Fluoroquinolones in the Peer-Reviewed Literature

Moxifloxacin 0.5%
BY DEEPINDER K. DHALIWAL, M.D.

Frevention of infection following cataract and refractive procedures is one of the areas of most concern to ophthalmic surgeons. This is especially true because recent reports suggest that potentially devastating conditions such as endophthalmitis may be on the rise. To provide the best patient protection against such infections, it is important for ophthalmologists to make evidence-based decisions in terms of which fluoroquinolone to use.

The advent of two fourth-generation fluoroquinolones in spring 2003 provided better weapons for fighting postoperative infections, and, today, moxifloxacin ophthalmic solution 0.5% (Vigamox) and gatifloxacin ophthalmic solution 0.3% (Zymar) account for nearly 90% of all fluoroquinolone prescriptions written within ophthalmology. At first glance, both agents may seem to provide similar advantages. However, a closer look may reveal significant differences in terms of the degree of patient protection they offer.

A surgeon's personal experience, as well as the published peer-reviewed literature are two of the most effective and reliable methods for evaluating the two different drugs. A deeper look into the literature may provide the answer.

Since moxifloxacin and gatifloxacin have entered the market, several studies have been conducted to compare their efficacy and safety. Only a few, however, have made it through the rigorous peer-review process of top-tier journals.

When evaluating fluoroquinolone efficacy, the two defining elements are potency and penetration. The function of each is critical, but the synergistic effects of the two determine overall effectiveness. In fact, fluoroquinolones must demonstrate activity (potency) against the pathogens of most concern to ophthalmologists, but they also must be able to reach the target tissues at high enough concentrations.

Potency

Gram-positive organisms are the most common causes of postoperative infections. Therefore, it is most critical for a fluoroquinolone to exhibit excellent potency, defined as the lowest minimum inhibitory concentrations (MICs) against such pathogens.

Two separate studies from the Charles T. Campbell Ocular Microbiology Laboratory here at the University of Pittsburgh evaluated the potencies of moxifloxacin and gatifloxacin against such pathogens. The first study, by Mather et al., evaluated fluoroquinolones against ocular isolates that had caused endophthalmitis. Moxifloxacin was found to be more potent than gatifloxacin against such Gram-positive organisms¹. The second study, by Kowalski and colleagues, corroborated Mather's results, this time evaluating these agents against keratitis isolates. Moxifloxacin was again found to be more potent than gatifloxacin against Gram-positive isolates². Both studies suggested a significant superiority in favor of moxifloxacin in terms of fluoroquinolone-resistant S. aureus susceptibility rates.

In regard to Gram-negative coverage, both moxifloxacin and gatifloxacin seem to have efficacies comparable to those of older fluoroquinolones. A few in vivo models have been used to evaluate their ability to eradicate Gram-negative keratitis. A study by Aliprandis et al. shows that moxifloxacin is as effective as the gold-standard ciprofloxacin in eradicating Gram-negative keratitis³.

Overall, in terms of potency against the most common infection-causing pathogens, the literature shows that both moxifloxacin and gatifloxacin are more effective than older agents. However, among the fourth-generation fluoroquinolones, moxifloxacin demonstrates superior potency as compared with gatifloxacin for Gram-positive isolates^1,2.

Penetration

As mentioned earlier, potency is one of the two key factors that define fluoroquinolone efficacy, penetration being the second. For a cataract surgeon, anterior chamber penetration is key to patient protection. The fluoroquinolone must penetrate the target tissues at levels that at least meet its MICs for the most common infection-causing bacteria. Because fluoroquinolones are concentration-dependent killers, the greater the concentration achieved above the MIC, the greater the patient protection. The MIC is the minimal amount of drug necessary to inhibit bacterial growth, not actually kill the organisms. The minimum amount of drug necessary to do that is known as the MBC, or minimum bactericidal concentration (typically 4 times the MIC). Actually, the concentration of antibiotic that is considered "ideal" in the tissue is the MPC, or mutation prevention concentration (typically 8 to 10 times the MIC). If the concentration of antibiotic at the target tissue reaches or exceeds the MPC, bacterial mutations that confer resistance would be prevented, allowing us to use that antibiotic effectively for a greater number of years. Therefore, it is clear that the antibiotic that is able to achieve the highest tissue levels is desirable and it does matter if the concentration in the target tissue exceeds or just barely meets the MIC.

All the literature available comparing the ability of moxifloxacin and gatifloxacin to penetrate the ocular tissues leads to the same conclusion: moxifloxacin penetrates significantly better. This has been established in animal models by Levine et al.⁴, as well as in multiple human studies. A recap of the published human data:

► In a study by Wagner et al. (in press)⁵, moxifloxacin achieved 18 ug/g in the conjuctiva vs. gatifloxacin's 2.5 ug/g (P<0.0001).

► In a study by Solomon et al.⁶, moxifloxacin achieved 1.31 ug/ml in the anterior chamber vs. gatifloxacin's 0.63ug/ml (P<0.05).

► In a study by Kim et al.⁷, moxifloxacin achieved concentrations 3.8 times greater than gatifloxacin in the anterior chamber (P=0.00003). Moxifloxacin's level met its MICs even against fluoroquinolone-resistant staph aureus whereas Zymar's did not.

Also, moxifloxacin is the only topical fluoroquinolone reported in the peer-reviewed literature to be capable of achieving therapeutic levels in the vitreous⁸.

Biocompatibility

Having established efficacy, it is also important to ensure that the agent chosen for cataract or refractive surgery prophylaxis is safe and well-tolerated. Overall, although fluoroquinolone therapy has long been established as safe and well-tolerated in surgical settings, we want to make sure that we are not introducing potentially toxic agents that may delay wound healing.

Herrygers and colleagues recently reported⁹ that no differences were found between moxifloxacin and gatifloxacin in terms of their relative toxicities in an animal model⁹. Human studies by Durrie and Trattler evaluate potential differences in wound healing in patients undergoing LASIK and LASEK. Both of these drugs were found to be safe and well-tolerated in these settings¹⁰. These findings are reassuring and consistent with experiences following 2 years and millions of prescriptions since their launch.

Proof of Principle on Prophylaxis

In a recently published study, Kowalski et al. demonstrated proof of principle that prophylactic use of antibiotic therapy before and after bacterial challenge can indeed prevent endophthalmitis. In this model, rabbits were treated with either moxifloxacin or placebo for 1 hour (5 drops total). The animals were then injected in the anterior chamber with 50,000 CFUs of S. aureus. Placebo or moxifloxacin therapy was then continued for 24 hours (additional 5 drops). At the end of the study, 100% of the placebo rabbits developed endophthalmitis vs. none of the moxifloxacin eyes¹¹. This shows that Vigamox with topical dosing, as we routinely do in cataract surgery, can prevent endophthalmitis in the rabbit model. This is the only study of its kind to be successfully completed with a topical fluoroquinolone.

The documented superior potency and penetration offered by moxifloxacin make it my anti-infective of choice, as I believe I am offering my patients the best degree of protection against postoperative infections. Knowing I have chosen an anti-infective that has objective, tangible advantages as documented by the peer-reviewed literature reinforces the proven track record I have had with this agent since its introduction.

Dr. Dhaliwal is an associate professor and the director of Cornea and External Disease and Refractive Surgery at the University of Pittsburgh School of Medicine's Department of Ophthalmology. She can be contacted at (412) 647-2214 and dhaliwaldk@upmc.edu.

References

1. Mather R, Karenchak LM, Romanowski EQ, Kowalski RP. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol. 2002;133:463-466.

2. Kowalski RP, Dhaliwal DK, Karenchak LM, et al. Gatifloxacin and moxifloxacin: an in vitro susceptibility comparison to levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitis isolates. Am J Ophthalmol. 2003;136: 500-505.

3. Aliprandis E, Ciralsky J, Lai H, et al. Comparative efficacy of topical moxifloxacin vs. ciprofloxacin and vancomycin in the treatment of P. aeruginosa and ciprofloxacin-resistant MRSA keratitis in rabbits. Cornea. In press.

4. Levine JM, Noecker RJ, Lane LC, et al. Comparative penetration of moxifloxacin and gatifloxacin in rabbit aqueous humor after topical dosing. J Cataract Refract Surg. 2004;30: 2177-2182.

5. Wagner RS, Cockrum PC, Abelson MB, et al. Evaluation of moxifloxacin, ciprofloxacin, gatifloxacin, ofloxacin, and levofloxacin concentrations in human conjunctival tissue following administration of moxifloxacin 0.5% (Vigamox®), ciprofloxacin 0.3% (Ciloxan®), gatifloxacin 0.3% (Zymar®), ofloxacin 0.3% (Ocuflox®), and levofloxacin 0.5% (Quixin®) ophthalmic solutions. Arch Ophthalmol. In press.

6. Solomon R, Donnenfeld ED, Perry HD et al. Penetration of topically applied gatifloxacin 0.3%, moxifloxacin 0.5%, and ciprofloxacin 0.3% into the aqueous humor. Ophthal. March 2005.

7. Kim DH, Stark WJ, O'Brien TP. Ocular penetration of moxifloxacin 0.5% and gatifloxacin 0.3% ophthalmic solutions in to the aqueous humor following topical administration prior to routine cataract surgery. Cur Med Res Opin. 21: 93-94, 2005.

8. Hariprasad SM, Blinder KJ, Shah GK, Apte RS, Rosenblatt B, Holekamp NM, Thomas MA, Mieler WF, Chi, J, Prince RA: Penetration pharmacokinetics of topically administered moxifloxacin 0.5% ophthalmic solution in human aqueous and vitreous. Arch Ophthalmol. 2005;123:39-44.

9. Herrygers LA, Noecker RJ, Lane LC, Levine JM. Comparison of corneal surface effects of gatifloxacin and moxifloxacin using intensive and prolonged dosing protocols. Cornea. 2005;24:66-71.

10. Durrie DS, Trattler W. A comparison of therapeutic regimens containing moxifloxacin 0.5% ophthalmic solution and gatifloxacin 0.3% ophthalmic solution for surgical prophylaxis in patients undergoing LASIK or LASEK. J Ocular Pharm Ther. In press.

11. Kowalski RP, Romanowski EG, Mah FS, Yates KA, Gordon YJ. Topical prophylaxis with moxifloxacin prevents endophthalmitis in a rabbit model. Am J Ophthalmol. 2004;138:33-37.

Gatifloxacin 0.3%
BY RANDALL OLSON, M.D.

For years, topical anti-infective agents have been used in ophthalmology for the treatment of active ocular infections as well as for prophylaxis of infection in surgical patients. Unfortunately, the pathogens these drugs target have also continuously evolved, and we are now at the point where most antibiotics have lost much of their efficacy against even common ocular pathogens. The recent introduction of fourth-generation fluoroquinolones, gatifloxacin 0.3% (Zymar) and moxifloxacin 0.5% (Vigamox), has provided clinicians with a new weapon against these microbes.

The purpose of this review is to discuss the efficacy of gatifloxacin against ocular pathogens and to evaluate the ocular tolerability of this medication.

Efficacy

In an in vitro comparison of gatifloxacin and moxifloxacin with the third-generation fluoroquinolones against bacterial keratitis isolates, the fourth-generation drugs exhibited increased susceptibility for S. aureus isolates that were resistant to the third-generation drugs and demonstrated significantly lower MICs than ofloxacin and ciprofloxacin for all Gram-positive bacteria tested. Comparing the two fourth-generation drugs, gatifloxacin demonstrated lower MICs than moxifloxacin for most Gram-negative bacteria, while moxifloxacin demonstrated lower MICs for most Gram-positive bacteria.¹

A study from Callegan and associates² also evaluated the antibacterial activity of the fourth-generation fluoroquinolones against ocular pathogens, including seven Gram-positive, four Gram-negative, and three atypical bacterial species isolated from patients with keratitis and endophthalmitis. In this sample, gatifloxacin demonstrated a broad spectrum of activity against several key ocular pathogens. The MIC₉₀ for gatifloxacin was statistically significantly lower than that for moxifloxacin against S. viridans and P. aeruginosa, and MIC₉₀ values for gatifloxacin against K. pneumoniae and E. aerogenes were one-fourth to one-fifth the values for moxifloxacin. Against atypical bacteria (N. asteroides and M. chelonae), the MIC₉₀ values for gatifloxacin were one-fourth the value for moxifloxacin.

A study by Hyon and associates³ supported the finding of superior efficacy against atypical bacteria by gatifloxacin. In that study, treatment with gatifloxacin was significantly more effective than treatment with ciprofloxacin against M. chelonae in an animal model of keratitis.

Gatifloxacin was also highly efficacious against ocular bacterial pathogens collected from clinically significant ocular infections from 10 countries across Europe.⁴ Susceptibility testing against gatifloxacin, ciprofloxacin, ofloxacin, fusidic acid, gentamicin, and chloramphenicol was performed on more than 500 isolates. Gatifloxacin was the most potent agent tested against isolates from every country as measured by MIC or percentage resistance.

Surgical Prophylaxis

Clearly, gatifloxacin is highly effective against the pathogens most often implicated in bacterial keratitis and endophthalmitis. Beyond the treatment of active infections, however, gatifloxacin is also frequently used for the prophylaxis of infection in surgical patients. Use of anti-infective agents in these patients poses its own set of considerations and challenges, as the clinician must be conscientious about how the selected medication will influence the delicate healing processes in the wounded eye.

Following surgery, it is critically important to rapidly re-establish a normal epithelial barrier and stromal structure to minimize the risk of infection as well as to achieve an optimal visual outcome^5,6, and this at-risk period extends until the wound is completely healed. Moreover, the risk of post-operative infection may be at least partially dependent upon the type of incision used in surgery. For instance, unsutured clear corneal cataract incisions have become associated with a recent increase in rates of endophthalmitis in some studies^7-9, and this increase may be related to the dynamic morphology of clear corneal wounds.

As demonstrated in a recent study, pathogens on the ocular surface might gain access to the anterior chamber through clear corneal incisions¹⁰, and the risk of developing infection with clear corneal incisions may continue for several days postoperatively. Consequently, the choice of a postoperative anti-infective is critical.

The efficacy of gatifloxacin for infection prophylaxis has been demonstrated by Tungiripat and associates using an animal model.¹¹ The investigators inoculated eyes of 28 rabbits with multiple drug-resistant S. aureus following lamellar keratectomy. Although more than 70% of eyes treated with ciprofloxacin or levofloxacin developed infectious infiltrates, gatifloxacin-treated eyes did not develop any signs of infection and exhibited lower mean inflammation scores.

Efficacy, however, is not the only consideration when selecting an agent for surgical anti-infective prophylaxis. In order to be effective as a therapeutic agent, the drug must be able to reach the targeted infection site. Chuck and associates¹² recently evaluated the penetration of gatifloxacin into corneal tissue with laser-induced fluorescence. The corneal penetration of gatifloxacin was approximately equivalent to that of ofloxacin and greater than that of levofloxacin and ciprofloxacin. A separate study by Levine and associates¹³ reported that, following topical dosing with either standard keratitis or cataract protocols (every 15 minutes for 4 hours or 4 times a day for 10 days, respectively), both gatifloxacin and moxifloxacin achieved aqueous levels in excess of the MIC for most pathogenic organisms.

Tolerability

Ocular tolerability should also be considered, however, because if a patient is noncompliant with a prescribed treatment regimen, even a highly efficacious drug with superior penetration is useless. The ocular tolerability of gatifloxacin was recently compared with that of moxifloxacin in a randomized, paired-eye study.¹⁴ Patients received gatifloxacin in one eye and moxifloxacin in the other. Compared with gatifloxacin, eyes receiving moxifloxacin experienced a significantly greater increase in hyperemia and conjunctival vascularity. Moreover, significantly less pain and irritation was reported with instillation of gatifloxacin than was reported with moxifloxacin.

In an evaluation of the corneal surface effects of intensive dosing with either gatifloxacin or moxifloxacin, rabbit eyes were dosed with either medication according to one of two treatment regimens: one drop every 5 minutes for 15 minutes, followed by one drop every 15 minutes for 4 hours; or one drop 4 times a day for 10 days.¹⁵ Despite the differences in formulations and preservatives, there was no significant difference between gatifloxacin and moxifloxacin in mean corneal damage scores and neither produced any greater damage than untreated controls.

Weighing the Evidence

Based on the published, peer-reviewed evidence, gatifloxacin has been demonstrated to be a highly efficacious anti-infective therapy with a broad spectrum of coverage. The fourth-generation fluoroquinolones provide improved coverage of Gram-positive pathogens compared with the third generation.¹ Moreover, when comparing gatifloxacin with moxifloxacin, gatifloxacin has been shown to be more effective than moxifloxacin against several important ocular pathogens and against atypicals.² Gatifloxacin has also been shown to provide effective prophylaxis against postoperative infection¹¹ and is able to penetrate the corneal layers¹² and the aqueous humor.¹³ Gatifloxacin has also been shown to be safe for the ocular surface¹⁵ and is less inflammatory and more comfortable than moxifloxacin.¹⁴

All available evidence demonstrates that gatifloxacin is an excellent choice for anti-infective therapy.

Dr. Olson is director of the Moran Eye Center at the University of Utah and professor and chairman of the University's Department of Ophthalmology and Visual Sciences.

References

1. Kowalski RP, Dhaliwal DK, Karenchak LM, Romanowski EG, Mah FS, Ritterband DC, Gordon YJ. Gatifloxacin and moxifloxacin: an in vitro susceptibility comparison to levofloxacin, ciprofloxacin, and ofloxacin using bacterial keratitis isolates. Am J Ophthalmol. 2003 Sep;136(3):500-5.

2. Callegan MC, Ramirez R, Kane ST, Cochran DC, Jensen H. Antibacterial activity of the fourth-generation fluoroquinolones gatifloxacin and moxifloxacin against ocular pathogens. Adv Ther. 2003 Sep-Oct;20(5):246-52.

3. Hyon JY, Joo MJ, Hose S, Sinha D, Dick JD, O'Brien TP. Comparative efficacy of topical gatifloxacin with ciprofloxacin, amikacin, and clarithromycin in the treatment of experimental Mycobacterium chelonae keratitis. Arch Ophthalmol. 2004 Aug;122(8):1166-9.

4. Morrissey I, Burnett R, Viljoen L, Robbins M. Surveillance of the susceptibility of ocular bacterial pathogens to the fluoroquinolone gatifloxacin and other antimicrobials in Europe during 2001/2002. J Infect. 2004 Aug;49(2):109-14.

5. Agrawal VB, Tsai RJ. Corneal epithelial wound healing. Indian J Ophthalmol. 2003;51:5-15.

6. Cellular changes following epithelial abrasion. Beuerman RW, Crosson CE, Kaufman HE, eds. In: Healing Processes in the Cornea. Portfolio Publishing; 1989.

7. John ME, Noblitt R. Endophthalmitis: scleral tunnel vs. clear corneal incision. Buzard KA, Friedlander MH, Febbraro JL eds. In: The Blue Line Incision and Refractive Phacoemulsification, Thorofare New Jersey: Slack, Inc., 2001;53-56.

8. Powe NR, Schein OD, Gieser SC, et al. Synthesis of the literature on visual acuity and complications following cataract extraction with intraocular lens implantation. Cataract Patient Outcome Research Team. Arch Ophthalmol. 1994;112:239-52.

9. Cooper BA, Holekamp NM, Bohigian G, Thompson PA. Case-control study of endophthalmitis after cataract surgery comparing scleral tunnel and clear corneal wounds. Am J Ophthalmol. 2003;136:300-305.

10. McDonnell PJ, Taban M, Sarayba MA, et al: Dynamic morphology of clear corneal cataract incisions. Ophthalmology. 2003;110:2342-8.

11. Tungsiripat T, Sarayba MA, Kaufman MB, Sweet PM, Taban M, Carpenter TR, McDonnell PJ. Fluoroquinolone therapy in multiple-drug resistant staphylococcal keratitis after lamellar keratectomy in a rabbit model. Am J Ophthalmol. 2003 Jul;136(1):76-81.

12. Chuck RS, Shehada RE, Taban M, Tungsiripat T, Sweet PM, Mansour HN, Grundfest WS, McDonnell PJ. 193-nm excimer laser-induced fluorescence detection of fluoroquinolones in rabbit corneas. Arch Ophthalmol. 2004 Nov;122(11):1693-9.

13. Levine JM, Noecker RJ, Lane LC, Herrygers L, Nix D, Snyder RW. Comparative penetration of moxifloxacin and gatifloxacin in rabbit aqueous humor after topical dosing. J Cataract Refract Surg. 2004 Oct;30(10):2177-82.

14. Donnenfeld E, Perry HD, Chruscicki DA, Bitterman A, Cohn S, Solomon R. A comparison of the fourth-generation fluoroquinolones gatifloxacin 0.3% and moxifloxacin 0.5% in terms of ocular tolerability. Curr Med Res Opin. 2004 Nov;20(11):1753-8.

15. Herrygers LA, Noecker RJ, Lane LC, Levine JM. Comparison of corneal surface effects of gatifloxacin and moxifloxacin using intensive and prolonged dosing protocols. Cornea. 2005 Jan;24(1):66-71.