Symposium: Improving Outcomes: Surgical and Clinical Applications of Fluoroquinolones

Fluoroquinolone structure

Terrence P. O’Brien, MD: Please provide a brief summary of the history of the fluoroquinolones and their molecular evolution.

Francis S. Mah, MD: Fluoroquinolones are synthetic fluorinated analogues of nalidixic acid. Nalidixic acid, the first antibacterial quinolone, was introduced in 1963 after discovery during chloroquine synthesis. Several advances followed. In a meticulous, labor-intensive process, researchers made various changes to the molecular body of the quinolone.

In the beginning, quinolones were mainly used against gram-negative organisms. The addition of the fluorine group at the sixth position enhanced the quinolones’ potency by increasing activity against gram-positive pathogens. After this advancement, the main issue to resolve was toxicity, because the fluorines and other halides increase phototoxicity. As different positions were altered, coverage of gram-positive organisms continued to increase.

The generations of fluoroquinolones are mainly defined by each one’s activity against gram-positive organisms, particularly Streptococcus pneumoniae. This increase in coverage has allowed for greater potency and a broader spectrum of activity.

Second-generation fluoroquinolones include norfloxacin, ciprofloxacin and ofloxacin. These have excellent activity against gram-negatives and some activity against gram-positives, but do not adequately cover S. pneumoniae.

The third generation, highlighted by levofloxacin, saw an improvement in gram-positive coverage. Levofloxacin is the pure L-isomer of ofloxacin. Ofloxacin is a racemic mixture and therefore contains only 50% of the active components of levofloxacin.

Finally, the 8-methoxy fluoroquinolones, such as moxifloxacin and gatifloxacin, have advanced the group to the point that S. pneumoniae and some resistant gram-positive pathogens are covered. It is difficult to bring a broad-spectrum fluoroquinolone to market that does not have toxicity, and that is why the 8-methoxy fluoroquinolones such as moxifloxacin represent such an advance. Toxicity has not increased with moxifloxacin, but the spectrum of activity has increased greatly.

O’Brien: In addition to the eighth position, what benefits or advantages does the molecular substitution at the seventh position provide?

Mah: The newer-generation fluoroquinolones are similar to previous fluoroquinolones such as ciprofloxacin in that they have the fluorine group in the sixth position and the cyclopropyl group in the first position, enhancing gram-positive coverage.

The key difference between the newer fluoroquinolones and the older agents is at the seventh position. The substitution here has decreased the propensity for resistance to occur in bacteria. These antibiotics are able to enter the bacterial cells, and the cells’ efflux mechanism is blocked because of the large size of the C7 side chain. The cells are not able to pump the antibiotic out.

Moxifloxacin has a bicyclic side chain, which seems to increase resistance inhibition. Several in vitro studies have shown that moxifloxacin has the ability to resist mutations much better than agents such as levofloxacin, ofloxacin and even other strong agents such as trovafloxacin and tosufloxacin.¹

Resistance

O’Brien: What patterns of resistance have been observed recently in ocular isolates?

Eduardo Alfonso, MD: The introduction of the ophthalmic fluoroquinolones in the late 1980s was encouraging; they were a new class of antibiotic compounds for ophthalmology to which most ocular bacteria had not been exposed. The sensitivity profile was excellent: many of the pathogens causing endophthalmitis, keratitis and conjunctivitis were sensitive to this new class of compounds.

As they began to be used in ophthalmology, as well as in the rest of medicine, we, at the Bascom Palmer Eye Institute, began to find that these organisms were showing in vitro resistance in our laboratory surveillance. Likewise, treatment failures were documented in the literature, especially for keratitis. So resistance was appearing both in the laboratory and in clinical use of these earlier-generation fluoroquinolones, primarily ciprofloxacin and ofloxacin in the United States.

As new generations were developed, some of the organisms that were previously resistant were now sensitive. For example, our facility had a significant gap in coverage against streptococci with ciprofloxacin and ofloxacin, but we found in our laboratory that we could cover this gap with levofloxacin.

With the newer-generation fluoroquinolones, gatifloxacin and moxifloxacin, we found that in the laboratory we were once again able to eliminate some gaps in coverage, this time for the gram-positives such as staphylococci. And once again, reports from the clinical side showed that these newer-generation fluoroquinolones effectively treat cases of conjunctivitis and keratitis.

In many of these cases, the organisms have been shown in the laboratory to be resistant to the earlier-generation fluoroquinolones. These encouraging findings are most likely related to the molecular changes already mentioned, as well as the pharmacodynamics of these antibiotics. They have better solubility and thus achieve higher concentrations, which is a positive characteristic because the mechanism of action against the bacteria is concentration dependent.

Potency of fluoroquinolones: MICs of 18 fluoroquinolone-resistant endophthalmitis isolates* Figure 1. Researchers are finding increasingly lower MIC levels as advances are made to the fluoroquinolone molecule.2 *Resistant to ciprofloxacin and ofloxacin as determined by disc diffusion. Coag-neg = coagulase-negative; Cip = ciprofloxacin; Ofx = ofloxacin; Lev = levofloxacin; Gat = gatifloxicin; Mox = moxifloxacin

Mah: At the University of Pittsburgh, we have published data on endophthalmitis, keratitis and conjunctivitis isolates, and we have found that, in every case, the gram-positive pathogens that were resistant to the older-generation fluoroquinolones, such as levofloxacin, ofloxacin and ciprofloxacin, are now covered by the newer-generation fluoroquinolones, such as moxifloxacin and gatifloxacin.

To a greater degree, we are finding lower and lower minimum inhibitory concentration (MIC) levels as advances to the molecule occur (Figure 1), and the gram-negative coverage that we grew to rely upon with the older-generation fluoroquinolones has not been lost.²

Ciprofloxacin is the gold standard in terms of MIC and in vitro coverage for organisms such as Pseudomonas, and that coverage has not been lost with moxifloxacin or gatifloxacin. In our laboratory, we were not only able to show sustained gram-negative coverage, we were also able to show expanded and improved coverage, in terms of streptococci, staphylococci and resistant organisms.

This improved activity is the reason physicians must change their thinking and use newer-generation fluoroquinolones when considering a fluoroquinolone. The use of these newer fluoroquinolones will actually delay the development of resistance because they have two strong sites of activity, instead of just the original site.

Joseph Colin, MD: In Europe, physicians are concerned because they do not have access to the newer-generation fluoroquinolones. As in the United States, resistance to third-generation fluoroquinolones has increased in Europe. The susceptibility of common pathogens found in conjunctivitis and keratitis isolates to third-generation fluoroquinolones has declined.

The incidence of resistance to ciprofloxacin or ofloxacin has increased up to 30% for Staphylococcus aureus. However, according to the most recent reports, this increase has stabilized since 2000.³ Recent studies have shown that normal conjunctival flora contains 76% coagulase-negative staphylococci (2% of which are resistant to gatifloxacin and moxifloxacin), 11.7% S. aureus, 4.9% group D streptococci and 6.7% gram-negative rods.

O’Brien: In Japan, the 8-methoxy fluoroquinolones are just beginning to be used. What has been observed in Japan regarding ocular isolates and resistance to previous-generation fluoroquinolones?

Yuichi Ohashi, MD: We have used the second- and third-generation fluoroquinolones since 1985. Therefore, Japan has a long history of clinical use, like the United States. According to recent surveys, 10% to 15% of isolates, especially staphylococci, are resistant to older-generation fluoroquinolones. In addition, I am concerned about the increased frequency of methicillin-resistant S. aureus (MRSA) and Staphylococcus epidermidis (MRSE), especially in the elderly population.

Yoshikazu Shimomura, MD: Seventy-five percent of S. aureus isolates in older hospitalized Japanese people are resistant to methicillin. The main cause of this is reliance on empiric treatment without performing cultures.

Mah: Antibiotics should be used for short periods at high dosing levels, until the risk of infection is eliminated. Studies by David G. Hwang, MD, at the University of California at San Francisco showed that even therapeutic doses, when used for chronic periods, can increase resistance.⁴ In Japan, the 50% rate of older-generation fluoroquinolone resistance and 75% rate of MRSA may be due to the fact that Japanese physicians are using these antibiotics for such long periods, up to 6 months following surgery. To avoid the development of resistance, education is important both in the United States and abroad to teach physicians to use antibiotics in high doses for shorter lengths of time.

Modern evaluation of antibacterial activity

O’Brien: Can you discuss the concepts of MIC, minimum bactericidal concentration (MBC) and mutation prevention concentration (MPC)? What are they, and what do they mean in clinical practice?

Mah: At laboratories including my own, Dr. Hwang’s in San Francisco and Drs. O’Brien and Alfonso’s in Miami, physicians have been talking more about defining antibiotic use clinically instead of empirically. Instead of dosing an antibiotic four times daily and continuing that use as long as the patient improves, it may be better to use pharmacodynamic information to determine optimum dosing to avoid inappropriate antibiotic use while maintaining clinical efficacy.

In Europe, physicians are concerned because they do not have access to the newer-generation fluoroquinolones. – Joseph Colin, MD

How long are these antibiotics in the tissues? What are the levels in the tissues, and what amount will efficiently kill the bacteria? In vitro information includes the MIC. The MIC is the concentration of antibiotic that is necessary to inhibit the growth of the bacteria — not to kill it. If one adds antibiotic at the MIC level to a broth solution containing a certain amount of bacteria and measures the bacteria in the broth later, the broth will contain the same amount.

The MBC is a more appropriate term for defining the levels that we want to achieve. At the MBC, 99.9% of the bacteria are killed. Only 0.1% of the bacteria remain after the antibiotic is added to the broth at this concentration. However, MBC testing is costly and time-consuming on a daily basis, so microbiologists have used MIC levels as the standard to describe antibiotic activity. Generally, the MBC is three to four times higher than the MIC. The MBC is somewhat lower for the fluoroquinolones because they kill bacteria so quickly. In the tissues, antibiotics should reach their MBC.

MPC is a newer, theoretical concept. It is the antibiotic concentration that will prevent mutations. If 0.1% of the bacteria remain and can mutate at the MBC, zero bacteria remain at the MPC. Dead bacteria cannot mutate. The MPC varies depending on the antibiotic. Moxifloxacin has one of the lowest MPC levels.⁵ Others have MPC levels eight, 10 or even hundreds of times higher than the MIC. Enough antibiotic must penetrate the tissue to eradicate the bacteria completely and prevent mutations. If antibiotics prevented mutations, their longevity would increase.

Alfonso: Evidence shows that once a single mutation exists that is resistant to the earlier-generation of fluoroquinolones, such as ciprofloxacin and ofloxacin, then the second mutation that is necessary to develop resistance to the newer-generation fluoroquinolones happens at a higher frequency. Organisms exposed to earlier generation fluoroquinolones may develop the first mutation and thus facilitate the development of the second mutation necessary to develop resistance to the newer-generation fluoroquinolones.

The activity of the newer fluoroquinolones is greater because the methoxy group at the C-8 position binds to both topoisomerase II and IV. In addition, moxifloxacin has a bulky side chain in the C-7 position. This side chain further increases activity and inhibits resistance. This side chain inhibits the cells’ efflux pump, which increases the drug’s stay within the bacterial cells. This improves efficiency and minimizes resistance.

Physicians must recognize the compulsion to use newer-generation fluoroquinolones exclusively and almost completely abandon the earlier-generation fluoroquinolones. Physicians must avoid creating that first mutation, especially if they will be treating patients for a long period. Therefore, it makes sense to immediately use moxifloxacin and gatifloxacin for conditions such as conjunctivitis.

O’Brien: In what other areas might clinicians see a difference with the new fluoroquinolones compared to previous generations?

Mah: We have published a paper showing that MRSA keratitis can be treated with a newer-generation fluoroquinolone alone.⁶ This study showed that with frequent dosing, fluoroquinolone resistance can be overcome. One of the main dilemmas in treating keratitis is when a report of antibiotic resistance occurs even though a patient is clinically improving. Rather than blindly following lab reports, we should use them to guide therapy. As clinicians, we need to follow the patients clinically, ensure they are compliant and continue the therapy that causes them to improve.

Potency and therapeutic penetration

O’Brien: Please define ways in which clinicians use data to select an antibiotic in terms of performance.

Mah: Two key parameters must be included in the clinical evaluation of antibiotics. One is the potency or the MIC; the other is penetration into the tissues. For example, if a physician is treating an infection in the cornea, an antibiotic that has excellent activity will not be of much use if it does not reach the corneal stroma. So the ideal antibiotic has a combination of low MIC levels, or excellent potency, and also excellent penetration, meaning the antibiotic reaches the site of the infection.

Topical fluoroquinolone antibiotic concentrations in human conjunctival tissue Figure 2. The mean conjunctival concentration of moxifloxacin was 7.1 µg/g higher than that of gatifloxacin.7 Cip = ciprofloxacin; Ofx = ofloxacin; Lev = levofloxacin; Gat = gatifloxicin; Mox = moxifloxacin

As long as the agent is nontoxic, the higher the levels of antibiotic, the better. Systemically, there are toxicity issues with any antibiotic at high levels, so physicians cannot treat systemically the way they do in the eye. For example, when a fluoroquinolone is administered, a level of 10 µg/mL is achieved in the serum, whereas one drop of 0.5% topical moxifloxacin is 5,000 µg/mL. So 500 times the concentration is achieved with that one drop compared to one oral dose. Many studies now include penetration data because it is an important factor in choosing an agent.

O’Brien: What data are available concerning antibiotic levels in the conjunctiva, cornea and aqueous humor?

Alfonso: Mark Abelson, MD, and colleagues took biopsies of the conjunctiva after one dose of moxifloxacin, ciprofloxacin, ofloxacin, levofloxacin or gatifloxacin (Figure 2).⁷ The mean conjunctival concentration of moxifloxacin (18 µg/g) was 7.1 µg/g higher than gatifloxacin (2.54 µg/g). The levels achieved were also well above the MIC of most pathogens.

Likewise, in a penetrating keratoplasty model, Terry Kim, MD, and colleagues found that the peak stroma levels of moxifloxacin (48.5 µg/g) were threefold higher than those for gatifloxacin (15.7 µg/g). ⁸ Another study that used a phacoemulsification model, performed at the Wilmer Eye Institute, found that the aqueous humor concentrations for moxifloxacin via high performance liquid chromatography (HPLC) analysis were 1.80 µg/mL, 3.8 times higher than those for gatifloxacin (0.48 µg/mL) (Figure 3). ^9,10 So ample evidence exists in humans that moxifloxacin delivers the highest concentration in any of these anterior segment tissues in which we want to both treat and prevent infection.¹¹

O’Brien: Well-controlled, randomized, comparative human data indicate that moxifloxacin achieves three-times greater concentrations in corneal tissue and almost four-times greater concentrations in the aqueous humor with identical dosing compared to gatifloxacin. What concentration is the formulation of gatifloxacin used in Japan?

Ohashi: The Japanese formulation of gatifloxacin contains 3 mg/mL.

O’Brien: Moxifloxacin is formulated at a higher concentration than gatifloxacin, 5 mg/mL. But these greater concentrations in the tissue exceed what we would expect to see. Is there any explanation for this?

Mah: Moxifloxacin appears to be slightly more lipophilic than other fluoroquinolones. Moxifloxacin can rapidly go through the epithelium as well as the stroma and through the Descemet’s membrane. Several in vitro scientific studies document moxifloxacin’s chemical properties.^12,13

Mean Cmax of moxifloxacin 0.5% and gatifloxacin 0.3% in human aqueous humor Figure 3. Improved peak levels of moxifloxacin in corneal and aqueous humor penetration enhance efficacy.10

Shimomura: In Japan, right now levofloxacin is the most popular fluoroquinolone. Are there data comparing levofloxacin and moxifloxacin in terms of flora sensitivity? Is there a keratoplasty or phacoemulsification model for levofloxacin?

O’Brien: Data show that moxifloxacin achieves higher levels than levofloxacin.

Mah: The Abelson study was a head-to-head study of various fluoroquinolones, and moxifloxacin levels were 7.7 times higher than was observed for levofloxacin (2.34 µg/g). Another recent study compares moxifloxacin with levofloxacin in a cataract surgery setting.

O’Brien: So at the same concentration, moxifloxacin provides greater accumulation in the tissues. Again, this speaks to some intrinsic properties of the molecule that allow it to reach higher levels in the ocular tissues than could be explained by formulation concentration alone.

What human data are there with regard to topical dosing to achieve high levels in the aqueous and vitreous humors?

Alfonso: A multicenter study examined two dosing regimens in the setting of cataract surgery.¹⁴ The study showed that moxifloxacin can reach high levels in the aqueous well beyond the MIC levels of most of the pathogens that cause endophthalmitis (25- to 35-fold higher than the median MICs for S. aureus and S. epidermidis isolates). Also, no significant difference in the maximum concentration of drug (C_max) was observed between dosing four drops at 15-minute intervals before surgery compared with four doses the day before surgery followed by four drops at 15-minute intervals before surgery.

Mah: Dr. O’Brien’s study at the Wilmer Eye Institute showed excellent penetration of moxifloxacin into the anterior chamber. A study by Seenu M. Hariprasad, MD, and colleagues showed that topical moxifloxacin dosing enters the vitreous.¹⁵ Dosing every 2 hours for several days resulted in levels of 0.11 µg/mL in the vitreous. This is a significant level because the MIC for many ocular isolates was exceeded. Dosing every 2 hours is aggressive, but preoperative vitreous levels can potentially be achieved this way.

Cataract surgery: antibiotic therapy goals

O’Brien: What are your goals when you establish an antibiotic regimen for either cataract or refractive surgery?

Colin: Given the potential for a devastating outcome, endophthalmitis must be prevented following cataract surgery, even if the incidence of complications is low (0.1% in a Swedish study in 2002¹⁶ and 0.5% in an Irish study in 2005¹⁷). Efforts are focused in two areas: eradicating bacteria on the surface of the conjunctiva and eyelids and reducing the incidence of intraocular contamination.

Ohashi: My goal is to keep the ocular surface clean throughout the surgery. I would like to do whatever is necessary to achieve this goal: preoperative topical fluoroquinolones for 3 days, ocular surface irrigation with povidone-iodine, neat draping of the lid margin and so on. I believe continuous irrigation of the ocular surface as well as thorough washing of the anterior chamber, including the posterior capsular bag, are strong weapons to eliminate invading pathogens. I routinely apply a copious amount of a fluoroquinolone topically to achieve the highest possible aqueous concentration at the end of the surgery.

O’Brien: So at the conclusion, you try to give a loading dose, to achieve therapeutic penetration.

Alfonso: That is the “monsoon” method of treating — applying as much antibiotic to the surface as possible in a short period — vs. the “earthquake” method, in which one tries to work outward from the interior. It is important not just to sterilize the ocular surface, but to penetrate the aqueous at a high therapeutic concentration. And the newer fluoroquinolones — moxifloxacin especially — do this.

It is important not just to sterilize the ocular surface, but to penetrate the aqueous at high therapeutic concentrations. And the newer fluoroquinolones — moxifloxacin especially — do this. –— Eduardo Alfonso, MD

Studies have shown that to get that high concentration, both in the cornea and the aqueous, physicians do not need to treat for so many days before surgery. Those concentrations can be achieved treating on the day of surgery preoperatively on a frequent basis. Whether we increase safety by starting a few days before surgery and possibly eliminating some of the surface flora, thereby decreasing the contamination rate, is an interesting concept. Studies show that may or may not be effective.¹⁸ I do not want to miss an opportunity to eliminate flora from the surface that may get inside the eye.

Sometimes I do not trust the systems in place for applying the drops, either the patient who is supposed to be using them before surgery or the nursing staff applying drops the day of surgery. By asking that both be done, I have a system that ensures that the patient receives drops at some point.

O’Brien: The idea of applying a substantial amount of antibiotic at the conclusion of the case makes sense, because we want to not only sterilize the surface before our incisions, but also try to eradicate any bacteria that may have entered the eye at the time of the procedure.

Shimomura: Beginning during cataract surgery and until after the IOL is implanted, I irrigate the surface of the IOL and inside the capsular bag as much as possible.

Ohashi: Antibiotics can be added in the irrigating solution. But I believe physical irrigation is more powerful to remove invading pathogens.

O’Brien: Dr. Ohashi, you have had the opportunity to use newer-generation fluoroquinolones in Japan. How will this new generation help you achieve your goals of sterilizing the surface or at least significantly reducing conjunctival colonization and, more importantly, achieving protective levels in the internal compartment?

Ohashi: The significant problem with ocular surface sterilization with topical antibiotics is the persistence of coagulase-negative staphylococci and Propionibacterium acnes. If newer-generation fluoroquinolones can eliminate these pathogens, it would be a great benefit for any ophthalmic surgeon. In addition, anterior chamber contamination can be more efficiently managed if the newer-generation fluoroquinolones can achieve protective levels inside the eye.

O’Brien: What other human data show the difference between the older and the newer fluoroquinolones in achieving these goals?

Mah: Our Japanese counterparts mentioned the two key components of preventing infection after surgery. The first is decreasing and eliminating the normal flora of the ocular surface. Many studies show the excellent potency of these newer agents against endophthalmitis isolates.

The other way of trying to decrease the incidence of endophthalmitis or postoperative infection is increasing the concentration of antibiotic in the anterior chamber to eradicate any bacteria that potentially enter the eye during or after surgery. Multiple studies have shown the conjunctival, corneal and anterior chamber levels that the newer fluoroquinolones can achieve.

Study after study has shown that the newer fluoroquinolones achieve better tissue levels than all other topical commercial antibiotics, including older fluoroquinolones. Other studies have found that these agents decrease conjunctival flora excellently. These agents outperform ofloxacin and levofloxacin in U.S. studies, in head-to-head comparisons.

Cataract surgery: infection prevention regimens

O’Brien: There has been some concern in the United States about a rise in rates of endophthalmitis after cataract surgery, despite advances in cataract surgery techniques and technological improvements. One theory is that the trend toward the use of a clear corneal incision without sutures is associated with this rise.

The other factor that is often cited is the changing patterns of resistance among the bacteria and the older-generation agents not being as effective. A study from The University of Utah in the United States that looked at older-generation agents found a higher rate of endophthalmitis, almost three times what has been traditionally found.¹⁹ The antibiotic that penetrated the best reduced the occurrence the greatest, so this concept of therapeutic penetration seemed to be validated in that series.

What are your preoperative and postoperative methods for preventing infection in your routine cataract cases?

Shimomura: I apply levofloxacin eye drops beginning 3 days before cataract surgery, three times a day, and immediately before cataract surgery I use 5% povidone-iodine and then irrigate the eye. For the surgery itself, I use a foldable IOL and an injector system, and I prefer a scleral tunnel incision. After implanting the IOL, I gently irrigate the IOL surface and then suture. It depends on the astigmatism. Sometimes I suture and sometimes I do not. Next, I administer a subconjunctival injection of gentamicin. Finally, I prescribe an oral cephalosporin and levofloxacin three times a day for 3 days.

Ohashi: My method is not very different from Dr. Shimomura’s. In addition to what he does, I administer one drop of levofloxacin 1 hour before the surgery to achieve the optimal aqueous concentration. During the surgery, I also prescribe a systemic fourth-generation cephalosporin, which may be powerful against staphylococci. Then, I apply a copious amount of levofloxacin topically at the end.

O’Brien: A study by Christopher Ta, MD, of Stanford University, showed that a wash was more effective than a single drop of povidone-iodine.²⁰

Shimomura: Hiroshi Shiota, MD, of the Japanese Association for Ocular Infection headed multicenter clinical trials of levofloxacin to determine whether preoperative application prevented endophthalmitis. The antibiotic was applied three times per day for 3 days before cataract surgery. The study results are not yet available.

Ohashi: Also, Dr. Ta published a report that 3-day application of ofloxacin is effective in reducing the isolates in the conjunctiva, during surgery and afterwards.²¹

Mah: Dr. Ta and colleagues recently performed a study with newer-generation fluoroquinolones.²² He compared 3 days of prophylaxis against administration on the day of surgery only, and there was no difference with the newer-generation fluoroquinolones. This appears to be an indication of their improved potency. Three days of treatment is unnecessary, in contrast to the older study he published using ofloxacin that showed that 3 days of treatment cleared the conjunctival flora better than using the antibiotic the day of surgery.

Colin: I use a combination of povidone-iodine 5% and topical fluoroquinolones. Antiseptics work immediately to kill bacteria, while anti-infectives require more time to reach the site of action. The combination of both results in a significantly greater reduction of bacterial colony counts than either applied alone. However, no definitive study has yet been performed that confirms that povidone-iodine decreases the rate of endophthalmitis.

I apply topical gel anesthesia after instilling the povidone-iodine. This technique does not interfere with the efficacy of the antiseptic and increases permeability by reducing the penetration barrier, resulting in a higher antibiotic concentration in the eye. In France, I use a fluoroquinolone preoperatively in four doses spaced 5 minutes apart, and postoperatively in brief pulses, every 2 hours for 48 hours, then six times per day for 5 days. I do not give any antibiotics prior to the day of surgery.

Alfonso: For cataract surgery, which in my case is primarily scleral tunnel cataract surgery under topical anesthesia, I instruct the patients to use moxifloxacin starting 2 days prior to the surgery, four times a day. The day they come into the hospital, as they are being prepared for surgery, the nurses will apply one drop of moxifloxacin every 5 minutes for a total of four drops.

As they come into the operating room suite, the nurse there will add an extra drop of moxifloxacin to the surface of the eye. At the conclusion of the surgery, I instill another one or two drops before the patient receives a plastic shield to protect the eye and goes home. I ask the patients to continue using the antibiotic at home four times a day, usually until they finish the bottle that I gave them preoperatively, so anywhere from 3 to 5 days postoperatively. That concludes the antibiotic treatment for routine cases.

In all cases, I use an antiseptic on the surface of the eye with enough contact time prior to the surgery, usually 5% povidone-iodine, to sterilize the surface. I ensure we use a sterile technique in terms of draping the lid margins.

For a case with intraoperative complications or for patients who may be at a higher risk of infection, I might supplement the topical treatment with systemic moxifloxacin. I give the patient this antibiotic orally starting 2 days before the surgery and continuing for 3 days after the surgery. So they will have received a total of 5 days of orally administered moxifloxacin in addition to the topical. This may enhance the aqueous and some of the vitreous concentration of moxifloxacin to eradicate organisms that may enter these tissues during surgery.²³

Mah: I try to identify patients at risk: patients with blepharitis meibomianitis, for example. I try to treat that before any type of intraocular surgery, for example by performing scrubs at least 1 week before with adjunctive oral doxycycline or bacitracin ointment. If the patient is identified as having blepharitis meibomianitis less than a week before surgery, the evidence suggests it is better to just treat with doxycycline and not do scrubs. In terms of antibiotics, I use them the day of surgery, not 2 or 3 days prior.

One of the compelling reasons to switch to the new generation is the data suggesting that 3 or 4 days of preoperative dosing is not necessary with these agents. — Terrence P. O’Brien, MD

We studied moxifloxacin and its ability to prevent endophthalmitis in rabbits.²⁴ In that study, we used a total of nine drops, including four drops 1 hour before an injection of bacteria into the anterior chamber. We injected 5 X 10⁴ bacteria, and nine drops of moxifloxacin 0.5% were able to prevent endophthalmitis. When we examined subdividing pre-injection and post-injection dosing, the combination of both types of dosing protected the best. If only one type was performed, there were some signs of endophthalmitis in the antibiotic group, although statistically it was still better than the saline group.

I use povidone-iodine, the 10% scrub around the eyes and the 5% solution in the eye. I wait at least 3 to 5 minutes for it to work. I also use draping and similar measures, which have been described. I primarily use a scleral tunnel incision unless a clear corneal incision is indicated. It is important to ensure the incision is meticulous. If it is a suspect incision, a suture should be used.

Following surgery, we do not patch but we use antibiotics every 1 to 2 hours because we use topical anesthesia. When the patient returns the next day, I decrease the dosing to four times a day if the following findings are present: the incision is Seidel negative and healing; the cornea is clear; the anterior chamber has a normal amount of inflammation following surgery; the IOL is centered and clear; and the anterior vitreous is clear without inflammation. If the patient is high risk, I use oral moxifloxacin (Avelox, Bayer) or gatifloxacin (Tequin, Bristol-Myers Squibb), to try to increase drug levels in the vitreous.

O’Brien: One of the compelling reasons to switch to the new generation is the data suggesting that 3 or 4 days of preoperative dosing is not necessary with these agents. A limbal incision rather than a clear corneal incision is used because radial keratotomy and penetrating keratoplasty incisions never heal completely, because the cornea is avascular. So if the surgeon makes the incision at the conjunctival vascular arcade and there is some bleeding, those wounds tend to heal better and may therefore seal more readily. If a surgeon has any doubt that the corneal valve is not working properly, a suture should be applied.

I have a low threshold for using a 10-0 Vicryl absorbable suture on any case that has a suggestion of a wound leak. I am concerned that organisms can gain entrance during this window of vulnerability in the early postoperative period. It is better to have an agent with therapeutic penetration.

Our study¹⁰ confirms that physicians can achieve therapeutic concentrations in the aqueous (Figure 4). But I still use the fluoroquinolones six to eight times per day for the first 48 hours and then four times a day for 5 days, before stopping. Unless there is evidence of a wound leak or another reason to extend treatment beyond that, it is better to stop. The resistance models show that if the antibiotics are continued, resistance increases. These are the only differences in my regimen.

Moxifloxacin and gatifloxacin gram-positive MICs2 in relation to Vigamox solution and Zymar† human aqueous concentrations10 Figure 4. 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 gatifloxacin and moxifloxacin in the study completed by researchers at The Wilmer Eye Institute. †Trademark is the property of its respective owner.

Refractive surgery

O’Brien: Are the goals for prevention in refractive surgery different than those for cataract surgery?

Colin: The goal of prophylaxis for refractive surgery is to reduce the risk of microbial keratitis. Antibiotics used must not only prevent bacterial infection, they must also not interfere with wound healing. Antisepsis is also a key point. Great care should be taken to avoid epithelial toxicity that may induce intraoperative or postoperative complications. Atypical microbial keratitis is the most common infection after LASIK. Surgeons must take care to prevent possible contamination of the surgical field with tap water or distilled water and to avoid the use of non-validated routine disinfectants.

Alfonso: Compared to cataract surgery, physicians are slightly more concerned about the immediate postoperative visual recovery of the patient after refractive surgery, because they are often operating on both eyes at the same time. So they are careful about not inducing any toxicity. With moxifloxacin, there is little or no toxicity.

I have not seen a difference in recovery of vision after LASIK in these patients compared to when I used previous generations of fluoroquinolones, such as levofloxacin or ofloxacin. The goals for visual recovery are slightly different now. The organisms that physicians are concerned with in terms of infection after refractive surgery include the atypical mycobacteria. This organism is not common in endophthalmitis, but in refractive surgery, either isolated cases or clustered cases from one surgeon or one surgery center are reported.

Data from our laboratory and from other laboratories show that the newer-generation fluoroquinolones are probably the best prophylactic agents that physicians can use against these organisms. We have not seen any of these infections at our refractive surgery center at Bascom Palmer since we began using the newer-generation fluoroquinolones. Overall, the incidence of these sporadic and cluster type of infections has probably decreased as surgeons have become more aware of the benefit of the newer-generation fluoroquinolones. Surgeons are also trying to avoid contamination of the ocular surface or instruments with water-containing instruments or devices because mycobacteria tend to grow best in these circumstances.

Mah: A comprehensive survey of the literature published by Margaret A. Chang, MD, MS; Dimitri Azar, MD; and colleagues in Boston and the most recent study by the ASCRS Corneal Committee on organisms causing corneal infections after LASIK and PRK provide interesting epidemiologic information. A review by Chang with Azar’s group²⁵ showed that, in the world literature, about 50% of the post-LASIK keratitis cases were caused by mycobacteria. In a review by Carol Karp, MD, from Bascom Palmer, they showed that the majority of the cases were mycobacteria.²⁶

It was repeated in case report after case report that mycobacteria were a significant pathogenic factor in terms of post-LASIK keratitis. In an ASCRS survey from 2001, refractive surgeons self-reported that about half of their infections were caused by mycobacteria. In 2004, ASCRS repeated the survey. Three years later, mycobacteria were responsible for less than 5% of the cases.^27,28 The one major change in that time was the release of the newer-generation fluoroquinolones in 2003 and their adoption by refractive surgeons. Up to 90% of U.S. ophthalmologists have adopted newer-generation fluoroquinolones. Most likely, the increase in the activity against mycobacteria has decreased the amount of mycobacteria reported. Because this was self-reporting, some biases may exist, but from 50% to less than 5% is a significant change.

Ohashi: Although LASIK is still not popular in Japan, we have never seen mycobacterial keratitis after LASIK. I wonder where this particular pathogen comes from.

The goals for refractive prophylaxis are the same as for cataract surgery. The only difference is that the antibiotic does not need to penetrate into the anterior chamber and the vitreous, only the cornea. — Francis S. Mah, MD

Alfonso: As we have shown in our laboratory, the mycobacteria are prevalent in the water supply, and it is probably a break in the sterility of instrument decontamination that brings in the mycobacteria, especially in the cluster cases. Because we know that the mycobacteria are going to be in water sources, we tell our post-LASIK patients not to go swimming or expose their eyes to areas where contamination can occur. This type of education for physicians, as well as patients, has been effective in decreasing the exposure to mycobacteria, in addition to the use of excellent prophylactic antibiotics, like moxifloxacin.

Shimomura: Most institutions in Japan use topical levofloxacin when they perform LASIK.

O’Brien: In the United States, one of the risk factors with LASIK surgery is an environment that does not meet the same standard as an operating room for intraocular procedures. Maintaining a surgically clean environment is important; regrettably, physicians often let down their guard and were performing LASIK in ambulatory settings that were not surgically clean. But the data that Dr. Mah mentioned are another compelling surrogate of evidence that prophylaxis works and that the newer generation is better than the older generation at protecting against atypical organisms. What is your method for refractive prophylaxis for LASIK and PRK cases?

Mah: The goals for refractive prophylaxis are the same as for cataract surgery. The only difference is that the antibiotic does not need to penetrate into the anterior chamber and the vitreous, only the cornea.

As refractive surgeons, we want to avoid causing toxicity, so we try to decrease the dosing a bit. Instead of using four drops 1 hour before the procedure, whether LASIK or PRK, we instill one drop 30 minutes prior to surgery. We do not place povidone-iodine in the eye because it may contribute to epithelial toxicity, since it can break the bonds between epithelial cells. We use it around the eyelids and lashes only. We try to stay as aseptic as possible, using drapes, gloves, masks and hats.

In the United States, no strict guidelines dictate where excimer laser refractive surgery can be performed, and that might be the reason that we have the prevalence of mycobacteria. At the conclusion of the refractive surgical procedure, whether it is LASIK or PRK, we use an antibiotic. We like to use the antibiotic every 1 to 2 hours for the first 24 hours. Then we reduce the dose to about four times a day for a week until the epithelium is healed.

For PRK, stopping antibiotics depends on when the epithelium is healed. For LASIK, the epithelium heals more quickly, so we stop the antibiotics sooner. It is important to stop the antibiotics without tapering to prevent antibiotic resistance.

Ohashi: I generally apply topical fluoroquinolones 30 minutes prior to surgery and add one drop before surgery begins. I finish the surgery as quickly as possible. And I believe careful washing of the stromal interface is important to eliminate possible pathogens attached there. Postoperatively, I use topical gatifloxacin or levofloxacin for 2 weeks.

Shimomura: Postoperatively, I prescribe oral cephalosporin for 3 days and topical levofloxacin three times per day for 1 week.

Colin: I use topical ciprofloxacin 0.3%, four doses spaced 5 minutes apart. I irrigate the corneal stromal bed with a nonpreserved aminoglycoside before replacing the flap. Postoperatively, I prescribe a topical combination of a corticosteroid and tobramycin, four times per day for 7 days.

O’Brien: The only way my regimen differs is that I apply an antiseptic directly to the surface. I usually apply two to three drops of moxifloxacin prior to the procedure, and then immediately prior to draping the patient I add a drop of 2.5% povidone-iodine. This does not seem to cause more toxicity. The time necessary for the LASIK flap to re-adhere or reposition is an opportunity to add several drops to achieve protective concentrations in the corneal tissue during the period of vulnerability.

Clinical applications: conjunctivitis and keratitis

O’Brien: Please describe or discuss the role of the newer-generation fluoroquinolones for clinical practices.

Ohashi: In Japan, physicians dose three times a day for 1 or 2 weeks for acute bacterial conjunctivitis. How do U.S. physicians dose for this condition?

O’Brien: Sometimes the dosing is as often as four times a day to six times a day for 1 week.

Alfonso: Conjunctivitis is probably the ocular infection most commonly treated with antibiotics. The newer-generation fluoroquinolones are a great benefit in the treatment of conjunctivitis for the reasons we discussed earlier: they are less likely to cause the development of resistant organisms. Using them frequently for a short period is the ideal treatment for conjunctivitis.

Clinical studies showed that, at 3 days of treatment with moxifloxacin, there was already significant clinical improvement in the conjunctivitis compared to the placebo-treated group. So long-term treatment is probably unnecessary. If by 3 days the condition has improved significantly, another few days of treatment may be sufficient. Again, there is no need to taper these antibiotics; just stop them.

O’Brien: Are there organisms that have been increasingly resistant in conjunctivitis?

Colin: In France, over the years, resistance to third-generation fluoroquinolones has increased, and common conjunctivitis and keratitis isolates have become less susceptible. In children, streptococci and Haemophilus influenzae are the most common species.

Shimomura: In Japan, among patients 80 years and older, there is a 30% to 60% rate of MRSA.

Ohashi: We often see chronic conjunctivitis caused by MRSA and MRSE in elderly patients. Unfortunately, the older-generation fluoroquinolones are not very effective for these patients. Topical chloramphenicol has been recommended, but perhaps the newer fluoroquinolones would be more effective.

O’Brien: In the United States, medicolegal concerns about using chloramphenicol exist because of rare reports of idiosyncratic bone marrow aplastic anemia cases. So again, the 8-methoxy fluoroquinolones might be the best choice for providing coverage against these isolates.

Mah: Also, chloramphenicol is bacteriostatic. Unlike the fluoroquinolones, which are bactericidal and actually kill the bacteria, chloramphenicol is an agent that inhibits the growth of bacteria so that the immune system can eradicate the bacteria. Another issue with chloramphenicol is its spectrum of activity, which does not include Pseudomonas. Finally, in the United States, chloramphenicol is not a therapeutic option due to rare reports of idiopathic aplastic anemia.

Shimomura: Chloramphenicol is effective for conjunctivitis, but it is not as effective for keratitis.

O’Brien: The in vitro data from the Bascom Palmer laboratory and the University of Pittsburgh laboratory show us that the new generation should be effective against these organisms. Is this rise in MRSA due to the longer exposure that these older patients have had to antibiotics?

Shimomura: The widespread use of levofloxacin and other second-generation fluoroquinolones may be a cause of this rise in MRSA.

Ohashi: Older patients are prone to longer hospital stays, becoming MRSA carriers.

O’Brien: In the United States, health care workers often become MRSA carriers.

Alfonso: The newer-generation fluoroquinolones have also been shown to be effective against H. influenzae, an organism that physicians are concerned about, especially in pediatric conjunctivitis. Moxifloxacin has been shown to be safe in children as young as 3 days old for conjunctivitis. That is an important feature because toxicity in children was a concern with the previous-generation fluoroquinolones.

O’Brien: How have these new agents changed our approach to the patient with suspected acute bacterial keratitis?

Ohashi: In Japan, the first choice is still second- or third-generation fluoroquinolones. They are still effective against keratitis caused by gram-negative rods, but sometimes we encounter difficulty in treating patients with MRSA or MRSE keratitis.

O’Brien: How does the pharmacokinetics of the new generation compare to those of the old generation?

Human stroma penetration (Cmax) of moxifloxacin and gatifloxacin in penetrating keratoplasty (n=48) Figure 5. Moxifloxacin’s concentration in the cornea was three times that of gatifloxacin’s.8

Mah: There is excellent new corneal data. A multicenter study compared moxifloxacin and gatifloxacin, the two newer-generation fluoroquinolones, in terms of corneal penetration (Figure 5).⁸ Moxifloxacin’s concentration in the cornea was three times that of gatifloxacin. Thus, to manage bacterial keratitis and corneal ulcers, it is important to have an agent that not only has good activity against the organism, but also can penetrate into the cornea to kill the bacteria.

We published a study looking at the efficacy of the newer agents against MRSA in a keratitis model.⁶ Again, it is important to monitor patients clinically despite laboratory results showing bacteria are resistant to therapy. Microbiology laboratory breakpoints utilize systemic standards that are probably not appropriate for ocular therapy, because high frequency dosing can result in significant levels in the tissues. It takes 1 day to identify organisms and another 3 to 4 days to identify their sensitivities. In that period, the physician can evaluate whether the patient’s condition is worsening or improving.

Colin: The availability of newer-generation fluoroquinolones in Europe will change how physicians there approach prophylaxis and therapy. These antibiotics are effective at killing ocular flora, including gram-positive bacteria resistant to older fluoroquinolones. The newer-generation fluoroquinolones have excellent ocular penetration and achieve adequate intraocular bactericidal levels. Europe urgently needs these antibiotics.

Shimomura: Is monotherapy acceptable for a corneal ulcer?

Mah: For small corneal ulcers — 2 mm, non-vision-threatening — we use fluoroquinolone monotherapy. For large corneal ulcers, we add a gram-positive agent, primarily because of the risk of perforation. Our laboratory is now showing about 70% susceptibility to the newer-generation fluoroquinolones. I believe the Bascom Palmer laboratory is showing similar figures. These figures are much better than those for the second- and third-generation agents. If we are concerned about a gram-positive organism, we add either cefazolin, 25 mg/mL or 50 mg/mL, or vancomycin drops, 25 mg/mL or 50 mg/mL.

Colin: If clinical aspects of the cornea suggest a bacterial cause of the ulcer, laboratory procedures are directed toward microorganisms. I immediately start treatment with a standard empiric regimen of broad-spectrum antibacterial therapy. I prescribe drops of ciprofloxacin 3% at 15-minute intervals for the first 24 to 48 hours.

I also prescribe a regimen of stronger antibiotics prepared by the hospital pharmacist: ticarcillin 6 mg/mL, gentamicin 14 mg/mL and vancomycin 50 mg/mL. The patient must be followed closely in the hospital or on an outpatient basis, according to the severity of the infection.

Alfonso: In the United States, corneal ulcers are treated primarily in the community-based setting. Cultures are not performed; the patient is treated empirically. The response rate to this treatment is 90% and higher. In the laboratory, the incidence of MRSA, for example, can be as high as 25% to 40%. Yet we are not seeing a 40% failure rate for the treatment of keratitis in the community. So we can deduce that if MRSA is in the community at a 30% to 40% level, with the use of the newer-generation fluoroquinolones, that resistance is overcome by the excellent penetration and the increased concentration of these antibiotics.

O’Brien: Globally, Pseudomonas aeruginosa causes some of the most severe corneal problems. Have there been any data to suggest that P. aeruginosa, being gram-negative, is not being covered as well by moxifloxacin or gatifloxacin?

Mah: The in vitro information does not show that physicians have lost any efficacy against P. aeruginosa with the newer-generation fluoroquinolones. We did a study examining these agents against Serratia and Pseudomonas in a rabbit model, and they performed better than fortified tobramycin 14%.²⁹ And there was no statistical difference between ciprofloxacin and the newer-generation fluoroquinolones.

Alfonso: From a practical, clinical, therapeutic standpoint, a newer-generation quinolone is more likely to be used by patients, because they do not have to buy a drop that is fortified. They are also less likely to stop treatment, because the drop is not toxic. Newer-generation fluoroquinolones facilitate patient adherence.

Biocompatibility

O’Brien: There have been some discussions in the United States about differences in safety between the newer-generation fluoroquinolones. Can we review the human data that compare gatifloxacin vs. moxifloxacin in terms of safety?

Alfonso: The most scrutinized and, therefore, most important set of data is that submitted to the U.S. Food and Drug Administration for the approval and continued use of the newer-generation fluoroquinolones. Looking at adverse event rates, we see that the incidence is lower for moxifloxacin than for gatifloxacin, but both are within the acceptable limits for safe use.

Our clinical experience with these antibiotics attests to the fact that adverse effects are almost nonexistent. Animal and human data are specifically related to adverse effects in terms of epithelial healing, stromal healing and direct effect on stromal keratocytes and endothelium.

The most interesting studies are those showing human models of PRK, LASEK and LASIK, which show that moxifloxacin and gatifloxacin are safe and do not affect epithelial or anterior stromal healing, when used for prophylaxis in the usual manner.

We performed a study using a confocal microscopy model in human volunteers. We dosed the patients as we would for prophylactic treatment, four times a day for 3 days. In confocal microscopy, we looked at the keratocytes and the endothelium both qualitatively and quantitatively. We could not find any difference between the patients treated with saline and those treated with moxifloxacin. Other studies since then have documented similar findings (Figure 6).^30,31

Comparison of the effect of fourth-generation fluoroquinolones on epithelial healing following PRK in humans Figure 6. Moxifloxacin (Vigamox) is biocompatible, does not interfere with wound healing and does not cause toxicity.32 *Trademark is the property of its respective owner.

O’Brien: The human data are reassuring and more relevant to the clinician using these antibiotics. Some studies have over-extrapolated animal data in species that may not be comparative to humans. Some models have suggested collagen toxicity in rodent and mouse species that may not apply to human usage.

Some of the most compelling data come from the U.S. military, where the greatest number of refractive procedures is being performed in the United States.

Mah: Jenna Burka, MD, and colleagues performed a nonsponsored contralateral study of surface PRK in the military.³² Because it was the military, the study was highly regulated. There were no corporate sponsors, and it was randomized and masked. They examined different rates of healing; one eye received gatifloxacin, the other moxifloxacin. They created a 9-mm epithelial defect and did PRK, and found that both groups did well.

Moxifloxacin-treated patients healed between 3 and 7 days while gatifloxacin-treated patients healed anywhere between 3 and 9 days. Statistically, moxifloxacin patients healed about 1 to 2 days faster. That was a statistically significant number in the 100 patients used in this bilateral PRK model.

O’Brien: In Japan, the regulatory requirements are stringent, even after a drug is marketed, for careful monitoring, surveillance and reporting. Have there been any concerns thus far in Japan with the use of the 8-methoxy fluoroquinolones?

Ohashi: I have not heard of any serious cornea problems with gatifloxacin, perhaps because the formulation used in Japan does not contain the preservative.

Shimomura: Can patients detect a difference between formulations?

Alfonso: In our study, the patients could not tell which eye was receiving what medication, and there was a contralateral control.

O’Brien: Another large study, by Daniel Durrie, MD, and colleagues, in LASIK and LASEK refractive surgery settings, showed a similar lack of toxicity and discomfort or irritation.³³ There was a low level of irritation as with any eye drop, but nothing significant. Patients could not tell the difference between the drops.

Mah: In an unpublished communication from Richard Yee, MD, from the Hermann Eye Center in Houston, Texas, while he was studying re-epithelialization of levofloxacin, moxifloxacin and gatifloxacin in PRK patients, he indicated that he stopped the levofloxacin arm because it was too toxic. It was not an intensive dosing schedule, only four times per day.

O’Brien: On behalf of Ocular Surgery News, I want to thank all of my colleagues for participating and sharing all of their information from Asia, Europe and North America. I want to thank our supporter, Alcon, for its educational grant that has helped make this possible. We look forward to receiving this information and disseminating it across the globe to try to change preferred practice patterns.

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