Symposium: New Trends in Pharmacotherapeutics: Maximizing Surgical Outcomes

Incidence of postoperative infection

Richard L. Lindstrom, MD: Fluoroquinolones are valuable weapons in an ophthalmologist’s pharmaceutical armamentarium. What are your thoughts on the incidence of infection following anterior segment surgery?

Samuel Masket, MD: Recently, a rise in rates of endophthalmitis after cataract surgery has caused concern. However, at the same time, data from a study conducted by Peter J. McDonnell, MD, showed a reduced incidence of infection after other forms of anterior segment surgery, such as glaucoma and corneal transplant surgery. Rates of infection for eye surgery in general have decreased, but the rate of infection with cataract surgery in particular has increased.

Lindstrom: What is the incidence of infection in corneal surgery?

Francis Mah, MD: A number of large studies show the incidence of infection to be approximately one in 1,000 for both cataract and refractive surgeries; however, as Dr. Masket mentioned, several meta-analyses show that cases may be increasing. Therefore, ophthalmologists must concentrate their efforts to prevent infections.

Terry Kim, MD: Atypical mycobacterial infections are a particular concern to refractive surgeons and have been investigated by the Centers for Disease Control and Prevention. As part of the American Society of Cataract and Refractive Surgery (ASCRS) Cornea Clinical Committee, we conducted a survey in 2001 that studied the rate of infections after LASIK. The incidence was found to be approximately one in 2,919, with a slight increase shown in a recent follow-up survey done in 2004.

On an encouraging note, the incidence of LASIK infections caused by atypical mycobacteria seems to be decreasing. In comparing the results from the two surveys, the percentage of infections caused by atypical mycobacteria decreased from approximately 50% to 5% of the cases. The use of fourth-generation fluoroquinolones, such as moxifloxacin (Vigamox, Alcon, Inc.), for prophylaxis may have attributed to this drastic change. However, the percentage of infections caused by Staphylococcus increased from approximately 30% to more than 60%. This increase is most likely due to cases of methicillin-resistant Staphylococcus aureus (MRSA).

Terrence O’Brien, MD: Emily J. West, PhD, from Johns Hopkins University, conducted a review of more than 500,000 cataract surgeries in the Medicare database. Dr. West found that a rise in the rate of endophthalmitis occurred between 1997 and 2000. Also, from 2000 to 2003 there has been an increase of approximately 0.26%, which is 2.5 to 3 times what is typically quoted.¹ That increase coincides with the widespread adoption of the clear cornea approach to cataract surgery without sutures.

Masket: If an increased incidence of infection is related to corneal incisions, wound construction must be the issue, supposing that microbes gain access to the anterior chamber after surgery. Surgeons, in defense against infection, should then employ protective antibiotics postoperatively. In particular, an antibiotic that penetrates the eye well and is sufficiently potent should be selected.

Figure 1 and 2. Moxifloxacin and gatifloxacin may differ in terms of susceptibility rates.

Routine preoperative standard of care

Lindstrom: What have clinical experience and science taught ophthalmologists regarding the routine preoperative standard of care?

Masket: The spectrum of infection prophylaxis begins with an evaluation of the patient prior to surgery to ensure there is no active blepharitis or conjunctivitis. I also consider patients who are at high risk for infection, such as patients with a nasolacrimal duct obstruction, immunocompromised patients and patients with a prosthetic fellow eye or an indwelling Jones tube. I perform ocular chemoprophylaxis to reduce the number of microbes on the ocular surface. I pay particular attention to draping, which is a “mechanical prophylaxis,” to reduce the opportunity for microbes to reach the chamber. I am as particular about draping as I am with the other aspects of the surgery.

O’Brien: In addition to chemoprophylaxis, mechanical measures are equally important. Trying to sequester the cilia, the meibomian glands and the skin of the eyelids from the operative field with the use of adhesive draping is tantamount to success.

Currently, the use of antiseptics such as povidone-iodine is evolving as the standard of care in combination with the use of a fourth-generation fluoroquinolone for added protection. In the future, corneal adhesives to secure the wound postoperatively and prevent organism access to the intraocular space may provide additional benefit as well. My colleagues at Wilmer Eye Institute have performed optical coherence tomography (OCT) studies and demonstrated that the presence of certain adhesives can prevent influx of fluid into the eye under various IOPs.

Eduardo Alfonso, MD: It is important to use a topical antibiotic with good penetration and excellent minimal inhibitory concentration (MIC) against the microbial flora that surgeons are most concerned with as causative agents for endophthalmitis.

Lindstrom: Surgeons must appreciate the possibility that the only drops the patient will receive are the ones that are put in by the staff on the day of surgery. Surgeons should ensure that, before the patient goes home, two or three doses are instilled in the eye.

Masket: Surgeons are learning to be careful about constructing anatomically sound clear corneal incisions. Part of that concept is to be certain that incisions are hermetically sealed at appropriate IOPs. The fourth-generation fluoroquinolones, such as moxifloxacin and gatifloxacin (Zymar, Allergan), have also been introduced; they may play an important role in decreasing endophthalmitis rates.

O’Brien: A recently published study conducted by researchers at the John A. Moran Eye Center evaluated the potential risk factors associated with post-cataract surgery endophthalmitis. Researchers reported that selection of an antibiotic that readily penetrates the anterior chamber is a statistically significant variable among endophthalmitis cases.²

Rolando Toyos, MD: Therapeutic levels in the anterior chamber can be achieved more easily and can potentially eliminate microcontamination, thereby preventing a case of endophthalmitis that otherwise may have occurred.

Lindstrom: The overall rate of infection is decreasing because surgeons are learning how to use the correct antibiotics at the appropriate time.

Fourth-generation fluoroquinolones

Lindstrom: Are fourth-generation fluoroquinolones the optimal drug to prevent endophthalmitis?

Mah: Fourth-generation fluoroquinolones have all the characteristics to be the best agents for prophylaxis. They are the broadest spectrum drugs, kill rapidly and are non-toxic. Surgeons also need an antibiotic that is potent and that safely penetrates into the ocular tissue, where infections can start. Among the antibiotics available for cataract surgeons, fluoroquinolones are the agent of choice in terms of ocular penetration.

Alfonso: Fourth-generation fluoroquinolones have an increased ability to prevent organisms from becoming resistant to them. If surgeons use an earlier generation fluoroquinolone and the bacteria mutate, the bacteria will have an easier time mutating against a fourth-generation fluoroquinolone. Therefore, surgeons should argue strongly for the abandonment of earlier generation fluoroquinolones to prevent organisms from becoming resistant to the fourth-generation fluoroquinolones.

Figures 1 and 2 illustrate the potential differences between moxifloxacin and gatifloxacin in terms of susceptibility rates. Also, the peer-reviewed literature indicates that moxifloxacin may have an advantage, especially when tested against fluoroquinolone-resistant Staphylococcus aureus.

Potency and penetration

Kim: An important issue regarding fourth-generation fluoroquinolones is the relationship of penetration to potency. Surgeons must become better educated about the concept of therapeutic index (C_max:MIC₉₀, which is the ratio of the maximum concentration of antibiotic [C_max] in the tissue to the minimum inhibitory concentration [MIC₉₀]), which relates the antibiotic’s penetration to its potency. Ideally, a higher therapeutic index in a fluoroquinolone is desired in order to achieve better effectiveness. An antibiotic can be potent with an extremely low MIC, but if it cannot reach the target tissue, it is not effective.

A number of studies in the peer-reviewed literature confirm the superior penetration and potency of moxifloxacin. These studies consistently demonstrate the excellent potency and high penetration of moxifloxacin into the human aqueous humor. For this reason, I agree that fourth-generation fluoroquinolones, such as moxifloxacin, possess the optimal characteristics to help prevent endophthalmitis.

Toyos: All human head-to-head data comparing the penetration levels of moxifloxacin and gatifloxacin have reported that moxifloxacin penetrates approximately two to four times better than gatifloxacin.³ The greater the concentration of antibiotic at the target site, the greater the protection against infection.

Lindstrom: Bacteria are present on the surface and can penetrate into the eye soon after surgery. Therefore, surgeons must treat the surface and inside of the eye. If surgeons are performing corneal refractive surgery, sufficient penetration into the cornea is necessary. Can you define the three terms MIC, minimal bactericidal concentration (MBC) and mutant prevention concentration (MPC), and explain what they mean to clinicians?

Mah: MIC refers to the concentration that inhibits the growth of bacteria. If a surgeon has the same two antibiotics with the same concentrations, but one has a lower MIC, theoretically, less antibiotic will need to be present in order to inhibit the same number of bacteria. Furthermore, resistance will potentially occur less often to the antibiotic with the lower MIC.

MBC refers to the eradication of bacteria. The definition states that 99.9% of the bacteria have been eradicated, so there is a potential for 1/1000 of the bacteria to remain. Surgeons should be concerned about that remaining bacteria in terms of resistance and mutations.

MPC refers to the concentration that prevents bacterial mutations from occurring, and therefore it is the concentration that prevents resistance. The MBC for fluoroquinolones is approximately three to four times the concentration of the MIC. The MPC is anywhere from eight to 10 times the concentration of the MIC, depending on the bacterial isolate and the antibiotic.

Figure 3. A Staphylococcus aureus endophthalmitis model was used to evaluate the effectiveness of topical moxifloxacin for preventing endophthalmitis in rabbits.

Figure 4. This study performed with moxifloxacin demonstrated the proof of principle that topical antibiotic therapy prevents endophthalmitis in 100% of the cases.4

The clinical corollary is an endophthalmitis experimental model my colleagues and I were able to develop. We performed a study in rabbits that were dosed with only an antibiotic to test whether the topical antibiotic could prevent endophthalmitis. Two groups were compared, with one group receiving moxifloxacin and a control group receiving only balanced salt solution. We were able to prevent endophthalmitis from occurring in the group that received moxifloxacin versus the group that received the balanced salt solution. These results may be similar to those that would occur when an antibiotic is applied on the eye.⁴

It is important to note that this study has been attempted with other antibiotics, such as gatifloxacin and ofloxacin, but they failed to prevent endophthalmitis.^5,6 The study we conducted with moxifloxacin demonstrates the proof of principle that topical antibiotic therapy prevents endophthalmitis in 100% of the cases (Figures 3-5).

Figure 5. Moxifloxacin-treated rabbit eyes (above) were free of infection.4

Lindstrom: If surgeons desire to have an impact on the incidence of infection in the cornea following cataract surgery or keratoplasty, they must reach at least the MBC level. It seems that the MIC₉₀ is not sufficient.

Mah: I agree. Surgeons should be achieving approximately three to four times the MIC. Reaching only the MIC level is not sufficient to prevent or treat infections effectively.

Lindstrom: In regard to potency, is a fluoroquinolone effective if it is placed directly on the microorganism?

Alfonso: One benefit of fluoroquinolones is that their mode of action is concentration-based; they are not time-dependent. The kill curves for the fourth-generation fluoroquinolones are much better than the kill curves of other classes of antibiotics that were used for prophylaxis. Once bacteria are exposed to a concentration that is higher than their MBC, they die quickly.

Lindstrom: Are there differences between moxifloxacin and gatifloxacin if they are stirred together with bacteria that are found with endophthalmitis?

Mah: In short, yes. My colleagues and I published in vitro data that investigated differences between all the topically available fluoroquinolones, including moxifloxacin and gatifloxacin. When we looked at the gram-positive endophthalmitis isolates, moxifloxacin had a lower MIC than gatifloxacin. In other words, moxifloxacin was more potent than gatifloxacin against gram-positive isolates, which cause approximately 94% of endophthalmitis.

In terms of gram-negative bacteria, no difference between any of the fluoroquinolones existed. Generally, fluoroquinolones are an excellent class of medication against gram-negative bacteria.

Lindstrom: How do fluoroquinolones protect against Streptococcus bacteria?

O’Brien: I chose to move toward the 8-methoxy group of fluoroquinolones because of the gap in the spectrum of activity, particularly against certain staphylococci, streptococci and enterococci. Moxifloxacin and gatifloxacin provide significantly better anti-streptococcal coverage than previous generations of fluoroquinolones.

Mah: Several studies have shown that moxifloxacin has lower MICs. Therefore, moxifloxacin may be slightly more efficient than gatifloxacin in protecting against Streptococcus bacteria.⁷

Kim: There is also rising concern for MRSA as a cause of keratitis and endophthalmitis. It is encouraging to know that there is better activity against MRSA with fourth-generation fluoroquinolones.

Lindstrom: Is penetration into the cornea and the aqueous humor concentration-dependent, or do any drugs penetrate better than others?

Alfonso: Moxifloxacin penetrates significantly better into the conjunctiva, the cornea and the aqueous humor than gatifloxacin (Figures 6-8).⁸

Toyos: I believe that concentration plays a role in penetration, but there are other, perhaps even more important, factors that explain its superiority. Solubility is key. The closer to physiological pH a drug is, the better the penetration will be. For example, at a pH of 6.8, moxifloxacin penetrates better than gatifloxacin or ciprofloxacin, which have respective pH levels of 6.0 and 4.5. The lower the pH, the higher the risk of corneal precipitates. For example, Shady Awwad, MD, and colleagues reported that precipitate-formation is associated with gatifloxacin (Figure 9).⁹

	Compared with gatifloxacin, moxifloxacin has better conjunctival penetration.28
	Corneal concentrations of commercially available moxifloxacin 0.5% and gatifloxacin 0.3% were measured in rabbits.
	Improved peak levels of moxifloxacin in corneal and aqueous humor penetration enhance efficacy.

Lindstrom: Therefore, a drug with a more neutral or alkaline pH penetrates the cornea better.

Masket: Yes, that is a likely explanation. In addition, moxifloxacin’s bicyclic side chain positively affects penetration because it adds biphasic properties to the molecule and maintains the agents’ concentration in the microbial cell.

Kim: When a drug has biphasic molecular properties, like moxifloxacin, penetration through the cornea is enhanced. Moxifloxacin has a bicyclic amino acid side chain in the C-7 position that adds a degree of lipophilicity to the molecule. Therefore, the inherent molecular structure is part of the reason why moxifloxacin has superior penetration.

Toyos: Moxifloxacin’s rapid penetration is clinically significant. Within 1 hour of giving a single drop of moxifloxacin, a surgeon will be able to see moxifloxacin in the anterior chamber of the eye.

The lower the pH, the higher the risk of corneal precipitates.9 Lippincott, Williams & Wilkins. Used by permission.

My colleagues and I performed a study in which we gave patients cyclopentolate (Cyclogyl, Alcon, Inc.) and told them the drug was instrumental in their preoperative routine. Results showed that only 10% of patients complied with our instructions. Therefore, I seek a fluoroquinolone drop that can be used the day of surgery and that will penetrate into the anterior chamber and kill bacteria instead of a drop that has to be dosed days before the initial surgery.

O’Brien: Also, perhaps more important than penetration into the anterior chamber is penetration into the vitreous humor. A recently published study shows that moxifloxacin achieves levels in the vitreous humor that at least meet the MICs for the majority of the organisms that cause pseudophakic endophthalmitis.¹⁰ To the best of my knowledge, this is the first time this result has been achieved with a topically applied fluoroquinolone.

Mycobacterial infections

Lindstrom: The incidence of corneal mycobacterial infection is surprising. Where are the mycobacteria coming from and how do drugs work against those organisms?

O’Brien: A survey conducted by ASCRS in 2001 indicated that more than 50% of infections post-LASIK were due to rare exogenous contaminants, such as non-tuberculous mycobacteria (Figure 10).¹¹ That study has recently been repeated. Since surgeons have adopted the use of 8-methoxy fluoroquinolones, non-tuberculous mycobacteria has no longer been a significant cause of keratitis after LASIK. Therefore, epidemiologic evidence indicates that the superior coverage of the new generation of fluoroquinolones against non-tuberculosis mycobacteria can be preventative.^12,13

An ASCRS survey in 2001 indicated that greater than 50% of infections post-LASIK were due to rare exogenous contaminants.31

Kim: In this survey that our committee conducted, approximately 50% of patients were on a second- or third-generation fluoroquinolone. Approximately 35% were taking a fourth-generation fluoroquinolone. It was interesting to note that none of the patients on the fourth-generation fluoroquinolone developed an atypical mycobacterial infection.

Lindstrom: This suggests that if ophthalmologists use fourth-generation fluoroquinolones properly in intraocular surgery, they will also see a significant reduction in mycobacterial infections.

Alfonso: Surgeons have seen a decrease in cases of sporadic keratitis due to mycobacteria. However, surgeons continue to see problems with cluster cases, which are defined as several cases that appear in a surgical suite on the same day or the same week. In a study that my colleagues and I performed in Miami, we proved that these organisms are in the water that is used to clean instruments. Patients use this water to wash their eyes or swim in it.

To avoid cluster cases, surgeons must not allow any breaks in sterility techniques in surgery centers. Surgeons must also instruct patients not to go into swimming pools or open their eyes under the shower for at least 7 days postoperatively.

Toyos: On that note, surgeons often use cold water or ice to cool down the balanced salt solution that is used to reduce the pain involved with epi-LASIK. If harmful bacteria are present in the water or ice that is used to cool the balanced salt solution, the bacteria are transferred to the eye along with the drop.

Lindstrom: What is known about the potency and penetration of antibiotics in treating mycobacteria?

O’Brien: The data suggest that the superior activity of the 8-methoxy fluoroquinolones is protective against developing infections. However, if surgeons experience a case of mycobacterial keratitis, they will need more than just one agent for treatment. I feel that poly-antimicrobial therapy, including moxifloxacin, along with an aminoglycoside and a macrolide, such as azithromycin (Zithromax, Pfizer) or clarithromycin, are effective in eradicating mycobacteria sequestered beneath a LASIK flap.

Biocompatibility, wound healing and toxicity factors

Lindstrom: Is there a difference between the biocompatibility of moxifloxacin and gatifloxacin?

O’Brien: After millions of prescriptions used, there have been no legitimate reports of increased toxicity or other adverse events made to the FDA or to other monitoring agencies. This is a testimony to the safety of 8-methoxy fluoroquinolones.

Alfonso: Moxifloxacin has shown excellent characteristics in terms of biocompatibility. Patient data show that the number of adverse events from the use of moxifloxacin is low compared to other commercially available antibiotics.

A significant amount of data from human, animal and in vitro studies show moxifloxacin has an excellent safety profile.⁷

A search of recent studies presented at this year’s Association for Research in Vision and Ophthalmology (ARVO) and ASCRS meetings supports the safety of the fourth-generation fluoroquinolones.

Although a handful of studies suggest that certain fluoroquinolones are safer than others, the majority of studies found both moxifloxacin and gatifloxacin to be equally tolerated (Figure 11).¹⁴

Most studies have found moxifloxacin and gatifloxacin to be safe and well tolerated.14

This claim is supported by the clinical experiences of thousands of ophthalmologists who have switched to moxifloxacin and gatifloxacin.

Mah: The body of knowledge and experience thus far that come from physicians who use these agents shows that, despite millions of patients exposed to these drugs, no credible evidence or reported cases of toxicity exist.

Lindstrom: Is there any evidence to show toxicity to the endothelium, epithelium and keratocytes?

Alfonso: My colleagues and I performed a confocal microscopy study and studied normal volunteers who were exposed to moxifloxacin four times a day for 3 days. In terms of keratocytes, endothelium and epithelium, we were not able to find any quantitative or qualitative differences compared to the control group who used an artificial tear preparation.

Toyos: Richard D. Yee, MD, and colleagues performed a PRK study that showed that wound healing takes place at a similar rate with moxifloxacin and gatifloxacin.¹⁵

My colleagues and I have been performing endothelial cell count studies comparing traditional and newer fluoroquinolones in patients undergoing phacoemulsification with AquaLase (Alcon, Inc.). We began the study using traditional fluoroquinolones like ciprofloxacin and ofloxacin then switched to moxifloxacin.

No significant change in endothelial cell counts was found post cataract surgery between the fluoroquinolones.

Kim: Jenna Burka, MD, and colleagues from the Walter Reed Army Medical Center completed a study comparing the effects of moxifloxacin and gatifloxacin on epithelial healing in patients undergoing PRK.

In this double-masked, contralateral, prospective study, human patients were randomized to moxifloxacin in one eye and gatifloxacin in the fellow eye following PRK with a 9-mm chemical debridement using a 20% alcohol solution.

Results showed a statistically significant difference; the moxifloxacin-treated eyes healed faster and experienced smaller epithelial defects. This study supports the finding that moxifloxacin is biocompatible, does not interfere with wound healing and does not cause toxicity (Figure 12).¹⁶

Moxifloxacin is biocompatible, does not interfere with wound healing and does not cause toxicity.32

Standard of care for routine cases

Lindstrom: How do you handle routine cases? An axiom for surgical prophylaxis is that surgeons should administer drugs preoperatively in a dose that will achieve adequate penetration into the tissue. How far in advance do you do this?

Masket: Ocular penetration studies in which I have participated have demonstrated that if moxifloxacin is administered four times on the day of surgery, the antibiotic levels inside the anterior chamber are barely below those found when antibiotics are also administered the day before surgery.

Therefore, what we have learned from pharmacokinetics is that moxifloxacin administered on the day of surgery can provide adequate intraocular levels.

Regarding pharmacodynamics, bacterial kill curves provide an opportunity to understand exactly how long before surgery antibiotics must be applied.

Recent studies of moxifloxacin that I have seen show that kill curves are approximately 45 minutes for Staphylococcus epidermidis. Therefore, if patients are treated with three or four doses up to 45 minutes before surgery, potent antibiotic levels will be adequate inside the chamber and on the ocular surface.

Figures 13 and 14 refer to a study done that was particularly relevant because it was performed at a 1:10 antibiotic dilution and mimicked tear concentrations shortly following topical dosing.¹⁷

When evaluating fluoroquinolones’ kinetics of kill, it is important to use dilutions of commercial formulations in order to mimic concentrations achieved on ocular surface.

O’Brien: In regard to penetration, moxifloxacin achieves 3.8 times the concentration in the aqueous humor compared to gatifloxacin.

Lindstrom: How long do you recommend patients continue to apply antibiotics postoperatively?

O’Brien: I tell my patients to apply the 8-methoxy fluoroquinolone antibiotics every 2 hours for 2 days, and then four times a day for 5 days.

Mah: For routine patients, antibiotic use on the day of surgery is standard. To ensure that antibiotics reach the anterior chamber and to clean the ocular surface, I use antibiotics 1 hour preoperatively. I then administer a drop at the conclusion of surgery.

I do not patch my patients, but ask them to administer the antibiotic 3 to 4 hours after they leave the operating room. After the initial home dose, patients should begin using the drops every 2 hours.

The next day, if the postoperative results show no suspicion for infection, the dose is decreased to four times daily for 1 week. Once the epithelium is healed and the incision is secure, the antibiotic is stopped without tapering in order to preserve the efficacy of these antibiotics for long-term use. I believe, and it has been proven in studies, that tapering of antibiotics causes rapid development of resistance. For high-risk patients, such as those colonized by MRSA, an antibiotic with excellent gram-positive ability is used for 1 day preoperatively as well.

This slide shows median minimum inhibitory concentrations (MIC) for gatifloxacin and moxifloxacin against a variety of gram-positive organisms compared with the mean aqueous concentration levels achieved by Vigamox and Zymar in the study completed by researchers at The Wilmer Eye Institute. Improved pharmacokinetic and pharmacodynamic of moxifloxacin may provide protection against postoperative infection.

Standard of care with LASIK or PRK patients

Lindstrom: In terms of LASIK or PRK, do you give a drop of antibiotic before the start of surgery or strictly at the end?

O’Brien: I administer two or three drops of the 8-methoxy fluoroquinolone, beginning approximately 30 minutes prior to the procedure. I also use an antiseptic, such as povidone-iodine 2.5%. In addition, I carefully drape the lids and lashes because any extra mechanical barriers to contamination are helpful. Postoperatively, I administer antibiotics three times daily for 5 days and stop.

Lindstrom: In refractive cases, I apply a drop of anesthetic and a drop of moxifloxacin immediately before the procedure. I then administer another drop of moxifloxacin at the end of the procedure.

Toyos: I use LADARVision (Alcon, Inc.), so my patients must have a dilated pupil. When my patients receive dilating drops, I administer moxifloxacin at the same time. I have never experienced problems with moxifloxacin in terms of healing or precipitates. I also have patients wear a sticker on their hand, and when the nurse puts drops in their eyes, he or she initials the sticker. Therefore, I know that the patient is adequately prepped at the time of surgery.

Lindstrom: Should all ophthalmologists use an effective antibiotic like moxifloxacin to decrease the incidence of endophthalmitis?

Masket: Chemoprophylaxis plays a key role in preventing endophthalmitis. That, in combination with architecturally sound wound construction and appropriate mechanical prophylaxis through careful draping technique, should reduce the incidence of endophthalmitis.

Mah: Our lab has been on record as stating that if surgeons switched to fourth-generation fluoroquinolones, there would be a transient decrease in the incidence endophthalmitis.

Kim: Peer-reviewed literature, and moxifloxacin’s and gatifloxacin’s prescribing information, suggests that the differences between the two agents have important clinical implications. Improved pharmacokinetics and pharmacodynamics of moxifloxacin provide a significant advantage in protecting patients against postoperative infection (Figure 15).

NSAIDs overview

Lindstrom: I do not feel that surgeons are taking advantage of the multiple benefits that NSAID therapy can provide. Also, when NSAIDs are used, they are often not used preoperatively, which is actually the proper time to begin therapy. When patients are being given drops of moxifloxacin preoperatively, they should be receiving a drop of NSAID as well. This can significantly help in blunting the onset of postoperative inflammation. If significant inflammation is present in the eye, what should surgeons be concerned about?

O’Brien: No matter how skilled a surgeon is, inflammation is created the moment the ocular tissue is touched, whether it be with a precision diamond blade or a phaco probe resting against the uveal tissue.

Obviously, surgeons want to prevent inflammation from leading to synechiae, contributing to deposits on IOLs and constricting the pupil. Potentiating mydriasis with the use of the topical NSAIDs preoperatively is essential.

Toyos: Patients’ expectations of cataract surgery and their postoperative experiences are different than they were 5 years ago. Patients expect LASIK-like results without any inflammation or problems with the iris. That is where NSAIDs come into play.

Lindstrom: When surgeons make an incision in the eye during surgery, a host of inflammatory mediators and prostaglandins are released and an increased permeability of vessels and cells in the eye occurs.

These factors can directly or indirectly cause cystoid macular edema (CME), damage to the endothelium and affectations of the trabeculum and capsule. What drugs are available that can be used to help reduce this inflammatory cascade?

Kim: Traditionally, corticosteroids, which inhibit the inflammatory cascade at an early stage, have been used. Once trauma to the ocular tissue occurs, phospholipids in the cell membranes are released to form arachidonic acid.

Typically, corticosteroids inhibit phospholipase and block the conversion of phospholipids to arachidonic acid. NSAIDs are another class of anti-inflammatory agents that inhibit the metabolism of arachidonic acid, once it is formed. They work on the cyclooxygenase (COX) portion of that pathway to further limit the release of inflammatory mediators, such as prostaglandins, prostacyclins, and thromboxanes (Figure 16).

Typically, corticosteroids inhibit phospholipase and block the conversion of phospholipids to arachidonic acid. 39

A study conducted by Ann McColgin, MD, and Michael Raizman, MD, showed that as many as 12% of patients who underwent cataract surgery and were dosed both pre- and postoperatively with only corticosteroids developed CME.

Also, none of the patients who received NSAID therapy in addition to corticosteroids developed CME.¹⁸ Recent studies have also shown that subclinical macular thickening correlates with decreased visual acuity after cataract surgery.

This finding may have an impact in terms of defining an important role for NSAIDs.¹⁹

Treatment regimens for CME

Lindstrom: What is your current regimen for treating patients with CME?

O’Brien: I recently published a paper that outlined the emerging trends for the use of NSAID therapy to optimize cataract surgery patient care.²⁰ In routine cataract cases, the consensus leans toward starting topical NSAIDs in the preoperative period and continuing therapy for 4 weeks postoperatively. Longer treatment duration should be considered for patients deemed to be “at risk” (Figure 17).

In routine cataract cases, topical NSAIDs are used in the preoperative period for 3 to 4 weeks.20

Masket: Conventional NSAIDs should be started days ahead of surgery. High-risk patients, such as those who have had CME in a previously operated eye, should be started on NSAIDs at least 1 week before surgery. Newer pro-drug NSAIDs achieve a much higher penetration into the eye and will allow for less onerous dosing regimens.

Mah: It is also imperative to continue to apply NSAIDs through the high-risk period for CME, which is 6 weeks following surgery.

Lindstrom: If patients contract mild CME in the early postoperative period that subsequently resolves, can it permanently impact their quality of vision?

Alfonso: I believe that even mild CME impacts a patient’s quality of vision. Therefore, I try to minimize tissue damage from inflammation at any cost.

O’Brien: Damage to the retinal pigment epithelium (RPE) that accompanies even milder CME is permanent. These cells do not regenerate. Therefore, any swelling that occurs has a lasting negative impact on patients’ visual outcomes.

Masket: There is some evidence of a permanent reduction in contrast sensitivity function that would elevate the need for NSAID prophylaxis as standard of care.

Toyos: It has been hypothesized that CME is caused by surgically induced prostaglandin formation in the aqueous and vitreous and/or a breakdown of the blood-aqueous and blood-retinal barriers (Figure 18). Therefore, an agent that will positively impact these processes may be beneficial in preventing CME.

Studies exist that show that NSAIDs not only decrease the inflammatory change, but also stabilize the blood-retina barrier so there is less leakage. Therefore, NSAIDs are used not only to reduce inflammation, but also to help stabilize the blood vessels.

Lindstrom: It seems that we have reached a consensus as a group that the wisest way to treat inflammation is preoperatively. Can this be done only with a topical steroid or should NSAIDs be used as well?

Alfonso: Studies have shown that cell membranes stabilize when they are exposed to an anti-inflammatory drug, both steroidal and nonsteroidal. Therefore, pretreating the cell membrane assists in preventing cell damage when inflammation occurs.

CME may be caused by surgically induced prostaglandin formation in the aqueous and vitreous and/or a breakdown of the blood-aqueous and blood-retinal barriers.36

Kim: Another benefit of NSAIDs compared to corticosteroids is side-effect profile, in terms of the decreased risk for glaucoma, cataract formation and delayed wound healing. NSAIDs can be used for a long duration with a safe side-effect profile, which is especially important when considering the high-risk period for the development of CME.

Masket: Dr. Toyos alluded to the reestablishment of the blood-ocular barrier, which is the key factor in preventing CME. A number of clinical conditions result in a chronic breakdown in the blood-ocular barrier, which creates high risk for postoperative inflammation. Surgeons will always need to be vigilant about treating patients who have a chronic defect of the blood-ocular barrier.

Lindstrom: What are some of the other potential benefits of NSAIDs?

Masket: Analgesia is another benefit of NSAIDs.

O’Brien: In an era of cataract surgery performed under topical anesthesia without injection, provision of analgesia is a significant adjunctive benefit of NSAIDs.

Lindstrom: Current literature suggests that pretreating the eye with an NSAID results in a 1-mm increase in pupil size. Do you agree?

Toyos: I agree. A 1-mm increase can mean the difference between excellent surgical results and complications.

Topical nepafenac 0.1%

Lindstrom: Nepafenac, the amide analog of the NSAID amfenac, has recently been examined for its bioactivation by ocular tissue components and its ability to permeate external ocular barriers.

Stephen S. Lane, MD, performed a prospective, randomized, double-masked, vehicle-controlled clinical trial and demonstrated the efficacy and safety of nepafenac 0.1% ophthalmic suspension (Nevanac, Alcon, Inc.) for reducing anterior segment inflammation and minimizing pain after cataract surgery. I would like to discuss nepafenac and how it works.

Kim: Nepafenac represents a novel breakthrough in NSAID therapy because of its pro-drug formulation, which enables the agent to safely and comfortably achieve a high concentration at the key intraocular tissues.

The nepafenac molecule actually penetrates the cornea well, with less accumulation on the ocular surface.

Once it penetrates into the eye, nepafenac is converted to amfenac, a highly efficacious NSAID, by intraocular hydrolases.

Patients may be less likely to experience adverse events such as burning and stinging because of the molecule’s pro-drug structure and its rapid intraocular distribution.

The penetration also looks encouraging, particularly to the target tissues of concern in CME, the retina and choroid (Figure 19).

Lindstrom: How does nepafenac penetrate versus other drugs that are available today?

Mah: Nepafenac penetrates much better than all of the drugs that surgeons have used previously. A study comparing the penetration coefficients of NSAIDs shows that nepafenac has the ability to penetrate into the intraocular tissues approximately seven times higher than conventional NSAIDs such as diclofenac (Figure 20).²¹

	Patients may be less likely to experience adverse events because of nepafenac's inherent safety profile.
	Nepafenac penetrates better than other drugs surgeons have previously used.31,40,41

Lindstrom: What is the reason for that?

Mah: The way the pro-drug is designed is the reason behind its efficient penetration levels. The enhanced permeability of nepafenac, combined with its rapid bioactivation to amfenac, makes it a target-specific NSAID for inhibiting prostaglandin formation in the anterior and posterior chambers of the eye.

Toyos: The pH of nepafenac is 7.4 — close to a physiological pH. Hydrolases break down the drug in the vitreous and help it reach the retina. Kyoichi Takahashi, MD, reported that it decreased the vascular endothelial growth factor level in the retina in mice. This results in a decrease in choroidal neovascularization.

O’Brien: Nepafenac is the first topical drug that has achieved significant levels after topical administration in the retina and choroid. Ophthalmologists have entered a new era where topical therapy can actually treat retinal disease.

Corneal analgesic efficacy

Lindstrom: Will nepafenac still be effective when used for analgesia in corneal refractive surgery? Are there enzymes on the surface as well that would convert it to amfenac?

Alfonso: Nepafenac’s enhanced permeability allows it to rapidly penetrate the cornea. Nepafenac, which appears to have inherent analgesic properties, bioactivates to amfenac intrastromally and may contribute to Nevanac’s analgesic efficacy.

Mah: A study evaluating NSAID analgesic efficacy in patients following PRK showed that using nepafenac on the surface of the eye resulted in an equal or greater reduction of pain compared to diclofenac (Figures 21 and 22).²²

	A study evaluating the analgesic efficacy of nepafenac 0.1% vs. diclofenac 0.1% showed that nepafenac provides equal or greater analgesia than diclofenac in patients undergoing PRK.37
	A higher number of patients on Nevanac were pain-free compared with patients on placebo at 1, 3, 7 and 14 days after PRK.

Kim: Typically, surgeons do not use NSAIDs after PRK for more than 24 to 48 hours after surgery because they are concerned about possible corneal complications. Nepafenac’s safety profile should offer patients a positive experience with regard to pain and inflammation when it is used after surface ablation surgery.

O’Brien: During the clinical trials, which were conducted in patients undergoing cataract surgery, Nevanac demonstrated excellent analgesic efficacy. The majority of patients (83%) in the Nevanac group were pain-free on the first postoperative day compared with only 41% of the patients in the placebo group. By postoperative day 14, pain-free scores were 93% for the patients in the Nevanac group and 45% for patients in the placebo group.

Mah: One of the biggest patient complaints regarding NSAIDs is the burning sensation that accompanies their use. As demonstrated in phase 3 trials, nepafenac is well-tolerated by patients, with no burning and stinging.

Anterior chamber anti-inflammatory efficacy

Lindstrom: The penetration of nepafenac is remarkable, especially when compared to previous medications. How does nepafenac compare to conventional NSAIDs in terms of its ability to suppress inflammation in the anterior chamber?

Mah: Following an intraocular surgery, such as cataract surgery, nepafenac should suppress inflammation better and faster than other agents. In a comparison of phase 3 trial results, data confirm that nepafenac performs better than other currently available agents.

In addition, when compared to diclofenac, nepafenac is superior in blocking COX-1 and COX-2 enzymes in a uniform manner.

The COX-1 enzyme is always on and continuously produces a low level of prostaglandins. The COX-2 enzyme is only significant when an inflammatory event, such as ocular surgery, takes place. To have a rapid and complete blockade of prostaglandin synthesis, both enzymes must be blocked. Scientific studies show nepafenac blocks these enzymes better than other currently available agents.²³

Kim: Nepafenac’s superior penetration rates and subsequent ability to stabilize the blood-aqueous barrier have been well-documented in the literature. In ex-vivo rabbit studies, a single dose of topical nepafenac was able to inhibit prostaglandin synthesis in the iris-ciliary body more effectively and for longer periods compared to topical diclofenac (Figures 23 and 24).²⁴

This study also supports the observation that nepafenac penetrates the ocular surface in high concentrations and undergoes intraocular bioactivation by hydrolases to its potent analog, amfenac. This results in superior suppression of intraocular inflammation, as measured by inhibition of aqueous humor protein and prostaglandin accumulation, from a topical formulation (Figure 24). Clinically, this should translate postoperatively to a quieter eye with better and more rapid visual recovery.

In rabbit studies, single-dose nepafenac inhibited prostaglandin synthesis more effectively and for longer periods compared with diclofenac.24 Nepafenac has been shown to inhibit blood-aqueous-barrier breakdown at significantly greater levels than conventional NSAIDs.24

Toyos: The anti-inflammatory efficacy of nepafenac was evaluated in two prospective, randomized, clinical studies. Both studies demonstrated that nepafenac suspension dosed three times daily, in the absence of steroid therapy, was effective in controlling pain and postoperative inflammation associated with cataract surgery. More than 80% of patients treated with nepafenac suspension were pain free on day one, compared to only 40% to 50% of patients in the placebo group. By day 14, approximately 93% of patients treated with nepafenac were pain free, compared to 45% of patients in the placebo group.

Results for inflammation control were similarly positive. Approximately 82% of patients treated with nepafenac suspension had no clinically significant inflammation at day 14, compared to approximately 25% of patients in the placebo group (Figure 25). These results were obtained in the complete absence of corticosteroid therapy. Nepafenac suspension was safe and well tolerated in both clinical studies.

Posterior chamber efficacy

Lindstrom: What can you tell me about nepafenac’s efficacy in the back of the eye and how it compares with conventional NSAIDs?

Masket: Nepafenac exhibits the ability to reach the back of the eye because of its pro-drug formulation and its rapid and efficient ocular penetration. It is also effective at suppressing the intravitreal release of prostaglandin E₂ (PGE₂). In one study, nepafenac significantly inhibited PGE₂ release in the vitreous, compared to little to no efficacy with diclofenac and ketorolac (Figure 26).²⁵

About 82% of nepafenac patients had no clinically significant inflammation at day 14.22 Nepafenac inhibits PGE2 release in the vitreous.23

O’Brien: Nepafenac has unique properties that allow for deeper activity into the posterior segment of the eye compared with earlier generation ophthalmic NSAIDs. Topical pro-drugs may offer advantages over traditional topical NSAID therapy in terms of both efficacy and safety.

Kyoichi Takahashi, MD, and colleagues at Wilmer Eye Hospital tested the effect of topical nepafenac in three murine models of ocular neovascularization in a masked trial on mice. Mice treated with nepafenac had less ischemic-induced retinal neovascularization than mice treated with diclofenac.²⁶ These findings are a result of the inhibitory effect nepafenac has on vascular endothelial growth.

Kim: Another attractive feature of nepafenac is its ability to effectively stabilize not only the blood-aqueous barrier, but also the blood-retinal barrier. Based on a recently published study that compares nepafenac to diclofenac and ketorolac, topical nepafenac 0.1% was able to demonstrate a significant reduction in blood-retinal barrier breakdown along with almost complete suppression of prostaglandin synthesis in the retina/choroid of rabbit eyes (Figure 27).²³ That is compelling evidence that nepafenac is a topical NSAID agent that has sufficient efficacy to suppress inflammation in the target tissues that are involved in the pathogenesis of CME.

Nepafenac showed significant efficacy in inhibiting blood-retinal barrier breakdown.23

Alfonso: If NSAIDs are to be most effective in treating CME, they must reach the back of the eye. Nepafenac, which is converted to amfenac in the iris-ciliary body, suppresses prostaglandin activity in the vitreous better than ketorolac and diclofenac.²² Conventional NSAIDs, because of their structure and lack of ability to penetrate, are less likely to be active in the posterior segment.

Mah: The superior ability of nepafenac to quell inflammatory markers in the posterior segment is critical for CME prophylaxis.

Lindstrom: What is the duration of action of the nepafanac? How often should it be used?

Mah: I believe that nepafenac should be used three times daily, which is convenient for patients when dosed with moxifloxacin, which is also indicated three times daily. This antibiotic and a three-times-daily NSAID regimen also offers ophthalmic surgeons the opportunity to scale back the steroid to three times daily, as well, making it consistent.

Surgical regimens of cataract and refractive surgeons

Lindstrom: I would like to discuss your therapeutic regimens in both cataract and refractive surgeries.

Masket: For cataract surgery, I typically administer an NSAID and moxifloxacin four times on the day before surgery. Preoperatively at the surgery center, in combination with dilating agents, the NSAID and moxifloxacin are applied in four doses, 1 hour prior to surgery. Postoperatively, I instill an antibiotic and an NSAID, as well as a steroidal agent every 3 hours on the day of surgery. The patient then uses the antibiotic four times daily for 1 week and a steroid and NSAID four times daily for 2 weeks. That amount is reduced by half for another 4 weeks.

Alfonso: My regimen is similar. I start NSAIDs 2 days prior to surgery. On the day of surgery, I add a steroid and an antibiotic to the NSAID. Regimens are changing as surgeons realize that they do not need to use antibiotics, such as moxifloxacin, for more than 1 day preoperatively. I continue the steroid on a tapering regimen and the NSAID four times daily for 4 weeks.

High-risk patient care

Lindstrom: Ophthalmologists routinely treat patients with diabetes. For these patients, it is reasonable to begin using steroids and NSAIDs 3 days to 1 week before surgery. Is that similar to your regimen?

Alfonso: I begin using steroids and NSAIDs 3 days to 1 week before surgery for any patient who has had previous intraocular surgery. These patients are at particularly high risk of developing CME and must be treated more aggressively with NSAIDs. Other patients considered to be at risk include those with pre-existing ocular inflammation, diabetes, a history of vascular or cardiovascular conditions, as well as patients with a history of retinitis pigmentosa (Figure 28).

Pre-existing ocular inflammation is a key risk factor for CME.30

Postoperatively, I treat these patients four times daily and continue treatment for 3 months. With patients who have retinitis pigmentosa, I extend treatment because these patients experience sustained macular edema. Surgeons provide these patients increased macular function with cataract surgery, because their peripheral retina is already depleted. I want to protect their macular function at all costs.

Masket: A group of patients that have not received adequate attention with regard to CME are those who have macular pucker or who have had prior macular pucker surgery. In my experience, these patients have a significant incidence of CME. I am aggressive with these patients in terms of pretreatment, prolonged treatment and, on occasion, the use of intravitreal steroids by injection at the time of surgery.

Lindstrom: I would like to talk about the safety profile of NSAIDs and the fact that so many ophthalmologists do not use these drugs.

O’Brien: The transient, negative experiences that surgeons have had with toxicity to the ocular surface are principally with generic forms of NSAIDs. This new generation of NSAIDs provides not only improved efficacy, but also a favorable safety profile.

Alfonso: Surgeons must realize that applying drops on only the surface of the eye causes inflammation. Therefore, timing the administration of the drops will be important. Nepafenac should be applied first to reduce the inflammation and pain that patients experience from using dilating drops.

Masket: Patients have come to expect a pain-free, quiet, non-inflamed eye that offers them the visual outcomes they desire. Nepafenac fits well into this expectation package. With respect to safety, the fact that nepafenac is a pro-drug with rapid ocular penetration suggests, and data indicate, that the toxicity to the corneal surface is greatly reduced when compared with existing topically applied NSAIDs.

Kim: The surgeons’ goal should be to maximize outcomes. If surgeons are going to use newer-generation IOLs that have the ability to minimize spherical aberration and provide pseudoaccommodation, it seems only logical for surgeons to incorporate NSAID therapy as part of their routine in order to maximize the enhanced visual outcomes offered by these IOLs. As technology has improved, patient expectations have also risen. Using state-of-the-art pharmacologic therapy like nepafenac should enable surgeons to meet these higher expectations in a more timely manner.

Toyos: Patients desiring pseudoaccommodative IOLs will most likely be more compliant than nonrefractive cataract patients when it comes to using the drops that are prescribed to them.

O’Brien: Technological advances on the mechanical side must be matched with pharmaceutical advances. Nepafenac is a new tool that a modern refractive cataract surgeon can employ to help meet increasingly high patient expectations.

Conclusion

The panel of experts: Moderator Richard L. Lindstrom, MD; Samuel Masket, MD; Terrence P. O’Brien, MD; Terry Kim, MD; Rolando Toyos, MD; Francis S. Mah, MD; and Eduardo Alfonso, MD.

Lindstrom: In closing, the panel’s consensus seems to be that post-cataract patient expectations are on the rise and that pre- and postoperative topical NSAID therapy has several advantages, including maximizing surgical outcomes. We also agree that appropriate duration of treatment must be administered for both routine and high-risk patients.

Nevanac, the first and only target-specific NSAID, represents a novel class of NSAID. Its unique pro-drug structure optimizes distribution to the key intraocular sites delivering superior inflammation suppression, especially in the retina and choroid. This is of particular importance, because posterior chamber inflammation leads to unwanted conditions such as CME.

A tremendous amount of information has been covered and there is great potential for further developments in drug formulations. On behalf of Ocular Surgery News, I would like to thank the participants and Alcon, Inc., for providing us with the opportunity to share information on the treatment options that are available to ophthalmic surgeons, specifically fourth-generation fluoroquinolones and the newest NSAIDs.

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