophthalmitis prophylaxis: potential role of moxifloxacin. J Cataract Refract Surg. 2007;33(10):1790-1800.
• Pilli S, Kotsolis A, Spaide RF, et al. Endophthalmitis associated with intravitreal anti-vascular endothelial growth factor therapy injections in an office setting. Am J Ophthalmol. 2008;145(5):879-882.
• Taban M, Behrens A, Newcomb RL, et al. Acute endophthalmitis following cataract surgery: a systematic review of the literature. Arch Ophthalmol. 2005;123(5):613-620.

• David F. Chang, MD, can be reached at Altos Eye Physicians, 762 Altos Oaks Drive, Suite 1, Los Altos, CA 94024; 650-948-9123; e-mail: dceye@earthlink.net.
• Uday Devgan, MD, FACS, can be reached at Maloney Vision Institute, 19021 Wilshire Blvd. #900, Los Angeles, CA 90024; 310-208-3937; e-mail: devgan@ucla.edu.
• Theodore Eickhoff, MD, can be reached at Division of Infectious Diseases, University of Colorado Denver School of Medicine, 4200 E. 9th Ave., Denver, CO 80262; 303-315-3052; e-mail: theodore.eickhoff@uchsc.edu.
• Francis S. Mah, MD, can be reached at University of Pittsburgh Medical Center, Eye and Ear Institute, 203 Lothrop St., 8th Floor, Pittsburgh, PA 15213; 412-647-2200; e-mail: mahfs@upmc.edu.
• Samuel Masket, MD, can be reached at Advanced Vision Care, 2080 Century Park East, Suite 911, Century City, CA 90067; 310-229-1220; e-mail: avcweb@aol.com.
• Andrew A. Moshfeghi, MD, can be reached at Bascom Palmer Eye Institute, 7101 Fairway Drive, Palm Beach Gardens, FL 33418; 561-355-8608; e-mail: amoshfeghi@med.miami.edu.
• Terrence P. O’Brien, MD, can be reached at Bascom Palmer Eye Institute, 7101 Fairway Drive, Palm Beach Gardens, FL 33418; 561-515-1544; e-mail: tobrien@med.miami.edu.
• Kerry D. Solomon, MD, can be reached at Medical University of South Carolina, Storm Eye Institute, 167 Ashley Ave., Room 221, Charleston, SC 29425; 843-792-8854; e-mail: solomonk@musc.edu.