In a few months, ophthalmic drug suppliers will introduce a new class of fluoroquinolone antibiotics for topical use. These fourth-generation fluoroquinolones are the result of extensive scientific research and reflect significant progress in our understanding of pharmacology and clinical therapeutics.
The new antibiotics represent a major advance in the management of infectious ocular disease. They are not just big guns that we should reserve only for severe infections. These new agents will be universal soldiers in the war on infection. In that sense, they are likely to redefine how we manage ocular infection and put much greater power in the hands of the practitioner.
Here, Ill review the class of fluoroquinolone antibiotics, explore the differences between current and next generation products, and report on the latest clinical and scientific data you will need to effectively use these new medications.
Fluoroquinonlone Dosing or Conjunctivitis: A Comparison Ciprofloxacin (Ciloxan, Alcon) * from FDA Phase III studies
Gatifloxacin and moxifloxacin were designed to be less likely to develop antibiotic resistance. Also, the new fluoroquinolones will be approved for treatment of conjunctivitis, but will surely be used off-label for other ocular infections and surgical prophylaxis.
In the Blink of an Eye
Before topical ciprofloxacin and ofloxacin were commercially available, optometrists usually referred patients with microbial keratitis to corneal specialists. Typically, these practitioners cultured the lesion and initiated treatment with specially prepared drops. These medications consisted of fortified tobramycin or gentamicin in combination with fortified cephazolin, vancomycin or bacitracin for added gram-positive coverage.
Studies have confirmed that an empirical approach using fortified antibiotics for microbial keratitis succeeds 92-93% of the timea result consistent with antibiotic treatment in systemic medicine.1,2 In cases that do not respond to treatment (especially if sensitivity testing indicates a more effective antibiotic), the clinician modified the therapeutic regimen.
With the introduction of topical fluoroquinolone drops, monotherapy of microbial keratitis yielded success rates comparable to those of fortified combination therapy. General ophthalmologists and primary care optometrists were able to treat patients more effectively. Consequently, primary care eye doctors made fewer specialist referrals.
What also happened due to the high rate of empirical success with fluoroquinolone monotherapy was a significant decrease in the number of clinicians who routinely cultured ulcers. Soon after topical fluoroquinolones were introduced, standards of care shifted away from the routine culturing of suspected microbial keratitis.
Ophthalmic Indications
First-generation quinolones were typified by nalidixic acid, the quinolone prototype introduced in 1962. The early quinolones achieved only minimal serum levels and were effective only against gram-negative bacteria. They had no activity against Pseudomonas.
Second-generation fluoroquinolones such as norfloxacin, ofloxacin and ciprofloxacin showed vastly increased gram-negative coverage and greater systemic activity. Ciprofloxacin still remains the most effective agent against Pseudomonas.3
Third-generation drugs such as levofloxacin show expanded activity against gram-positive bacteria, atypical pathogens and increased solubility.
Finally, the fourth-generation 8-methoxy fluoroquinolone drugs show vastly increased gram-positive coverage combined with significant activity against anaerobes and atypical pathogens.
For ophthalmic indications, the fourth generation fluoroquinolonesmoxifloxacin (Alcon Laboratories) and gatifloxacin (Allergan)appear to offer considerable advantages over second- and third-generation predecessors. These fourth-generation agents possess broader-spectrum bactericidal activity, including effective coverage against gram-positive, anaerobic and atypical pathogens.4,5,6 Also, the newer fluoroquinolones show excellent bioavailability and significantly improved penetration. This is significant for surgical prophylaxis.
A compelling advantage of the fourth-generation fluoroquinolones over previous drugs is their reduced potential for the development of antibiotic resistance.
1-2 drops q2-4h, days 1-2
1-2 drops qid, days 3-7
Ofloxacin (Ocuflox, Allergan)
1-2 drops q2-4h, days 1-2
1-2 drops qid, days 3-7
Levofloxacin (Quixin, Santen)
1-2 drops q2h, days 1-2
1-2 drops q4h, days 3-7
Gatifloxacin (Allergan)*
1-2 drops q2h, days 1-2
1-2 drops qid, days 3-5
Moxifloxacin (Alcon)*
1-2 drops tid for 4 days
Fluoroquinolones prevent bacterial replication by keeping bacterial DNA in a naturally supercoiled state. They block the enzymes DNA gyrase and topoisomerase IV. DNA gyrase is essential for the replication, transcription and repair of bacterial DNA. It nicks and seals DNA during replication and is especially important in replication of gram-negative bacteria. Topoisomerase IV is involved in the portioning of chromosomal DNA during cell division and is a primary fluoroquinolone target in gram-positive bacteria.
Second- and third-generation fluoroquinolones primarily target DNA gyrase. Because moxifloxacin and gatifloxacin attack both topoisomerases, simultaneous independent mutations in two bacterial genes would have to occur to enable resistancean event far less likely than the single mutation necessary for a mutation to overcome prior-generation fluoroquinolones.
Bacteria may also develop fluoroquinolone resistance through efflux mechanisms that effectively pump antibiotic out of the cell. As an example of fourth-generation engineering, moxifloxacin was created with a bulky bicyclic amine side chain at the C-7 position that serves to block the bacterial membrane-associated efflux pump. This provides an additional line of defense against resistance. Of particular clinical relevance, the fourth-generation agents show no cross-resistance with bacteria resistant to second-and third-generation fluoroquinolones.
Going Off-Label How to Tell if an Antibiotic is Really Effective
Although both moxifloxacin and gatifloxacin will be approved strictly for treatment of conjunctivitis, off-label use for other ocular infections and surgical prophylaxis is certain to occur. These off-label uses will likely include:
Conjunctivitis and blepharoconjunctivitis. With a broad spectrum of activity and less likelihood to foster resistance, both antibiotics will be extremely effective for treating conjunctivitis and moderate to severe lid infections. Moxifloxacin is currently under FDA review for use in infants.
The Gatifloxacin Study Group reported on the susceptibility of ocular isolates from bacterial conjunctivitis patients to gatifloxacin, levofloxacin and ciprofloxacin.7 They found that essentially all of 170 gram-positive isolates were susceptible to gatifloxacin, with lesser effectiveness shown for levofloxacin and the least effectiveness for ciprofloxacin, which was as expected because of the high percentage of gram-positive species. All of the gram-negative isolates (n=65) were susceptible to all three antibiotics.
Microbial keratitis. Because bacterial keratitis is potentially devastating and yet is usually treated empirically, the fourth-generation fluoroquinolones may rapidly become the drugs of choice for infectious keratitis due to their excellent penetration, rapid kill rate and broad spectrum of activity.
One study reported minimum inhibitory concentrations (MICs) of moxifloxacin, gatifloxacin, ciprofloxacin, ofloxacin and levofloxacin for 177 bacterial keratitis isolates.4 The study found that moxifloxacin and gatifloxacin demonstrated greater potency against gram-positive bacteria than did levofloxacin, ciprofloxacin and ofloxacin.
The fourth-generation fluoroquinolones also demonstrated enhanced in vitro activity for isolates that were resistant to second- and third-generation fluoroquinolones. The fourth-generation drugs showed no advantage against gram-negative organisms.
Another study compared the effectiveness of moxifloxacin and levofloxacin in a rabbit model of Staphylococcus keratitis.8 The investigators infected rabbit corneas with both ciprofloxacin-sensitive and ciprofloxacin-resistant Staph. aureus. They found that moxifloxacin was significantly more effective than levofloxacin in treating both ciprofloxacin-sensitive and -resistant Staph. aureus.
Surgical prophylaxis. The superior solubility, excellent penetration and pharmacokinetics/pharmacodynamics profile will make the fourth-generation drugs a natural choice for surgical prophylaxis. Several studies already support this use.
One study reported in vivo susceptibility using MICs for moxifloxacin, gatifloxacin, ciprofloxacin, ofloxacin and levofloxacin in 98 bacterial endophthalmitis isolates.6 The researchers found the order of significant susceptibility for gram-positive bacteria was MOX>GAT>CIP=LEV>OFX. The order of significant susceptibility for second-generation fluoroquinolone-resistant Staph. aureus was MOX>GAT>LEV>CIP=OFX. The order of significant susceptibility for second-generation fluoroquinolone-resistant coagulase-negative Staph. was MOX=GAT>LEV=CIP= OFX. For gram-negative bacteria, the order of significant susceptibility was MOX=GAT=CIP=LEV> OFX.
How do you measure the effectiveness of an antibiotic? The minimum inhibitory concentration (MIC) is likely the most recognizable measure. MIC provides an indirect, yet clinically relevant, measure of antibiotic effectiveness against a specific pathogen, and it serves as a basis for clinical comparison of one antibiotic agent to another.
Keep in mind that lab studies determine MIC values. They may not reflect clinical effectiveness in vivo. More refined measures are necessary.
So, pharmacologists began to focus on pharmacokinetic (PK) measures. Pharmacokinetics relates to how the body absorbs, processes and interacts with a drug. The prototypical PK measure is drug concentration over time. While PK measures help determine effective dosing and can describe the antibiotic distribution in tissues, they do not describe the effectiveness of an antibiotic in the target tissue.
To that end, pharmacodynamic (PD) measures were developed. Pharmacodynamics expresses the effect of a drug on the host and target organisms, essentially describing the relationship between drug concentration and pharmocologic effect. The development of PD indices over the past decade has spurred the development of new antibiotics, and has assisted clinicians in developing objective standards for prescribing. Studies have directly correlated PD indices such as AUC/MIC and Cmax/MIC to clinical outcome.11,12
For example, antibiotics typically behave in either a time-dependent or a concentration-dependent manner. Time-dependent antibiotics, such as macrolides and vancomycin, kill bacteria at the same rate and extent once they reach a threshold concentration. Increasing the antibiotic concentration at this point does not increase antibacterial efficacy.
Concentration-dependent antibiotics, such as aminoglycosides and fluoroquinolones, are self-explanatory. Increased dosing will raise tissue concentrations, and therefore heighten the clinical outcome. The next generation fluoroquinolones were designed and tested using several classic PD measures. These and other measures not only reflect an antibiotics clinical performance; they also help predict it.
The researchers conclude that fourth-generation fluoroquinolones are more potent than second- and third-generation medicines for gram-positive bacteria, and are equally as potent for gram-negative bacteria. The fourth-generation fluoroquinolones appear to cover second- and third-generation fluoro- quinolone resistant organisms.
A group from the New York Eye and Ear Infirmary compared the in vitro susceptibility profiles of gentamicin, ciprofloxacin, ofloxacin, gatifloxacin, moxifloxacin and vancomycin against microorganisms responsible for endophthalmitis following cataract and glaucoma filtering surgery.9
The researchers tabulated MICs of 43 post-cataract and three bleb-related endophthalmitis isolates. The order of significant susceptibility for Staph. epidermidis and Staph. aureus post-cataract endophthalmitis isolates (37 of 43 isolates) were VAN>MOX=GAT>GENT> CIP=OFX. The order of significant susceptibility for Staph. epidermidis and Staph. aureus bleb-related endophthalmitis isolates (23 of 37 isolates) were VAN>MOX=GAT> CIP=OFX >GENT. All post-cataract and bleb endophthalmitis Streptococcus isolates were 100% susceptible to VAN. The order of significant susceptibility of Strep. isolates was MOX=GAT>CIP= OFX.
Antibiotic prophylaxis for refractive surgery is common, and it is likely that the fourth-generation antibiotics will play a role here as well. One study investigated the efficacy of gatifloxacin compared with ciprofloxacin in preventing Strep. pneumoniae keratitis using a rabbit LASIK model.10
The researchers created bilateral lamellar flaps in the eyes of 12 rabbits and used gatifloxacin 0.3%, ciprofloxacin 0.3%, or no antibiotic (which served as the control). The researchers instilled one drop of antibiotic prior to creation of the lamellar flap, at the conclusion of flap formation, and then qid for three days. All corneas were inoculated with Strep. pneumoniae following flap formation.
On day three, the control group had eight corneal infiltrates and all control eyes had positive cultures. The ciprofloxacin group had seven infiltrates, and six of eight eyes had positive cultures.
The gatifloxacin eyes had three areas of 1mm central corneal haze and no infiltrates. Only one of eight rabbits had positive cultures. As expected, gatifloxacin 0.3% was found superior to ciprofloxacin 0.3% (because of better gram-positive coverage) for prophylaxis against Strep. pneumoniae.
In terms of side effects, current fluoroquinolones are generally well tolerated. Transient burning and discomfort are the most frequently reported adverse reactions. Other events include white crystalline deposits, foreign body sensation, and metallic taste. Fourth-generation fluoroquinolones may likely have a similar profile.
The fourth-generation fluoroquinolones could fundamentally change the way we manage ocular infection. Improved effectiveness, greater solubility, enhanced penetration and lower risk of resistance will weigh heavily in favor of moxifloxacin and gatifloxacin.
Both products are still months away from introduction. (Maybe three to nine months, depending upon FDA action. In late December 2002, Alcon filed a new device application with the FDA for moxifloxacin.) And while both are yet to be formally named, differences in formulation may make for a significant battle between the two. The details are still tightly controlled because of FDA requirements, but informal discussions with investigators and information gathered from company-sponsored presentations indicate that moxifloxacin will be introduced as a self-preserved 0.5% concentration, and gatifloxacin as a 0.3% concentration in a conventional BAK-preservative.
Dr. Epstein is chief medical editor of the e-mail newsletter Optometric Physician, and is in private practice in Roslyn, N.Y. He is director of the Contact Lens Service at North Shore University Hospital of the New York University School of Medicine, Great Neck, N.Y.
1. Hyndiuk RA, Eiferman RA, Caldwell DR, et.al. Comparison of ciprofloxacin ophthalmic solution 0.3% to fortified tobramycin-cefazolin in treating bacterial corneal ulcers. Ciprofloxacin Bacterial Keratitis Study Group. Ophthalmology 1996;103(11):1854-62; discussion 1862-3.
2. OBrien TP, Maguire MG, Fink NE, et al. Efficacy of ofloxacin vs cefazolin and tobramycin in the therapy for bacterial keratitis. Report from the Bacterial Keratitis Study Research Group. Arch Ophthalmol 1995;113(10):1257-65.
3. Kowalski RP, Pandya AN, Karenchak LM, et al. An in vitro resistance study of levofloxacin, ciprofloxacin, and ofloxacin using keratitis isolates of Staphylococcus aureus and Pseudomonas aeruginosa. Ophthalmology 2001 Oct;108(10):1826-9.
4. Kowalski RP, Karenchak LM, Romanowski EG, et al. Will The Fourth-generation Fluoroquinolones Provide Any Advantage in The Future Treatment of Bacterial Keratitis? Ocular Microbiology and Immunology Group (OMIG) 2002 Meeting Abstract. http://eyemicrobiology.upmc.com/ 2002Abstracts/
5. Perry CM, Ormrod D, Hurst M, Onrust SV. Gatifloxacin: a review of its use in the management of bacterial infections. Drugs 2002;62(1):169-207.
6. Mather R, Karenchak LM, Romanowski EG, Kowalski RP. Fourth generation fluoroquinolones: new weapons in the arsenal of ophthalmic antibiotics. Am J Ophthalmol 2002 Apr;133(4):463-6.
7. Monica ML, Jensen H. Susceptibility of Ocular Isolates to Gatifloxacin and Older Fluoroquinolones. The Allergan Gatifloxacin Study Group. Ocular Microbiology and Immunology Group (OMIG) 2002 Meeting Abstract. http://eyemicrobiology.upmc.com/2002Abstracts/
8. O"Callaghan R, Dajcs J, Austin M, et al. Effectiveness of Moxifloxacin and Quixin in a Rabbit Model of Staphylococcus Keratitis. Ocular Microbiology and Immunology Group (OMIG) 2001 Meeting Abstract. http://eyemicrobiology.upmc.com/2001Abstracts/
9. Shah M, Ritterband D, Dingley A, et al. Will the new generation of fluoroquinolone antibiotics become the antimicrobials of choice in endophthalmitis prophylaxis? Ocular Microbiology and Immunology Group (OMIG) 2002 Meeting Abstract. http://eyemicrobiology.upmc.com/2002Abstracts/
10. Donnenfeld RS, Stein JJ, Jensen HG, et al. Prophylaxis of Streptococcus Pneumoniae keratitis with Gatifloxacin in a Rabbit LASIK Model. Ocular Microbiology and Immunology Group (OMIG) 2002 Meeting Abstract. http://eyemicrobiology.upmc.com/2002Abstracts/
11. Nicolau DP. Predicting antibacterial response from pharmacodynamic and pharmacokinetic profiles. Infection 2001 Dec;29 Suppl 2:11-5.
12. Rodvold KA, Neuhauser M. Pharmacokinetics and pharmacodynamics of fluoroquinolones. Pharmacotherapy 2001;21(10 Pt 2):233S-252S.
