DEC 2012

EyeWorld is the official news magazine of the American Society of Cataract & Refractive Surgery.

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16 EW NEWS & OPINION December 2012 Antibiotics continued from page 15 ���[Fourth-generation ���uoroquinolones are] so effective in vitro against so many different organisms that it makes sense to use them even though they don���t have the label��� rial corneal ulcers because there were not enough of those cases in comparison to the bacterial conjunctivitis cases,��� Dr. de Luise said. W. Barry Lee, M.D., practicing partner, Eye Consultants of Atlanta, and Piedmont Hospital, Atlanta, explained that it���s much more cost effective for companies to go after FDA approval for treatment of bacterial conjunctivitis because ���that���s the label that is the easiest to get and that saves them the most amount of money.��� In the off-label box Only three fluoroquinolones are approved for bacterial keratitis. ���One was the very first that became effective, which is ciprofloxacin,��� Dr. Lee said. ���It has a bacterial keratitis label.��� He pointed out that the other two fluoroquinolones with a label for bacterial keratitis are the secondgeneration fluoroquinolone ofloxacin, and the third-generation fluoroquinolone levofloxacin, the latter of which received keratitis labeling for its more concentrated 1.5% Iquix formulation (Vistakon Pharmaceuticals, Jacksonville, Fla.). However, continued use of these agents may not be wise, Dr. de Luise fears, precisely because they have been around for so long; the concern is that the bacteria are already becoming resistant. Still, he thinks, it may be possible to use Iquix, the newest of the fluoroquinolones that are FDA-labeled for keratitis, because of its higher concentration. ���Since fluoroquinolones are concentrationdependent antibiotics, the higher concentration of Iquix at 1.5% gives it a superior efficacy profile against at least some ocular isolates,��� Dr. de Luise said. This makes use of the newer fluoroquinolone medications an obvious choice for practitioners, but with a hitch. ���Any time we use a fourth-generation fluoroquinolone for corneal ulcers, whether it be moxifloxacin [Vigamox, Alcon, Fort Worth, Texas], gatifloxacin [Zymar, Allergan, Irvine, Calif.], or besi- floxacin [Besivance, Bausch + Lomb, Rochester, N.Y.], we���re using it offlabel,��� Dr. Lee said. ���But they���re so effective in vitro against so many different organisms that it makes sense to use them even though they don���t have the label.��� Despite the labeling, Dr. de Luise pointed out that it is up to practitioners to be acquainted with the standard of care here. ���A licensed physician has the ethical and legal ability to choose in terms of good medical practice and the best interest of the patient,��� he said. ���Physicians are allowed to use legal, available drugs, biologics, and devices according to their best knowledge and judgment.��� However, the FDA dictates that there are three responsibilities for physicians using medications offlabel. First and foremost, a practitioner must be well-informed about a particular product, Dr. de Luise explained. ���Number two would be to base the use of that product on scientific rationale and sound medical evidence,��� he said. ���The third would be to maintain records of the products used in that particular patient, including side effects.��� When drugs are used off-label, companies have their hands tied on what they can say about products. Representatives of products such as gatifloxacin, moxifloxacin, and besifloxacin are only allowed to discuss these antibiotics with regard to bacterial conjunctivitis. ���It is commonly accepted that the physician will do what he or she feels is appropriate,��� Dr. de Luise said. Therefore, many physicians are using fourthgeneration fluoroquinolones as their go-to medication for the corneal ulcer patient that comes into the office as they���re about to finish their afternoon of patients. Ironically, he pointed out that those who don���t adhere to the community standard of care may do so at their own legal peril. ���The legal definition of malpractice is whether there was a deviation from the standard of care,��� Dr. de Luise said. This ultimately trumps the FDA label in cases where community standards are to use a medication off-label, he stressed. Reliable regimens Kathryn Colby, M.D., associate professor of ophthalmology, Harvard Medical School, Boston, finds that moxifloxacin and gatifloxacin are commonly used as first-line treatments for infectious keratitis-related corneal ulcers. After taking a good history and where possible culturing the ulcer, she finds that most practitioners move to these broad-spectrum fluoroquinolones. ���Probably the vast majority of corneal ulcers in the United States get treated empirically with one of those broad-spectrum fluoroquinolones,��� Dr. Colby said, adding that these are generally much better tolerated than previously used compounded, fortified antibiotics. She pointed out that while there has been an increase in resistance to the fluoroquinolones, for corneal ulcers this is not as much of an issue, thanks to ready accessibility. ���The cornea is right there so you can give drops every hour and provide a high local concentration,��� Dr. Colby said. ���Despite the resistance in the laboratory, we still use those agents, primarily gatifloxacin and moxifloxacin, as the primary therapy for most corneal ulcers.��� She does not have a particular drug preference here, apart from insurance access. ���In my experience there is not any dramatic evidence to prefer one broad-spectrum fluoroquinolone over the other,��� Dr. Colby said. She acknowledged, however, that the more concentrated fluoroquinolones would allow for more drug to be delivered. Dr. Lee emphasized the importance of culturing the ulcer and then empirically starting the patient on an antibiotic while awaiting results. This can be in the form of fluoroquinolone monotherapy or in conjunction with another fortified antibiotic. He tends to prefer besifloxacin. ���It���s the newest of the generations and it has been shown to be more effective against methicillin-resistant Staph aureus and methicillinresistant Staph epidermidis,��� he said. ���So far, in vitro it looks as if it���s the best of the fluoroquinolones against those two bad bugs.��� For larger ulcers in particular Dr. Lee prefers this because practitioners are seeing more resistant bacteria in these cases. ���The difference with besifloxacin is it has DuraSite [InSite Vision, Alameda, Calif.], which makes it stay in contact with the ocular surface, thereby increasing retention time,��� Dr. Lee said. ���You don���t have to dose it every hour like you do with some of the other agents because its contact time is higher.��� But for smaller ulcers, when using other fluoroquinolones, Dr. Lee tends to dose these at one drop every 1-2 hours. He may urge patients to continue this regimen throughout the night or use some type of fluoroquinolone ointment like Ciloxan (ciprofloxacin, Alcon) in the eye right before bedtime. Once the ulcer begins improving, this can be decreased to four to six times a day. ���Once I get to where the epithelium is intact I���ll typically stop the fluoroquinolone,��� Dr. Lee said. Dr. de Luise also sees besifloxacin as having an edge against resistance since this is the only fluoroquinolone designed specifically for the eye. As a result, there has been no systemic exposure of bacteria to systemically applied besifloxacin. In addition to a fluoroquinolone during the day, he advocates use of a broad-spectrum ointment such as polymyxin B/bacitracin at night. In cases where insurance is an issue, he emphasized that it is perfectly reasonable to choose the older antibiotic Polytrim (trimethoprim sulfate and polymyxin B sulfate, Allergan). This is a combination antibiotic and one that the bugs haven���t seen in a while, he pointed out, and it has good efficacy against many methicillin-resistant staphylococcal (MRSA and MRSE) isolates. Going forward, while the fluoroquinolones remain the first choice for the moment, Dr. de Luise envisions that ultimately ophthalmic biopharma will go in other directions and begin to develop different types of ocular antibiotics, such as a topical formulation of linezolid, to combat corneal ulcers and other ocular infections. Meanwhile, Dr. Lee thinks that the fourth-generation fluoroquinolones have been an amazing addition to antimicrobial treatment for ophthalmology in general. ���Hopefully we���ll continue to develop new products,��� he said. EW Editors��� note: Drs. Colby and de Luise have no financial interests related to this article. Dr. Lee has financial interests with Bausch + Lomb and Allergan. Contact information Colby: 617-573-3938, kacolby@meei.harvard.edu de Luise: 203-263-3300, vdeluisemd@gmail.com Lee: 404-556-2202, lee0003@aol.com

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