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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