This patient presented with a pronounced Pseudomonas ulcer. What is the most effective treatment strategy?

The management of bacterial eye infections was revolutionized by the development of topical fluoroquinolones. All fluoroquinolones have an FDA indication for the treatment of bacterial conjunctivitis. In 2004, Iquix (1.5% levofloxacin, Vistakon), a third-generation agent, received an additional FDA approval for the treatment of bacterial corneal ulcers. Since then, fourth-generation fluoroquinolones evolved with varying concentrations and dosing (see “Commonly Prescribed Topical Fluoroquinolones,” below).

Nonetheless, all newer generation fluoroquinolones are used off-label for numerous conditions from ulcerative keratitis to infection prevention in pre- and post-surgical care. Looking back over the last 20 years, we must ask if these drugs are living up to their promise and what will the future of ocular infection management and prevention look like? Regardless, our biggest concern going forward is the development of emerging resistance patterns to topical fluoroquinolones.

Mechanism of Action
Topical fluoroquinolones are antibiotic agents that block bacterial DNA synthesis by inhibiting the topoisomerase enzymes. Older-generation topical fluoroquinolones (ciprofloxacin, ofloxacin and levofloxacin) specifically target the DNA enzyme topoisomerase IV, which is more susceptible in gram-negative bacteria.^1,2 However, the fourth-generation fluoroquinolones (moxifloxacin, gatifloxacin) contain a substitution of a methoxy group at position eight of the quinolone ring, which additionally facilitates topoisomerase II (DNA gyrase) inhibition in gram-positive organisms.

This dual mechanism of action promotes increased bactericidal activity against gram-positive organisms without sacrificing the gram-negative coverage provided by older-generation fluoroquinolones.³ Most importantly, targeting both topoisomerase II and IV likely reduces resistance because concomitant mutations in both genes are much less likely to occur than a single mutation in one gene.^4,5

Drug Penetration and Tissue Concentration
For topical fluoroquinolones to be effective in the treatment of ocular infections, they must exhibit satisfactory minimum inhibitory concentration (MIC) scores, high penetration rates into ocular tissues/aqueous and broad susceptibility profiles, as well as posess the ability to thwart resistance.

The MIC is defined as the lowest possible concentration of an antibiotic that is able to prevent overnight micro-organism growth in a tissue culture. Typically, MIC90 (the MIC score required to inhibit bacterial growth in at least 90% of targeted strains) is the standard measure of bactericidal efficacy for topical anti-infective agents. Note that the lower the MIC90 value, the more potent the agent is against a given isolate.

The ocular surface poses a challenge to drug administration and pharmacokinetics. Tears act as a drug-delivery barrier, effectively diluting the agent and facilitating drainage via the nasolacrimal system upon rapid blinking following instillation.⁶ Therefore, MIC scores derived from in vitro laboratory testing may not accurately reflect on-eye MIC values. Delivering the drug to the target tissue, as well as remaining there long enough to be effective in vivo, is of equal importance. Compared to their systemic counterparts, topical antibiotics often must be dosed at higher concentrations to increase drug penetration and sustain effective therapeutic levels.

The fourth-generation fluoroquinolones offer the best penetration profile; in particular, moxifloxacin and 1.5% levofloxacin fared well in corneal penetration studies.^{7-9, 15-18}

Drug Enhancements

Commonly Prescribed Topical Fluoroquinolones
Generic Name	Brand Name and Approval Date	Manufacturer	Classification	Indication
0.3% Ciprofloxacin	Ciloxan, December 1990	Alcon, generic	2nd Generation	Bacterial Conjunctivitis
0.3% Ofloxacin	Ocuflox, July 1993	Allergan, generic	2nd Generation	Bacterial Conjunctivitis
0.5% Levofloxacin	Quixin, August 2000	Vistakon	3rd Generation	Bacterial Conjunctivitis
0.3% Gatifloxacin	Zymar, March 2003	Allergan	4th Generation	Bacterial Conjunctivitis
0.5% Moxifloxacin	Vigamox, April 2003	Alcon	4th Generation	Bacterial Conjunctivitis
1.5% Levofloxacin	Iquix, March 2004	Vistakon	3rd Generation	Bacterial Corneal Ulcers
0.6% Besifloxacin	Besivance, May 2009	Bausch + Lomb	Novel (no systemic equivalent)	Bacterial Conjunctivitis
0.5% Gatifloxacin	Zymaxid, May 2010	Allergan	4th Generation	Bacterial Conjunctivitis
0.5% Moxifloxacin	Moxeza, November 2010	Alcon	4th Generation	Bacterial Conjunctivitis

In an effort to amplify antibiotic concentration on the ocular surface and improve penetration, many ocular pharmaceutical companies developed enhanced or reformulated versions of existing fluoroquinolones during the last eight years. For example, Vistakon released Iquix in 2004, which contained more than double the concentration of levofloxacin in Quixin.¹⁰ Also, in May 2010, Allergan brought Zymaxid to the market, which contained 0.2% more gatifloxacin than Zymar.¹¹

Then, in November 2010, Alcon released Moxeza as a successor to Vigamox. In this instance, the concentration of moxifloxacin was not increased. Instead, the company reformulated Vigamox with a new delivery vehicle, xanthan gum. In clinical trials, the xanthan gum facilitated increased corneal penetration of moxifloxacin. Most significantly, the increased drug penetration of Moxeza permitted b.i.d. dosing vs. t.i.d. dosing for Vigamox.¹²

Bausch + Lomb’s release of Besivance (besifloxacin) in 2009 was a significant development in ocular antibiotics. Besifloxacin was developed for the sole purpose of ophthalmic use, and has no systemic counterpart.¹³ This unique aspect could potentially help minimize resistance to the drug over the long term. The drug features a unique chlorine group located at position eight of the quinolone ring, as well as an aminoazepinyl component at the C-7 location, which may enhance activity against gram-positive bacteria.¹⁴

Additionally, Besivance uses the DuraSite vehicle (InSite Vision), which prolongs the drug’s contact time on the ocular surface and enhances corneal penetration. Finally, it is important to note that Besivance just received an additional FDA indication for the treatment of conjunctivitis associated with Pseudomonas aeruginosa in September 2012.

The Effect of BAK
For many years, researchers have debated the potential benefits and limitations of the preservative benzalkonium chloride (BAK) in topical antibiotics. In topical medications that are commonly used long-term, such as glaucoma agents, the presence of BAK has been shown to cause ocular surface inflammation and corneal damage.¹⁵ However, it has been suggested that, because BAK disrupts the ocular surface, it actually may enhance corneal penetration of the drug. Furthermore, BAK has been shown to increase epithelial permeability and trans-scleral drug delivery.¹⁶ Currently, Vigamox, Moxeza and Iquix are the few topical fluoroquinolones that do not contain BAK.

Interestingly, some studies indicated that BAK-preserved Zymar is more effective at targeting methicillin-resistant Staphylococcus aureus (MRSA) than BAK-free Vigamox in vitro.¹⁷ Other in vitro research suggested that, while BAK may enhance an antibiotic’s effect, it is cleared by the tears rapidly.¹⁸ More specifically, the study author noted that the concentration of BAK in the tears is undetectable five minutes after installation.18

Bactericidal Resistance
In addition to corneal penetration, pharmacodynamics (e.g., kill rates, resistance patterns and susceptibility profiles) is another crucial aspect of topical fluoroquinolones. Studies suggest that MICs for fourth-generation fluoroquinolones are lower (better) than second-generation fluoroquinolones for all gram-positive organisms.^19,20 The MIC90 for ciprofloxacin was lower in gram-negative bacteria compared to the newer-generation fluoroquinolones, and was the most effective against Pseudomonas among all topical fluoroquinolones tested.^19,20

Bactericidal resistance is a result of many factors, including overprescribing and negligent prescribing of antibiotics (e.g., errant use of antibiotics for a viral condition), improper dosing (including patient non-compliance), and widespread use of antibiotics in the livestock industry. Infection by drug-resistant organisms such as MRSA and methicillin-resistant Staphylococcus epidermidis (MRSE) is a growing concern in the ophthalmic community. According to the Centers for Disease Control and Prevention, 1.5% of the population (4 million Americans) are MRSA carriers.²¹ Patients in nursing care facilities, health care workers, and those who live in communities where skin-to-skin contact is prevalent are at higher risk for MRSA infections.²¹

The Antibiotic Resistance Monitoring in Ocular Microorganisms (ARMOR) study was designed to monitor antibiotic susceptibility trends in ocular isolates.²² The results indicated that 39% of S. aureus ocular isolates were methicillin resistant and 38% were fluoroquinolone resistant. Among the coagulase-negative staphylococci isolates sampled from ocular infections, 53% were methicillin resistant and 43% were fluoroquinolone resistant.²² This is similar to the original data collected by The Surveillance Network (TSN) from 2001 to 2006, which revealed multidrug-resistant MRSA in ocular isolates.²³ Of interest, TSN researchers noted that trimethoprim was the most effective agent against MRSA.²³

Currently, the Ocular Tracking Resistance in the United States Today (TRUST) program is the largest annual, longitudinal, nationwide surveillance of antibiotic resistance. Since the program’s launch in 2005, Ocular TRUST researchers have evaluated the in vitro susceptibility of Staph., Strep., and Haemophilus ocular isolates to numerous antibiotics.²⁴ The most recent data from Ocular TRUST suggests that just 15% to 30% of MRSA isolates are susceptible to currently available topical fluoroquinolones (Besivance was not evaluated, because it was not yet FDA approved at study initiation).²⁴

The combined results from ARMOR, TSN and Ocular TRUST show that resistance to multiple antibiotics is prevalent among ocular bacterial pathogens. Again, keep in mind that in vitro resistance does not necessarily equate to in vivo resistance. Still, eye care clinicians must consider the potential danger associated with such expanding resistance patterns.

Recommendations for Fluoroquinolone Use

• Don’t underdose an active infection. Antibiotics with the lowest MIC values and the highest delivery concentration are best suited to eradicate ocular infections. For active infections, dose antibiotics at their recommended frequency to eliminate the bacteria quickly. The greatest risk for the development of antibiotic resistance comes from sustained sub-therapeutic dosing, which doesn’t eradicate the infection but potentially affords it time to mutate. • Be judicious in prophylactic use. When used for surgical prophylaxis, antibiotics can be discontinued sooner than in cases of active infection. A recent study found that repeated fluoroquinolone use after intravitreal injection led to increased rates of resistance.30 So, instead of using prophylactic antibiotics, many retinal specialists now are using facemasks and iodine/aseptic techniques during injection to minimize the risks of infection. For infection prevention in cataract surgery, good wound architecture is critical. Today, with femtosecond laser-assisted surgery, wound leaks and consequent endophthalmitis risks may be less likely. • Avoid overprescribing. Improper diagnosis of red eye is a specific instance when topical antibiotics frequently are overprescribed. Too often, pediatricians, urgent care physicians and even optometrists/ophthalmologists prescribe antibiotics for conditions other than bacterial conjunctivitis, when the diagnosis is not clear. Overprescribing propagates bactericidal resistance, so exercise good clinical judgment when using an antibiotic. • Choose an appropriate antibiotic. Consider reserving a “big gun” antibiotic, such as a fourth-generation fluoroquinolone, for the most serious infectious cases. Second-generation fluoroquinolones, aminoglycosides or azithromycin (Azasite, Merck) are alternative antibiotic choices for infections that are not sight threatening. Such alternatives may be effective, and choosing them could potentially limit fourth-generation antibiotic resistance. Also, review the FDA drug safety classification for children and pregnant patients. For example, Azasite may be a good choice for pregnant or nursing mothers because it is a Category B drug. • When in doubt, culture. Smears and cultures are recommended in cases that involve a large infiltrate (>3mm); are chronic in nature or appear unresponsive to broad-spectrum antibiotic therapy; or that exhibit atypical clinical features indicative of fungal, amoebic or Mycobacterium keratitis. The sensitivities from cultures can help guide appropriate antibiotic selection. In cases of suspected bacterial keratitis, fourth-generation fluoroquinolones routinely are used off-label and are widely accepted as first-line therapy. Depending on its location and severity, microbial keratitis can be a sight-threatening condition. For central or severe keratitis, a loading dose (q15m for the first hour) followed by frequent applications (q1h around the clock) is recommended. For drug-resistant pathogens, such as MRSA or MRSE, fluoroquinolones may not prove effective. If a bacterial infection is not clinically responsive to aggressive treatment with a fluoroquinolone, suspect MRSA/MRSE. Consider treatment with fortified vancomycin, trimethoprim or sulfacetamide.31 In these instances, be certain to obtain cultures in an effort to select the most effective antibiotic. Additional therapeutic options that may be effective against MRSA/MRSE include bacitracin ointment, cefazolin injection and oral linezolid. Concurrent use of oral rifampin and linezolid have been shown to be more effective in the treatment of preseptal cellulitis/cutaneous infections than intravenous vancomycin.32 • Be wary of Mycobacterium. Regarding refractive surgery, infection rates fortunately are low. But, if an infection occurs, atypical Mycobacterium infiltrates may be of greatest concern. Although rare, Mycobacterium are found in ultrasound water baths used for instrument processing or in surgical field moisture. In any confirmed case of Mycobacterium chelonae infection, researchers at Johns Hopkins recommend 500mg clarithromycin b.i.d., topical tobramycin and a fourth-generation fluoroquinolone.33 • Consider the cost. Because of rising medication prices, patients are sometimes forced to use generic antibiotics in lieu of branded medications. Newer-generation fluoroquinolones have the broadest antimicrobial spectrum. But, if patients cannot afford these, which generic agent is best? To date, no studies offer a real solution to this question, and practitioners are faced with the ongoing dilemma of cost vs. efficacy. However, generic trimethoprim-polymyxin B should be considered when there is a risk of MRSA. Despite being an older drug, more than 90% of MRSA isolates were susceptible to trimethoprim in vitro.28 Also, the second-generation fluoroquinolones are cost effective, and have a broad spectrum of coverage. They are a good choice if a generic is needed. Regardless, educate patients about the potential risks associated with having to choose between the lower cost of generic medications and the therapeutic superiority of branded drugs.

Use in Surgical Prophylaxis
Topical antibiotics are used routinely for infection prevention in all forms of ocular surgery. The discussion about appropriate use of prophylactic antibiotics is a hot topic among eye care professionals due to increased resistance patterns. Some studies have reported increased endophthalmitis rates since 2000 despite prophylactic antibiotic use.²⁵

There are several possible reasons why endophthalmitis is on the rise. For example, more surgeons perform cataract surgery using sutureless, clear corneal incisions, which are more prone to leakage. Additionally, intravitreal anti-VEGF and steroidal injections are being administered more frequently for the treatment of macular degeneration and diabetic eye disease.

Most cases of postoperative endophthalmitis are due to S. epidermidis, followed by S. aureus.²⁶ Further, epidemiologic evidence suggests that MRSA is responsible for approximately 3% of all endophthalmitis cases.²⁶

The overall rate of endophthalmitis after uncomplicated cataract surgery in patients who received prophylactic treatment with gatifloxacin and moxifloxacin was 0.07%.²⁶ Another study found a similar endophthalmitis rate for those who received gatifloxacin and moxifloxacin (0.056%), but a higher incidence in patients who were treated with ciprofloxacin and ofloxacin (0.197%).²⁷

These data suggest that the fourth-generation fluoroquinolones are more effective against gram-positive organisms and may be the superior choice for surgical endophthalmitis prevention. Fortunately, the risk of post-surgical infection is extremely rare. And ultimately, the low rates of endophthalmitis also make it exceedingly difficult to compare the prophylactic efficacy of different antibiotics exhaustively.

During the last few years, intracameral antibiotics have been evaluated for use in ocular surgery. A recent study by the European Society of Cataract & Refractive Surgeons (ESCRS) showed that cefuroxime injection can reduce endophthalmitis risk in cataract surgery.²⁸ Further, intracameral injections have the potential to help reduce postoperative patient noncompliance/drop confusion, and could be more cost effective than topical anti-infective use.

The primary barrier to wider adoption of intracameral antibiotic administration in the United States is the lack of a commercially available drug. Cefuroxime, for example, must be compounded manually, which exposes the patient to bacterial contamination and toxic anterior segment syndrome.

In lieu of cefuroxime, some American cataract surgeons are using intracameral administration of moxifloxacin and vancomycin to reduce or eliminate postoperative antibiotic drops.²⁹ However, we must be cautious in recommending this practice––especially considering that, in the ESCRS study, patients still used levofloxacin postoperatively for one week.²⁸

Newer-generation fluoroquinolones have become the topical antibiotic of choice in the prevention and treatment of ocular infections due to their high tissue concentrations, low MIC rates and broad spectrum of coverage. Nonetheless, eye care providers must be educated about the rising rates of increased fluoroquinolone resistance in certain pathogens, including MRSA.

We should make every effort to ensure an accurate diagnosis of bacterial infections to avoid unnecessary overuse of antibiotics. In cases where topical antibiotics are indicated, use them aggressively for a defined period. For infections that do not respond, perform cultures.

Today, we are fortunate to have several extremely effective antibiotic agents in our armamentarium. But, to prevail in the battle against ocular infection, we must use these drugs in a judicious capacity to limit further bactericidal resistance.

Dr. Muckley is the director of optometric services at Northeast Ohio Eye Surgeons in Kent and Stow, Ohio. She has no financial interest in any of the products mentioned. She can be contacted at 330-678-0201 or DrEDM1@aol.com.

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