The fluoroquinolones, the newest class of agents to be developed, are based on the prototype nalidixic acid (1,8-naphthyridine), which was synthesized in 1962.⁴⁶

In the 1980s, the fluoroquinolones were created from nalidixic acid by adding a fluorine atom to position 6 of the molecule (Fig. 39.1). This addition widened the antibacterial spectrum of activity and resulted in decreased development of resistant organisms. The newer fluoroquinolones available for ophthalmic use include gatifloxacin ophthalmic solution 0.5% (Zymaxid, Allergan, Inc., Irvine, California), gatifloxacin 0.3% (Zymar, Allergan, Inc.), moxifloxacin HC1 ophthalmic solution 0.5% (Moxeza, Alcon Laboratories, Inc., Fort Worth, Texas), moxifloxacin 0.5% (Vigamox, Alcon Laboratories, Inc.), besifloxacin ophthalmic suspension 0.6% (Besivance, Bausch and Lomb, Rochester, New York), levofloxacin ophthalmic solution 1.5% (Iquix, Vistakon Pharmaceuticals, LLC, Jacksonville, Florida), and levofloxacin ophthalmic solution 0.5% (Quixin, Vistakon Pharmaceuticals, LLC). In addition to the fluoroquinolone eyedrops, there is a fluoroquinolone ophthalmic ointment, ciprofloxacin (Ciloxan, Alcon Laboratories, Inc.), and generic formulations available of the prior-generation fluoroquinolones, ofloxacin and ciprofloxacin. The previous-generation fluoroquinolones predominantly either inhibit topoisomerase II (DNA Gyrase) or topoisomerase IV and, therefore, only require one genetic mutation for bacteria to develop resistance.⁴⁷ Fourth-generation fluoroquinolones are equally effective against bacterial topoisomerases II and IV, which significantly expands their spectrum of action against gram-positive agents and atypical mycobacteria and Nocardia.⁴⁸, ⁴⁹ This duality of action of the fourth-generation fluoroquinolones requires that for bacteria to become resistant to these agents, the bacteria must undergo two genetic mutations resulting in a significantly decreased chance of an organism developing resistance.⁵⁰ The fluoroquinolones are bactericidal by interfering with bacterial DNA replication, transcription, repair, and recombination.

Gatifloxacin differs from the prior-generation ciprofloxacin in two positions, but the enhanced activity of the molecule compared with ciprofloxacin is due to a methoxy group at the 8-position of the fluoroquinolone structure. Moxifloxacin has the same group at the 8-position, but differs from gatifloxacin at the 7-position of the molecule. The 8-methoxy substitution yields a better coverage against gram-positive organisms, including resistant strains, while preserving the similar coverage against gram-negative organisms seen in prior generations of fluoroquinolones.⁵¹

The ophthalmic fluoroquinolones are indicated for the treatment of conjunctivitis. However, because of their broad-spectrum antibacterial activity, they are also used to minimize the risk of postoperative endophthalmitis after cataract surgery, postoperative keratitis after keratorefractive procedures, and to treat bacterial keratitis.⁵² Minimum inhibitory concentrations determined in vitro suggest that fourth-generation fluoroquinolones are more effective than second- and third-generation fluoroquinolones against gram-positive bacteria, including Staphylococcus sp. found in endophthalmitis and bacterial keratitis cultures.⁵⁰, ⁵³ When selecting a fourth-generation fluoroquinolone, it is important to consider potency, ocular penetration, efficacy, and safety. In addition, the acute management of bacterial corneal ulcers requires rapid access to therapy. The cost and toxicity of antibiotic therapy must also be considered. Fortified antibiotics are not commercially available and must be prepared on request. The fluoroquinolones are superior with respect to accessibility, cost, and low toxicity. The fluoroquinolones perform at least as well as, and often better than, the aminoglycosides in the treatment of gram-negative corneal ulcers. Prompt, appropriate treatment decreases the length of time to eradication of the infection, minimizes the risk of sequelae, helps prevent the spread of infection, and reduces the time away from daily activities.

Since there are two ophthalmic formulations of gatifloxacin and moxifloxacin, and no current generic formulations, brand names will be used in this section. The commercial ophthalmic formulations of gatifloxacin, Zymar and Zymaxid, and the commercial formulation of besifloxacin contain the preservative benzalkonium chloride (BAK) 0.005%, whereas the commercial ophthalmic formulations of moxifloxacin 0.5%, Vigamox and Moxeza, contain no BAK. As noted, Zymaxid contains a higher concentration (0.5%) of the antibacterial agent gatifloxacin found in Zymar (0.3%). In addition, Iquix is also a preservative-free formulation.

The addition of the methoxy group at the 8-position of the ring structure increased the potency against gram-positive bacteria by 4-fold from ciprofloxacin to gatifloxacin, resulting in a lower minimal inhibitory concentration (MIC). In comparing gatifloxacin with moxifloxacin, gatifloxacin was shown to be significantly more active against ocular isolates of P. aeruginosa with an MIC₉₀ of 1.28 versus 2.60 mg/mL for moxifloxacin.⁵⁴ In addition, gatifloxacin was demonstrated to have slightly better activity than moxifloxacin against some gram-negative pathogens. As noted, Zymar and Zymaxid are formulated with the preservative BAK. The preservative is frequently included to prevent contamination of the bottle that could be picked up by skin flora if the bottle comes in contact with the skin during instillation. In addition, the antibiotic formulation is not antifungal, but the Zymar and Zymaxid formulations are resistant to contamination by fungi. It has been reported that BAK in the Zymar and Zymaxid formulations may enhance their antibacterial activity as shown by more rapid killing and lower MICs.⁵²

Moxeza⁵⁵ is a reformulation Vigamox with a new vehicle, xanthan gum, which supports BID labeling because the new formulation allows the antibiotic to remain on the eye longer and increases penetration into the ocular tissues. Moxeza is dosed two times per day for 7 days and is indicated for patients 4 months of age and older.

A multicenter, vehicle-controlled, randomized, doublemasked, parallel group study was conducted on Moxeza to evaluate in vivo safety and efficacy.⁵⁵ The study group included clinically diagnosed bacterial conjunctivitis in 1,180 patients aged greater than 28 days (range 30 days to 92 years). Moxeza or its vehicle was dosed one drop twice daily for 3 days. Microbiologic specimens were obtained from affected eyes on day 1, prior to the initial dose, and on day 4 after 3 days of dosing. All recovered bacteria were identified to the species level. The microbiologic success rate for patients treated with Moxeza twice daily for 3 days was 74.5%, compared with 56.0% of patients treated with its vehicle control (P < .0001). Moxeza was also statistically more effective than vehicle in eradicating the three principle conjunctivitis pathogens, H. influenzae (98.5% vs. 59.6%, respectively), Streptococcus pneumoniae (86.4% vs. 50.0%, respectively), and Staphylococcus aureus (94.1% vs. 80.0%, respectively) (P < .001). This clinical study demonstrated that the use of Moxeza resulted in effective eradication of the three principal causative pathogens of bacterial conjunctivitis across all age groups when dosed twice daily for 3 days.⁵⁵

As indicated by Tauber et al., the majority of topical ophthalmic antibiotic products approved in the United States for the treatment of bacterial conjunctivitis have a 7- to 10-day treatment regimen, totaling a minimum of 21 to 42 or more drops over a course of therapy. A full course of therapy with Moxeza is 14 drops over 7 days. Results from this Tauber’s demonstrate that Moxeza, when dosed topically twice daily for 3 days (total six drops per eye), was statistically superior to its vehicle in the percentage of patients classified as microbiologic successes after 3 days of treatment (75% vs. 56%, P < .0001). Moxeza was also significantly more effective than its vehicle in eradicating the three principle conjunctivitis pathogens. The eradication rate of H. influenzae was 98.5% for Moxeza versus 59.6% for its vehicle; Streptococcus pneumoniae was 86.4% for Moxeza compared with 50.0% for vehicle, and Staphylococcus aureus was 94.1% for Moxeza compared with 80.0% for vehicle.⁵⁵ BAK alone has significant in vitro cytotoxicity to cultured ocular epithelial cells. As Moxeza is preservative-free, there is no risk of corneal toxicity that may occur secondary to the BAK preservative. With respect to the issue of the potential of enhanced potency of Zymar due to BAK, some have argued that the BAK does not enhance potency because it is rapidly diluted in the tear film, weakening its ability to enhance potency when it reaches the ocular surface. In addition, it has been pointed out that the less-concentrated ophthalmic formulation of moxifloxacin, Vigamox, does not need a preservative because of the intrinsic antibacterial and antifungal activities of its formulation.

The fluoroquinolones have low rates of adverse effects.⁷⁰ The most frequently reported adverse events of Zymaxid were worsening of the conjunctivitis, eye irritation, dysgeusia, and eye pain. For Zymar, the most frequently reported adverse reactions occurring in 5% to 10% of patients were conjunctival irritation, increased lacrimation, keratitis, and papillary conjunctivitis. Less frequently reported reactions found in 1% to 4% of patients were chemosis, conjunctival hemorrhage, dry eye, eye discharge, eye irritation, eye pain, eyelid edema, headache, red eye, reduced visual acuity, and taste disturbance.

The most common side effects of Moxeza are eye irritation, fever, and conjunctivitis. The most frequently reported ocular adverse events secondary to the use of Vigamox found in 1% to 6% of patients were conjunctivitis, decreased visual acuity, keratitis, ocular discomfort, ocular hyperemia, ocular pain, ocular pruritus, subconjunctival hemorrhage, and tearing.

The ocular adverse events occurring from use of Iquix in 1% to 2% of patients included decreased/blurred vision, instillation site irritation/discomfort, ocular infection, and ocular pain/discomfort. The nonocular adverse events occurring in approximately 8% to 10% of patients were headache and taste disturbance. The most frequently reported adverse events, which occurred in 1% to 3% of patients, were transient decreased vision, fever, foreign body sensation, headache, transient ocular burning, ocular pain or discomfort, pharyngitis, and photophobia. Other reactions that were reported in less than 1% of patients included allergic reactions, lid edema, ocular dryness, and ocular itching.

With respect to Besivance, the most common adverse events in clinical trials were conjunctival redness, blurred vision, eye pain, eye irritation, eye pruritus, and headache, reported in approximately 1% to 2% of patients 1 year and older.⁷¹

In a randomized, masked, placebo-controlled animal study evaluating the anterior chamber toxicity of the two
topical ophthalmic formulations containing DuraSite (Besivance and Azithromycin), it has been determined that these two formulations are toxic to the anterior chamber. When injected into the anterior chamber, the following side effects were noticed: conjunctival injection, moderate limbal vascularity, and severe, diffuse corneal edema, corneal ectasia, and bullous keratopathy.⁷² Because of the corneal edema, the anterior chamber could not be viewed, but vital staining and histopathologic evaluation revealed glaucomatous and toxic damage in eyes given DuraSitebased medications, whereas the groups without the DuraSite polymer showed minimal changes. Two mechanisms of damage were identified in the eyes injected with Besivance or AzaSite: acute glaucoma and direct toxic reaction. The authors noted that besifloxacin and azithromycin are completely different classes of drugs, and that the concentrations of BAK are radically different in these two drugs, so they believe that it is reasonable to conclude that DuraSite is most likely responsible for the toxicity results. While further studies are warranted to determine whether these problems are of clinical importance, the authors concluded that DuraSite blocks the trabecular meshwork and may be additionally toxic when introduced as a large bolus. The authors recommended that until the safety of these medications is established with further studies using smaller injected volumes, there should be placement of a suture over a clear corneal wound if DuraSite-based medications are used.⁷²

The most commonly reported adverse effect from topical ciprofloxacin treatment is the formation of a white crystalline precipitate in approximately 17% of treated eyes.⁷³, ⁷⁴ and ⁷⁵ This results from precipitation of the drug (formulated at pH 4.5), which is poorly soluble at the nearneutral pH of the tear film. The relationship between this precipitate and antibacterial efficacy is unknown. The precipitate resolves spontaneously without sequelae after cessation of the medication. Like the 0.3% solution, the ciprofloxacin ointment has also been shown to cause a white precipitate that resolves spontaneously without sequelae after discontinuing it. Other adverse effects from the ointment include burning, punctate epitheliopathy, blurred vision, and tearing.⁷⁶