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COVER STORY New Options for Treating Ocular Infection The eye care specialist’s armamentarium has been strengthened by the recent approvals of several new agents to combat bacterial and viral infections of the eye. BY MARC BLOOMENSTEIN, OD, AND DEREK N. CUNNINGHAM, OD B etween 2003 and 2009, few topical antimicrobials made it through the rigorous and expensive FDA approval process, and those that did have failed to gain any significant market share. During the last 2 years, however, a new antiviral and several new antibiotics have become available. The increased costs of clinical trials coupled with more demanding and strict requirements by the FDA will continue to limit what comes to market in the future. Currently, the FDA has no ongoing clinical trials for new topical ocular antibiotics and only one trial for a new antiviral. Eye care specialists can therefore anticipate a paucity of new antiinfective topical ocular medications over the next several years, and the latest products promise to be eye care specialists’ go-to drugs during that period. This article provides an overview of these agents. ANTIVIRAL AGENT Widely used internationally for more than 15 years, Zirgan (ganciclovir ophthalmic gel 0.15%; Bausch + Lomb) recently entered the US market. Until then, the only topical antiviral medication available in this country for treating herpetic keratitis was Viroptic (trifluridine ophthalmic solution 1%; Monarch Pharmaceuticals, Inc.). Although effective, Viroptic induces significant toxicity.1,2 That problem combined with possible keratitis can often lead to noncompliance. For that reason, many clinicians avoid prescribing the drug and instead choose oral antivirals such as acyclovir and valacyclovir. The corneal toxicity with Viroptic prompted most European doctors to abandon the use of this topical agent decades ago in favor of topical acyclovir and ganciclovir. Efficacy and tolerability are the main factors that distinguish Zirgan from Viroptic. Trifluridine is a nonselective inhibitor of DNA replication in both viral and host cells, leading to corneal cellular toxicity and likely delayed wound healing. In contrast, ganciclovir is a prodrug that preferentially activates infected cells. Ganciclovir is transformed by viral and cellular thymidine kinases to ganciclovir triphos40 ADVANCED OCULAR CARE NOVEMBER/DECEMBER 2010 phate, which works as an antiviral agent. Another differentiating feature of Zirgan is its preservative—benzalkonium chloride—whereas Viroptic is preserved with thimerosal. In terms of dosing, Zirgan has an advantage over Viroptic. The former is stored at room temperature, and one drop should be administered in the affected eye five times a day until the dendritic ulcer resolves. Thereafter, it is instilled three times a day for 7 days. Viroptic requires refrigeration and must be instilled nine times a day. Zirgan is indicated for the treatment of herpetic keratitis. In addition, some clinicians are evaluating the agent as an off-label treatment for conditions such as viral conjunctivitis and the drug’s concomitant but off-label use with oral antiviral medication. ANTIBIOTICS Background Manufacturers develop new antibiotics to address the constant evolution of bacteria (ie, organisms that were once susceptible and now are not). Surveillance studies by research groups such as Tracking Resistance in the US Today (TRUST) have documented a rapid increase in organisms such as methicillin-resistant Staphylococcus aureus (MRSA) and the emergence of multidrug-resistant bacteria.3 Although newer-generation antibiotics are capable of treating most common bacteria, even more effective medications are needed to combat resistant strains. Within the last year, the FDA has approved three antibiotics that appear capable of tackling some of the more resilient bacteria. Besivance Bausch + Lomb’s Besivance (besifloxacin 0.6%) is approved for the treatment of bacterial conjunctivitis. Unlike other quinolone antibiotics, this drug is the first chloro-fluoroquinolone, and it has demonstrated tremendous success in the elimination of common ocular pathogens as well as MRSA in preliminary microbiological studies.4 The availability of an antibiotic that demonstrates significant effectiveness at minimum inhibitory concentra- COVER STORY tions should be a real boon to physicians and their patients as the threat of MRSA grows. Besivance is formulated as an ophthalmic suspension using DuraSite (InSite Vision, Inc.) as the vehicle that prolongs the contact time of the antibiotic with the ocular surface. This extended contact time has exhibited significant anti-inflammatory properties, including the prohibition of 14 different cytokines and/or inflammatory mediators.5 As a strong bactericidal agent with anti-inflammatory properties, Besivance may eradicate infection while causing less discomfort and damage to tissue than previous generations of antibiotics. The extended contact time and high kill rates, however, have produced some ambiguity as to the drug’s dosing schedule. In FDA studies, the therapeutic effect of the drug was maintained for 12 hours, but the agent was initially submitted for t.i.d. dosing. The FDA therefore approved the medication for dosing every 4 to 12 hours with a t.i.d. indication. Bausch + Lomb is now re-evaluating the drug for submission to the FDA for a b.i.d. indication. Zymaxid Zymaxid (gatifloxacin ophthalmic solution) 0.5% from Allergan, Inc., is indicated for the treatment of bacterial conjunctivitis. At 0.5%, this topical agent is now the highestconcentration gatifloxacin solution commercially available in the United States (the previous formulation of gatifloxacin had a concentration of 0.3%). Because fluoroquinolones must bind to an adequate number of binding sites on their target, the higher the agent’s concentration, the greater its bactericidal activity. In terms of off-label indications, Zymaxid should prove to be an effective adjunctive agent for the prophylactic treatment of bacteria in ophthalmic surgery. The goal of pretreatment of the eye is to eliminate the bacteria that commonly reside on the ocular surface in a rapid and highly effective manner. Zymaxid can be safely administered up to eight times a day, but a loose dosing schedule of two to four times daily on days 2 through 7 allows more drops of the drug to be delivered to the ocular surface per day. Tobradex ST The antibiotic-steroid combination Tobradex is available as a generic formulation but just received a makeover from Alcon Laboratories, Inc. Tobradex ST (tobramycin 0.3%/dexamethasone 0.05% ophthalmic suspension) is approved for the treatment of steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated, and the drug is also indicated when superficial bacterial ocular infection or a risk of bacterial ocular infection exists. The most obvious change from the original formulation is the reduction of dexamethasone from 0.1% to 0.05%. This decrease will likely alleviate some concerns related to safety. The second change is less obvious but more substantial: the replacement of hydroxyethyl cellulose in the original Tobradex with xanthan gum in Tobradex ST. According to Alcon Laboratories, Inc., xanthan gum decreases settling of the drug in the bottle and increases its viscosity on the eye. Thus, the contact time between Tobradex ST and the ocular surface is supposed to be similar to that of the DuraSite vehicle that is used in other ophthalmic drugs. Tobradex ST has the same indications and dosing as the original formulation with an emphasis on treating blepharitis. The landscape for blepharitis-specific therapy is sure to expand, and this drug appears to be an important addition to the existing options for treatment. CONCLUSION The development of anti-infectives will continue as bacteria continue to mutate. Manufacturers will also update existing formulations to meet the changing needs for treatment. Alcon Laboratories, Inc., is currently working on a reformulation of Vigamox (moxifloxacin ophthalmic solution ) 0.5% that will have a higher concentration than the original and will contain xanthan gum to increase the agent’s contact time with the ocular surface. Alcon’s expected approval date for this drug is November 22, 2010. The new anti-infectives will allow eye care specialists to be more effective in their treatment of patients. These agents address many limitations of earlier pharmaceuticals, as clinicians are just beginning to appreciate. Anecdotal stories and discussions of the drugs’ off-label applications suggest that these products will be quite successful. Clinical experience will make the final determination. ■ Marc Bloomenstein, OD, is the director of optometric services at the Schwartz Laser Eye Center in Scottsdale, Arizona. He sits on advisory panels for Alcon Laboratories, Inc.; Allergan, Inc.; and Bausch + Lomb. Dr. Bloomenstein may be reached at [email protected]. Derek N. Cunningham, OD, is the director of optometry at Dell Laser Consultants in Austin, Texas. He is a consultant to Allergan, Inc.; Bausch + Lomb; and Inspire Pharmaceuticals, Inc. Dr. Cunningham may be reached at [email protected]. 1. Imperia PS,Lazarus HM,Dunkel EC,et al.An in vitro study of ophthalmic antiviral agent toxicity on rabbit corneal epithelium. Antiviral Res.1988;9(4):263-272. 2. Lass JH,Langston RH,Foster CS,Pavan-Langston D.Antiviral medications and corneal wound healing. Antiviral Res. 1984;4(3):143-157. 3. Asbell PA,Colby KA,Deng S,et al.Ocular TRUST:nationwide antimicrobial susceptibility patterns in ocular isolates. Am J Ophthalmol.2008;145(6):951-958. 4. Haas W.Besifloxacin,a novel fluoroquinolone,has broad-spectrum in vitro activity against aerobic and anaerobic bacteria. Antimicrob Agents Chemother.2009;53(8):3552-3560. 5. Zhang JZ,Ward KW.Besifloxacin,a novel fluoroquinolone antibiotic agent,exhibits potent inhibition of pro-inflammatory cytokines in human THP-1 monocytes. J Antimicrob Chemother.2008;61(1):111-116. NOVEMBER/DECEMBER 2010 ADVANCED OCULAR CARE 41