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Up Front | Jan 2003

Fourth-Generation Fluoroquinolones

New weapons in the arsenal of ophthalmic anti-infectives.

The fluoroquinolone antibiotics are a unique class of antibacterial agents with a broad spectrum of antimicrobial activity as well as an excellent safety profile. Important discoveries during the past 3 decades have served to rapidly expand the quinolone class of antibiotics. The expected addition of two fourth-generation topical fluoroquinolone agents, moxifloxacin and gatifloxacin, to the armamentarium for treating ocular infection has generated considerable excitement within the ophthalmic community. These newer agents have shown a wider spectrum of antibiotic activity and improved pharmokinetic profiles compared with older agents.

Agent Classification
Currently, there are three major topical fluoroquinolone agents available in the US: ofloxacin (Ocuflox; Allergan, Inc., Irvine, CA), ciprofloxacin (Ciloxan; Alcon Laboratories, Inc., Fort Worth, TX), and levofloxacin (Quixin; Santen, Inc., Napa, CA). Based on their chemical structure, spectrum of action, and clinical indications, all three agents are classified in the pharmacologic literature as second-generation fluoroquinolone agents.1 The ophthalmic literature often categorizes levofloxacin as a third-generation agent, although its chemical structure is akin to that of the other second-generation agents (Table 1).

The history of the fluoroquinolones began in 1962, when Lesher et al identified nalidixic acid as a byproduct of chloroquine synthesis.2 This identification ultimately led to the discovery that nalidixic acid inhibits a critical enzyme for bacterial multiplication. Later, Gellert et al purified this enzyme and named it DNA gyrase (topoisomerase II).3 The quinolone agents exert their antimicrobial effect by binding to and inhibiting topoisomerase II (DNA gyrase) and topoisomerase IV. These bacterial enzymes are responsible for the coiling and uncoiling of DNA, which bacterial cells need to repair and replicate themselves.

The classification of the fluoroquinolones is somewhat informal and nonstandardized. The pharmacology and systemic antibiotic literature often classify the agents according to their spectrum of action and clinical indication, as well as their date of introduction to the marketplace. The ophthalmic literature classifies these agents according to their time of introduction to the marketplace in the US, and many of the ophthalmic periodical supplement inserts have misrepresented or ignored the actual chemical family trees.

Increased Potency
The ability to chemically manipulate the nucleus of the quinolones to produce new compounds with greater antibacterial activity, improved pharmokinetics, and fewer toxic side effects has led to successive generations of increasingly potent agents. The antimicrobial spectrum of the first-generation quinolones was largely limited to aerobic gram-negative bacillary infections, particularly of the urinary tract. The second-generation agents introduced in the 1980s displayed enhanced activity (1,000-fold) against aerobic gram-negative bacteria and were also active against aerobic gram-positive pathogens including streptococci and staphylococci.4 The second-generation fluoroquinolone antibiotics are ideal topical agents due to their wide spectrum of antimicrobial activity, low toxicity, high potency, prolonged tear film concentration, and stability in solution. In the last decade, they have become the anti-infective of choice for treating conjunctivitis and bacterial keratitis and a mainstay for presurgical prophylaxis.

The third-generation fluoroquinolone antibiotics (sparfloxacin and grepafloxacin) were biochemically altered to improve their activity against gram-positive bacteria, especially the pneumococcus, without losing their broad gram-negative coverage. Fourth-generation agents (moxifloxacin, gatifloxacin, and trovafloxacin) exhibit the most potent activity against gram-positive bacteria, particularly pneumococcus, and have improved anaerobic coverage and longer half-lives that permit once-daily oral dosing.

The latter-generation fluoroquinolones resulted from drug development strategies based on furthered understanding of the structure/activity relationships and the structure/side-effect relationships of the fluoroquinolone molecule. Key structural observations include (1) a fluorine in the C-6 position enhances antimicrobial activity; (2) a bulky side-chain at C-7 binds to DNA gyrase, impedes efflux of the quinolone out of the bacterial cell, and increases the serum half-life and potency against gram-positive organisms; and (3) a C-8 methoxy group increases potency and decreases toxicity.5

The structural characteristics of moxifloxacin make it an ideal antibiotic agent because it incorporates all the previously mentioned molecular characteristics (Figure 1). Moxifloxacin appears to have an enhanced and equal affinity for topoisomerase II (DNA gyrase) and topoisomerase IV. This capability makes it potent against a wide range of pathogens and lessens the likelihood of a mutant emerging that has a single resistance target to either topoisomerase enzyme.6 Evidence suggests that compounds with the C-8 methoxy group (moxifloxacin and gatifloxacin) can kill bacterial cells that are not multiplying, which also lessens the selection of resistant mutants. Furthermore, the bulky side-chain at position C-7 found in a few of the representative fourth-generation fluoroquinolones such as moxifloxacin and trovofloxacin may reduce the risk of toxicity and decrease the susceptibility of the antibiotic to actively efflux from the bacterial cell. Enhanced efflux is an important first-line mechanism of bacteria that permits its short-term survival until it develops resistance via mutation.7,8

Fighting Bacterial Resistance
The emergence of resistance among gram-positive organisms to second-generation fluoroquinolone agents was first noticed in the mid-1990s in patients with community-acquired pneumonia (particularly among pneumococcus isolates) according to the systemic literature.9 Subsequently, reports of increasing resistance to the fluoroquinolone antibiotics, predominately by gram-positive organisms in cases of bacterial keratitis, have flooded the ophthalmic literature in the last 5 years.10 In 2001, at the New York Eye and Ear Infirmary, 52% of 739 coagulase-negative Staphyloccus isolates were resistant to ofloxacin or ciprofloxacin. In 1996, 85% of coagulase-negative Staphyloccus were resistant to ofloxacin and ciprofloxacin.11

Fluoroquinolone antibiotics are concentration-dependent killers in that they must reach the minimum inhibitory concentration (MIC) to work effectively. A key parameter to consider in comparing antibiotic potency is the MIC value based on National Committee of Clinical Laboratory Standards for effective therapy in systemic penetration. It is generally assumed that following topical administration, antibiotic concentrations in ocular tissues are equivalent to if not higher than systemic levels. Therefore, the antibiotic with the lowest MIC would be the most potent and the anti-infective with the most potency would have the least chance of inducing resistance because its rapid killing rate would prevent resistant strains from developing.

The in vitro activities and pharmacodynamic properties of moxifloxacin and gatifloxacin have been studied extensively, especially in beta-lactam and second-generation fluoroquinolone resistant respiratory pneumococcus strains. Of those agents most frequently used against pneumococcus strains, moxifloxacin is twice as potent as gatifloxacin, whereas levofloxacin is four to eight times less active.4,12
Several recent studies have focused on the in vitro susceptibility of fourth-generation fluoroquinolones against endophthalmitis isolates. Mather et al found that fourth-generation fluoroquinolone agents provide better in vitro coverage of bacteria that are resistant to second- and third-generation agents (ciprofloxacin, ofloxacin, and levofloxacin). These agents were more potent than the second- and third-generation agents for both gram-positive bacteria and gram-negative bacteria. In general, moxifloxacin exhibited greater potency than gatifloxacin for gram-positive bacteria.13 The results of this study were supported by data that my colleagues and I presented, which was similar to MIC and potency data from ocular isolates of keratitis and endophthalmitis at The New York Eye and Ear Infirmary.14

The Fluoroquinolone Pipeline
Moxifloxacin and gatifloxacin, two novel fourth-generation fluoroquinolone agents, are poised to enter the marketplace in 2003. Moxifloxacin will most likely be available in a self-preserved 0.5% formulation. It will have an excellent solubility profile, and its pH will be at or near 6.8. Gatifloxacin will be available in a 0.3% formulation and will have a slightly more acidic pH, at or near 6.0. It will also contain the preservative benzalkonium chloride 0.005%. Both fourth-generation fluoroquinolone agents will offer expanded antimicrobial activity against pathogens currently resistant to older fluoroquinolones and provide improved gram-positive coverage.

New and Promising
Moxifloxacin, in particular, appears to be the most promising of the new agents. Its structural characteristics enhance its affinity for DNA gyrase and topoisomerase IV, a capability that results in potent activity against a wide variety of bacterial pathogens. Its near-neutral pH and a self-preserved formulation provide ideal characteristics for topical use. All the fourth-generation fluoroquinolone agents hold great promise in treating ocular infections and preventing postsurgical endophthalmitis.

David C. Ritterband, MD, serves as Associate Clinical Professor of Ophthalmology at the New York Medical College, as well as Assistant Director of the Cornea and External Disease Service at The New York Eye and Ear Infirmary, both in New York. He holds no financial interest in any product mentioned herein. Dr. Ritterband may be reached at (212) 505-6550; ritterband@msn.com.

1. Andriole VT. The quinolones: Prospects. In: Andriole VT, ed. The Quinolones. 3rd ed. London: Academic Press; 2000;477-491.
2. Lesher GY, Froelich ED, Gruett MD, et al. 1,8-Naphthyridine derivatives. A new class of chemotherapeutic agents. J Med Pharm Chem. 1962;5:1063-1068.
3. Gellert M, Mizuuchi K, O'Dea MH, et al. DNA gyrase. Proc Natl Acad Sci USA. 1976;73:3872-3876.
4. Andriole CL, Andriole VT. Are all quinolones created equal? Medicguide Infect Dis. 2002;21:1-5.
5. Andriole VT. Overview of the Fluoroquinolones focus on moxifloxacin. Formulary June 2002: (suppl) 37 3:13-15.
6. Zhao X, Wang J-Y, Xu C. Killing of Staphylococcus aureus by C-8 methoxy fluoroquinolones. Antimicrob Agents Chemother. 1998;42:956-958.
7. Domagala JM. Structure-activity and structure-side-effect relationships for the quinolone antibacterials. J Antimicrob Chemother. 1994;33:685-706.
8. Peterson LR. Quinolone molecular structure-activity relationships: What we have learned about improving antimicrobial activity. Clin Infect Dis. 2001;33(suppl 3):S180-S186.
9. Borek AP, Dressel DC, Hussong J, Peterson LR. Evolving clinical problems with Streptococcus pneumoniae:increasing resistance to antimicrobial agents, and failure of traditional optochin identification in Chicago, Illinois, between 1993-1996. Diagn Microbiol Infect Dis. 1997;29:209-214.
10. Goldstein MH, Kowalski RP, Gordon YJ. Emerging fluoroquinolone resistance in bacterial keratitis: A 5-year review. Ophthamology. 1999;106:1313-1318.
11. Data presented at the Association for Research in Vision Meeting. Antibiotic susceptibilities of ocular isolates to moxifloxacin a fourth generation fluoroquinolone. May 6, 2002, Ft. Lauderdale, Florida.
12. Boswell F, Andrews JM, Jevons G, Wise R. Comparison of the in vitro activities of several new fluoroquinolones against respiratory pathogens and their abilities to select fluoroquinolone resistance. J Antimicrob Chemother. 2002 Oct;50:4:495-502.
13. Mather R, Karenchak L, Romanowski E, et al. Fourth Generation Fluoroquinlones: New weapons in the arsenal of ophthalmic antibiotics. Amer J Ophthal. 2002;133:463-466.
14. Data presented at the Ocular Microbiology and Immunology Group Meeting. October 17, 2002, Orlando, Florida.

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