How to Manage Ocular Infection
Anti-infective agents play a key role in the management of several conditions. But, which drugs provide the best efficacy in which situations?
Anti-infective agents play an important role in containing and eliminating bacterial contamination and colonization in the eyes of our patients. Also, they can be used in prophylaxis in cases of trauma or surgery. This course is a review of several such topical anti-infective agents and combination drugs, as well as the conditions that necessitate them, such as bacterial conjunctivitis, blepharitis and bacterial keratitis.
Alan G. Kabat, O.D.
This course is COPE qualified for 1 hour of CE Credit. COPE ID 20711-AS. Please check with your state licensing board to see if this approval counts toward your CE requirement for relicensure.
This continuing education course is joint-sponsored by the University of Alabama School of Optometry.
This course is sponsored by an unrestricted educational grant from Alcon Laboratories, Inc.
Dr. Kabat is a member of Alcon’s Speakers Alliance and a consultant to Cynacon/OCuSOFT.
The ability to control bacterial contamination and colonization of ocular structures is fundamental to ensure the visual welfare of our patients. Anti-infective agents are invaluable weapons in our pharmaceutical armamentarium. Such drugs are widely prescribed for both active infection and prophylaxis.
Here is a review of the most common conditions that require an anti-infective treatment, and a rundown of current topical anti-infective agents and combination drugs.
Many situations call for the use of anti-infective agents. Here are the most likely conditions:
- Bacterial conjunctivitis. Most topical antibiotics are indicated for the treatment of bacterial conjunctivitis. While generally not sight-threatening, bacterial conjunctivitis is a highly contagious disorder that often disrupts patients’ normal activities (e.g., work or school) for a week or longer if not treated promptly. The symptoms of bacterial conjunctivitis can be particularly unpleasant; a thick, mucopurulent discharge is characteristic, though patients may also complain of severe ocular irritation, photophobia, periocular swelling and variably disrupted vision (figure 1).
- Blepharitis. Blepharitis is another indication for the use of topical anti-infective agents. Although lid hygiene with detergent-based products (e.g., OCuSOFT Lid Scrub Foam) is sometimes adequate to control bacterial overgrowth on the lid margins, many practitioners prefer to employ anti-infectives for more severe cases.
- Bacterial keratitis. Bacterial keratitis (e.g., bacterial corneal ulceration) is a sight-threatening disorder that demands prompt and aggressive management with topical anti-infective agents. Untreated keratitis can result in permanent corneal scarring and subsequent degradation of vision. In severe cases, untreated bacterial ulcers can lead to corneal perforation. Since most practicing clinicians do not routinely culture bacterial keratitis, broad-spectrum anti-infective agents with maximal efficacy and minimal resistance must be used.1
- Prophylaxis. Cases of ocular trauma often warrant the use of a topical anti-infective for prophylaxis. Some conditions, such as corneal abrasions or conjunctival lacerations, can compromise the ocular surface, leaving the eye vulnerable to potential bacterial colonization due to a loss of barrier function. Likewise, the eye may be predisposed to infection following chemical or thermal burns, and requires protection from antimicrobial drugs.
But, the most common reason for employing topical anti-infective drugs is probably peri-operative prophylaxis. While sterile techniques significantly reduce the risk of microbial infection in cataract and refractive surgery patients, broad-spectrum antibiosis employed before and after procedures is the current standard of care. Surgeons typically select their agent of choice based upon its potency against a wide range of common bacterial pathogens, as well as the drug’s ability to penetrate and achieve significant concentrations in the cornea and anterior chamber.
Weigh the Options
More than a dozen brand-name topical ophthalmic antibiotics are currently available in the United States, in addition to many generic options.
Many older drugs, such as sulfacetamide, erythromycin or neomycin compounds, have developed resistance to community-acquired infections and have the potential for generating local toxicity reactions.
Aminoglycosides, such as gentamicin and tobramycin, are still widely used; yet, these drugs have similar shortcomings. Developed for topical use in the 1980s, aminoglycosides have also developed bacterial resistance, and gentamicin in particular can be extremely corneotoxic when used at high doses or for prolonged periods of time.2,3
Even the earlier fluoroquinolones, like ciprofloxacin and ofloxacin, are being used less frequently today because of complications regarding efficacy and toxicity.4
So, newer topical anti-infective agents may provide a more reliable treatment option.
- Zymar (gatifloxacin, Allergan),
a fourth-generation fluoroquinolone, achieves bactericidal activity
by interfering with DNA synthesis
and simultaneously blocking two
key enzymes necessary for bacterial
replication (DNA gyrase and topoisomerase IV). This is significant
because earlier fluoroquinolones,
such as ciprofloxacin and ofloxacin,
typically block only one of these
enzymes in a given pathogen.
Such increased potency allows gatifloxacin to demonstrate greater activity against a wide range of gram-positive organisms (e.g., Staphylococcus and Streptococcus) while maintaining similar efficacy against gram-negative bacteria (e.g., Haemophilus).5
Approved in early 2003, Zymar is indicated for the treatment of bacterial conjunctivitis in patients one year of age and older. Dosing is every two hours for the first two days, then every six hours for the next five days.
Zymar is preserved with benzalkonium chloride (BAK), which has the propensity to cause epithelial toxicity.6-8 Still, Zymar has been widely utilized for both the treatment of ocular surface infections and ocular prophylaxis since its release.
- Vigamox (moxifloxacin, Alcon) is also a bactericidal fourth-generation fluoroquinolone. In addition
to blocking DNA gyrase and topoisomerase IV, moxifloxacin
incorporates a unique strategy
against bacterial efflux, the defense
mechanism whereby pathogenic
organisms pump anti-infective drugs
out of the cellular cytoplasm. Moxifloxacin incorporates a bulky chemical side-chain at the C-7 position,
effectively anchoring itself within the
bacteria, and cannot be extruded.
This increases its residence time and
further combats resistance.9
Vigamox was approved in April 2003 for the treatment of bacterial conjunctivitis, but rapidly became prescribed for a variety of clinical applications, including keratitis management and surgical prophylaxis. In addition to demonstrating superior gram-positive coverage, Vigamox is very biocompatible.10
This low incidence of toxicity arises from two factors: Vigamox is self-preserved and does not contain additional agents like BAK, and it boasts a near-neutral pH (6.8), allowing for greater comfort and less risk of precipitate.11
In cases of bacterial conjunctivitis, dosing for Vigamox is t.i.d. for seven days.
- zaSite (azithromycin, Inspire).
The most recent addition to the field
of topical ophthalmic antibiotics,
azithromycin is, by current standards, a relatively old drug. The oral formulation (Zithromax, Pfizer)
received FDA approval in 1991.
A member of the macrolide family, azithromycin works by interfering with protein synthesis. But, unlike other drugs that use this strategy (e.g., tobramycin), azithromycin is merely bacteriostatic. In addition, the activity of this drug is limited by intrinsic bacterial efflux mechanisms.12
AzaSite was approved in early 2007 for the treatment of bacterial conjunctivitis. Its most appealing aspect is improved dosing for bacterial conjunctivitis: b.i.d. application for the first two days, followed by once-daily dosing for five additional days—nine total drops per affected eye. This is possible because AzaSite incorporates a polymeric mucoadhesive delivery system that enhances residence time on the eye.13
When selecting the best antibiotic for a given situation, consider not only the convenience of the dosage schedule, but also the efficacy of the drug. In terms of anti-infective agents, efficacy is best expressed in terms of the drug’s ability to eradicate a wide range of potential pathogens.
Among the three aforementioned agents, Vigamox demonstrates clinical efficacy against 12 bacterial strains and in vitro efficacy against 43 organisms.10 Zymar has documented clinical efficacy against six organisms and in vitro efficacy against 37.5 AzaSite is more limited, showing clinical efficacy against five organisms and in vitro efficacy against 15 (figure 2).14
Clinical studies have consistently shown that Vigamox penetrates ocular tissues more readily than Zymar—and that it achieves higher tissue concentrations as well. This is uniformly true for the conjunctiva, cornea and anterior chamber.15-17
Moxifloxacin also exhibits lower MIC90 values than gatifloxacin for many bacterial pathogens, including Staphylococcus epidermidis, Propionibacterium acnes and atypical mycobacteria, such as M. chelonae and M. avium.18,19
But, to date, no in vivo head-to-head comparisons between Vigamox and AzaSite or Zymar and AzaSite have been published. There is concern over the use of azithromycin in the ophthalmic arena, due to a significant macrolide-resistance rate among common pathogens.20 A recent study by David Stroman, Ph.D., and associates revealed alarmingly high resistance to azithromycin in organisms cultured from conjunctivitis and blepharitis, especially Staphylococcus aureus, S. epidermidis and Haemophilus influenza.21
Similar results were observed by Ohnsman and associates (figure 3). MIC90 values from conjunctival cultures of S. aureus, S. epidermidis, H. influenza and Streptococcus pneumoniae were all found to be substantially higher than the resistance breakpoint for azithromycin—in some cases, more than 128 times higher.22
Studies suggest that the most significant driving force for macrolide resistance is the continued inappropriate use of these drugs, and that even ophthalmic use can potentially drive systemic resistance.23,24
In contrast, bacterial resistance is exceedingly rare with drugs like gatifloxacin and moxifloxacin due to bactericidal mechanisms of action and limited systemic use.25 Practitioners must consider this when deciding what drug to use for routine ocular infection and prophylaxis.
Two Drugs: Better Than One
One category of ophthalmic agents that has exceptional utility in clinical practice is the antibiotic-corticosteroid combination. These drugs carry a class indication “for steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists.”26
In other words, combination drugs are most appropriately used to treat inflamed, red eyes that require concurrent antibiotic prophylaxis (figure 4). While there are no specific indications, some of the clinical disorders in which combination agents may be useful include: Staphylococcus blepharitis, marginal keratitis (i.e., “sterile ulcers”), superficial corneal trauma and shield ulcers in vernal or atopic keratoconjunctivitis.
Then, too, there are various “non-specific” presentations that may benefit from these drugs; Ron Melton, O.D., and Randall Thomas, O.D., have suggested that as many as half of all red eye cases warrant treatment with a combination agent.27
Ideally, the quintessential combination drug would combine the most broad-spectrum antibiotic that has the lowest potential for toxicity with the most potent corticosteroid with exceptional bioavailability to ensure rapid resolution of the inflammation. Hypothetically, that would be equivalent to the efficacy of a fourth-generation fluoroquinolone combined with the potency of prednisolone acetate 1%—in reality, however, dexamethasone 0.1% is a prime steroid for use in such combination drugs.
The seven commercially-available antibiotic-steroid combinations possess different strengths and weaknesses by virtue of their respective components. Of these, three deserve further discussion:
- Maxitrol (dexamethasone 0.1%/neomycin 0.35%/polymyxin B, Alcon). This combination agent has the benefit of an extremely potent corticosteroid, but incorporates neomycin as an antibiotic, which can induce contact allergy.28
- TobraDex (dexamethasone 0.1%/tobramycin 0.3%, Alcon). Given the options, the most effective and least toxic antibiotic available in a combination agent is likely tobramycin, the anti-infective found in TobraDex.
- Zylet (loteprednol etabonate 0.5%/tobramycin 0.3%, Bausch & Lomb). Like TobraDex, Zylet incorporates the effective tobramycin, but replaces the steroid with loteprednol.
Both TobraDex and Zylet are very effective, very useful drugs for patients with infection and inflammation. Still, is one steroid more effective than the other? Is one steroid safer than the other? Only one head-to-head comparison between TobraDex and Zylet has been published so far.29
In this study of 40 eyes with moderate to extensive blepharokeratoconjunctivitis, patients were prescribed either TobraDex or Zylet b.i.d. for three to five days. Those treated with TobraDex demonstrated clinically and statistically greater improvement in conjunctival and lid inflammation, as well as ocular discharge, when compared with those treated with Zylet.
On the issue of safety, consider all factors carefully. Loteprednol, a ketone-based steroid, has an overall lower propensity than prednisolone or dexamethasone to induce intraocular pressure (IOP) elevation.30,31
Then again, corticosteroid-induced IOP elevation is typically a function of both duration and dosage; the more frequently and the longer a steroid is used, the greater the potential for IOP rise. In most cases, this phenomenon takes four to six weeks to develop.32 Combination agents are usually prescribed for only four to seven days, and rarely for more than two weeks. So, secondary glaucoma is not likely a substantial concern for most patients.
In the empirical treatment and prophylaxis of ocular infection and inflammation, it is science—not sentiment—that must dictate the logical choice. Convenience and perceived safety, while important in overall drug selection, must be secondary considerations after clinical efficacy. The drug that achieves the most rapid and complete cure is the one that we must select for our patients.
Dr. Kabat is an associate professor at Nova Southeastern University College of Optometry, in Fort Lauderdale, Fla., where he also serves as an attending physician at The Eye Care Institute.
- McDonnell PJ, Nobe J, Gauderman WJ, et al. Community care of corneal ulcers. Am J Ophthalmol 1992 Nov 15; 114(5):531-8.
- Egger SF, Ruckhofer J, Alzner E, et al. In vitro susceptibilities to topical antibiotics of bacteria isolated from the surface of clinically symptomatic eyes. Ophthalmic Res 2001 MarApr;33(2):117-20.
- Lin N, Gong XM, Xie QJ, Shao MR. Study in cytotoxicity of gentamycin to corneal epithelium and endothelium in tissue culture. Yan Ke Xue Bao 1989 Jun;5(1-2):32-5.
- Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistance in bacterial keratitis: a 5-year review. Ophthalmology 1999 Jul;106(7):1313-8.
- Allergan. Zymar package insert. Irvine, CA, 2004.
- Ichijima H, Petroll WM, Jester JV, Cavanagh HD. Confocal microscopic studies of living rabbit cornea treated with benzalkonium chloride. Cornea 1992 May;11(3):221-5.
- Tripathi BJ, Tripathi RC, Kolli SP. Cytotoxicity of ophthalmic preservatives on human corneal epithelium. Lens Eye Toxic Res 1992;9(3-4):361-75.
- Labbe A, Pauly A, Liang H, et al. Comparison of toxicological profiles of benzalkonium chloride and polyquaternium-1: an experimental study. J Ocul Pharmacol Ther 2006 Aug; 22(4):267-78.
- Pestova E, Millichap JJ, Noskin GA, Peterson LR. Intracellular targets of moxifloxacin: a comparison with other fluoroquinolones. J Antimicrob Chemother 2000 May; 45(5):583-90.
- Mather R, Karenchak LM, Romanowski EG, et al. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol 2002 Apr; 133(4):463-6.
- Alcon. Vigamox package insert. Fort Worth, TX, 2004.
- Pechere JC. Macrolide resistance mechanisms in Gram-positive cocci. Int J Antimicrob Agents 2001;18 Suppl 1:S25-8.
- Protzko E, Bowman L, Abelson M, Shapiro A; for the AzaSite Clinical Study Group. Phase 3 safety comparisons for 1.0% azithromycin in polymeric mucoadhesive eye drops versus 0.3% tobramycin eye drops for bacterial conjunctivitis. Invest Ophthalmol Vis Sci 2007 Aug;48(8):3425-9.
- Inspire Pharmaceuticals. AzaSite package insert. Durham, NC, 2007.
- Wagner RS, Abelson MB, Shapiro A, Torkildsen G. Evaluation of moxifloxacin, ciprofloxacin, gatifloxacin, ofloxacin, and levofloxacin concentrations in human conjunctival tissue. Arch Ophthalmol 2005 Sep;123(9):1282-3.
- Holland EJ, Lane S, Kim T, et al. Human cornea and aqueous humor concentrations of moxifloxacin and gatifloxacin following topical ocular dosing with Vigamox solution or Zymar. Invest Ophthalmol Vis Sci 2006;47: ARVO E-Abstract 3577.
- Kim DH, Stark WJ, O'Brien TP, Dick JD. Aqueous penetration and biological activity of moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% solution in cataract surgery patients. Ophthalmology 2005 Nov;112(11):1992-6.
- Stroman DW, Cupp G, Dahlin DC, et al. Human ocular concentrations following topical fluoroquinolone administration relative to susceptibility of ocular pathogens. Invest Ophthalmol Vis Sci 2006;47: ARVO E-Abstract 1881.
- Schlech BA, Stroman DW, Alfonso E, et al. The threat of atypical mycobacteria in ophthalmology. Presented at the Ocular Microbiology and Immunology Group (OMIG) meeting. November 15, 2003; Anaheim, CA.
- Lavergne V, Thibault L, Garceau R. Macrolide resistance in streptococcal pharyngitis. Can Med Assoc J 2007 Jul 17;177(2):177.
- Stroman DW, Cupp GA, Schlech BA. Resistance patterns in conjunctivitis and blepharitis in 2006. Invest Ophthalmol Vis Sci 2007;48: ARVO E-Abstract 2680.
- Ohnsman C, Ritterband D, O’Brien T, Girgis D, Kabat A. Comparison of azithromycin and moxifloxacin against bacterial isolates causing conjunctivitis. Curr Med Res Opin 2007 Aug 8; [Epub ahead of print].
- Malhotra-Kumar S, Lammens C, et al. Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: a randomised, double-blind, placebo-controlled study. Lancet 2007 Feb 10;369(9560):482-90.
- Gaynor BD, Chidambaram JD, Cevallos V, et al. Topical ocular antibiotics induce bacterial resistance at extraocular sites. Br J Ophthalmol 2005 Sep;89(9):1097-9.
- LaPlante KL, Rybak MJ, Tsuji B, et al. Fluoroquinolone resistance in Streptococcus pneumoniae: area under the concentration-time curve/MIC ratio and resistance development with gatifloxacin, gemifloxacin, levofloxacin, and moxifloxacin. Antimicrob Agents Chemother 2007 Apr;51(4): 1315-20.
- Alcon. TobraDex package insert. Fort Worth, TX, 2002.
- Melton R, Thomas R. 2007 Clinical Guide to Ophthalmic Drugs. Rev Optom 2007 Jun; 144(6):Suppl 22A.
- Menezes de Padua CA, Schnuch A, Lessmann H, et al. Contact allergy to neomycin sulfate: results of a multifactorial analysis. Pharmacoepidemiol Drug Saf 2005 Oct; 14(10):725-33.
- Rhee SS, Mah FS. Comparison of tobramycin 0.3%/dexamethasone 0.1% and tobramycin 0.3%/loteprednol 0.5% in the management of blepharo-keratoconjunctivitis. Adv Ther 2007 Jan-Feb;24(1):60-7.
- Controlled evaluation of loteprednol etabonate and prednisolone acetate in the treatment of acute anterior uveitis. Loteprednol Etabonate US Uveitis Study Group. Am J Ophthalmol 1999 May;127(5):537-44.
- Bartlett JD, Holland E, Pribadi–Behm M, et al. Ocular tolerance and IOP effects of Zylet compared to TobraDex administered four times daily for four weeks in healthy volunteers. Invest Ophthalmol Vis Sci 2006;47: E-Abstract 5559.
- Becker B. Intraocular pressure response to topical corticosteroids. Invest Ophthalmol 1965;4:198-205.