In Vitro and In Vivo Potency of Moxifloxacin and Moxifloxacin Ophthalmic Solution 0.5%, A New Topical Fluoroquinolone

doi:10.1016/j.survophthal.2005.06.002

Survey of Ophthalmology

Volume 50, Issue 6, Supplement, November 2005, Pages S16-S31

https://doi.org/10.1016/j.survophthal.2005.06.002 Get rights and content

Abstract

Fluoroquinolones are a class of synthetic antibacterial agents that were approved for ocular therapy in 1991 and have become popular therapy for the treatment and prevention of various ocular infections. These agents are synthetic, broad-spectrum, rapidly bactericidal, and have good penetration into ocular tissues. Their main mechanism of action is the inhibition of bacterial enzymes needed for bacterial DNA synthesis. However, antibiotic resistance occurred swiftly to the earlier fluoroquinolones and better fluoroquinolones were needed. The fourth-generation fluoroquinolones, such as moxifloxacin and gatifloxacin, have enhanced activity against gram-positive bacteria while retaining potent activity against most gram-negative bacteria. These fourth-generation fluoroquinolones have improved penetration into the anterior chamber and have also demonstrated increased in vivo efficacy in several animal models of ocular infections. In addition, topical ophthalmic antibiotic products can deliver antibiotic concentrations directly to the eye that are thousands of times higher than their MICs. This article reviews published data describing the in vitro potency of moxifloxacin and its in vivo activity for treating and preventing experimental ocular infections.

Introduction

Fluoroquinolones are synthetic, broad-spectrum, bactericidal antibiotics that were approved for treatment of ocular infections in 1991. The effectiveness of second- and third-generation fluoroquinolones (e.g., ofloxacin, ciprofloxacin, levofloxacin) has been offset by the emergence of fluoroquinolone-resistant organisms.46, 68, 73 The fourth-generation fluoroquinolones (moxifloxacin and gatifloxacin) show an enhanced spectrum of activity against gram-positive bacteria and comparable activity to second- and third-generation fluoroquinolones (ciprofloxacin and levofloxacin) against gram-negative bacteria.7, 11, 12, 25, 26 New ocular antibiotic formulations with improved potency, such as moxifloxacin ophthalmic solution 0.5% (VIGAMOX®, Alcon Laboratories, Fort Worth, TX) or gatifloxacin ophthalmic solution 0.3% (Zymar®, Allergan, Irvine, CA), are currently available and have been shown to inhibit growth of organisms resistant to second- and third-generation fluoroquinolones.⁷⁸ The purpose of this article is to review a) the in vitro activity of moxifloxacin against clinical ocular isolates and b) the in vivo effectiveness of moxifloxacin ophthalmic solution 0.5% in treating or preventing experimental ocular infections.

Section snippets

Mechanism of Action

The fluoroquinolones are potent antibacterial agents that target bacterial enzymes necessary for DNA synthesis (i.e., replication, transcription, repair, and recombination). These important bacterial enzymes are DNA gyrase and topoisomerase IV.10, 31, 32, 33, 34, 35 The principal event in the action of the fluoroquinolone is the trapping of gyrase or topoisomerase IV on DNA as ternary drug-enzyme-DNA complexes.31, 34, 116 The fluoroquinolone-enzyme-DNA complexes prevent uncoiling and/or

Mechanisms of Resistance

Resistance to fluoroquinolones emerged shortly after the introduction of the second-generation compounds, ofloxacin and ciprofloxacin.3, 46, 73 Resistance to fluoroquinolones requires significant genetic changes in one or more of four major bacterial mechanisms: a) enzymes for DNA synthesis, b) gyrase protecting proteins, c) cell permeability, or d) drug efflux.56, 99 Also, enzymes that degrade fluoroquinolones have not been reported in bacteria, but have been found in fungi.¹¹⁹

In Vitro Susceptibility of Bacteria Recovered from Ocular Infections

Moxifloxacin has been shown to possess potent in vitro activity against a wide spectrum of bacteria and is more active against Staphylococcus and Streptococcus species than previous generation fluoroquinolones.7, 41, 45, 54Table 2 (gram-positives), 3 (gram-negatives), and 4 (atypicals) present a comparison of intrinsic susceptibilities to fluoroquinolones for bacterial species routinely encountered in ocular infections. Intrinsic susceptibility to an antibiotic is typified by the median (50%)

Assessment of Fluoroquinolone Therapy in Rabbit Keratitis Models

Several reports have established the effectiveness of fluoroquinolones in the treatment of experimental keratitis. Data from Barequet et al have shown the improved efficacy of a third-generation fluoroquinolone (trovafloxacin) as compared to ciprofloxacin and ofloxacin in a rabbit model of S. aureus and P. aeruginosa keratitis.⁶ Their results showed that the third-generation fluoroquinolone had approximately a 2-log greater reduction in CFU/cornea relative to the second-generation

Conclusions

In vitro studies have shown that moxifloxacin has improved activity for gram-positive and atypical organisms and similar activity against gram-negative organisms compared to second and third-generation fluoroquinolones (i.e., ofloxacin, ciprofloxacin, levofloxacin). Moxifloxacin inhibited the growth of bacteria frequently isolated from ocular infections and had a faster rate of killing of fluoroquinolone-resistant organisms than ciprofloxacin. Furthermore, in vivo studies demonstrated that

Method of Literature Search

A literature search for this article was performed based on MEDLINE database searches from 1966 to 2005, using varying combinations of the search terms ocular infections, fluoroquinolones, generations, mechanism of action, mutant prevention concentration, ocular penetration, prophylaxis, animal models of keratitis, keratitis, endophthalmitis, and resistance. Relevant journal articles were selected for review. Articles cited in the references of journal articles were also included. An effort to

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: Dr. Stroman, Dr. Dajcs, Ms. Cupp and Dr. Schlech are employees of Alcon Research, Ltd.

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In Vitro and In Vivo Potency of Moxifloxacin and Moxifloxacin Ophthalmic Solution 0.5%, A New Topical Fluoroquinolone

Abstract

Introduction

Section snippets

Mechanism of Action

Mechanisms of Resistance

In Vitro Susceptibility of Bacteria Recovered from Ocular Infections

Assessment of Fluoroquinolone Therapy in Rabbit Keratitis Models

Conclusions

Method of Literature Search

Clin Ther

Ophthalmology

Surv Ophthalmol

Int J Antimicrob Agents

Am J Ophthalmol

Can J Ophthalmol

Int J Antimicrob Agents

Curr Opin Microbiol

Ophthalmology

Am J Ophthalmol

J Biol Chem

Surv Ophthalmol

Lancet

Ophthalmology

Am J Ophthalmol

Ophthalmology

Am J Ophthalmol

J Cataract Refract Surg

Am J Ophthalmol

Lancet

J Cataract Refract Surg

Am J Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

J Cataract Refract Surg

Surv Ophthalmol

Am J Ophthalmol

Comparative in vitro activities of linezolid, telithromycin, clarithromycin, levofloxacin, moxifloxacin, and four conventional antimycobacterial drugs against Mycobacterium kansasii

Antimicrob Agents Chemother

Comparative efficacy of topical moxifloxacin versus ciprofloxacin and vancomycin in the treatment of P. aeruginosa and ciprofloxacin-resistant MRSA keratitis in rabbits

Cornea

The mutant prevention concentration (MPC): a review

J Infect Dis Phamacother

Treatment of experimental bacterial keratitis with topical trovafloxacin

Arch Ophthalmol

Comparison of the antibacterial activities of the quinolones Bay 12-8039, gatifloxacin (AM 1155), trovafloxacin, clinafloxacin, levofloxacin and ciprofloxacin

J Antimicrob Chemother

The effect of intracameral, pre-operative antibiotics on microbial contamination of anterior chamber aspirates during phacoemulsification

Eye

Differential behaviors of Staphylococcus aureus and Escherichia coli type II DNA topoisomerases

Antimicrob Agents Chemother

A review of the comparative in-vitro activities of 12 antimicrobial agents, with a focus on five new respiratory quinolones

J Antimicrob Chemother

Mutant prevention concentrations of fluoroquinolones for clinical isolates of Streptococcus pneumoniae

Antimicrob Agents Chemother

Rapid development of ciprofloxacin resistance in methicillin-susceptible and -resistant Staphylococcus aureus

J Infect Dis

Comparison of the in vitro activities of several new fluoroquinolones against respiratory pathogens and their abilities to select fluoroquinolone resistance

J Antimicrob Chemother

Bactericidal properties of moxifloxacin and post-antibiotic effect

J Antimicrob Chemother

Quinolone resistance locus nfxD of Escherichia coli is a mutant allele of the parE gene encoding a subunit of topoisomerase IV

Antimicrob Agents Chemother

Penetration of ofloxacin and ciprofloxacin in aqueous humor after topical administration

Ophthalmic Surg Lasers

Mutant selection window in levofloxacin and moxifloxacin treatments of experimental pneumococcal pneumonia in a rabbit model of human therapy

Antimicrob Agents Chemother

The effectiveness of tobramycin and Ocuflox in a prophylaxis model of Staphylococcus keratitis

Curr Eye Res

Effectiveness of ciprofloxacin and ofloxacin in a prophylaxis model of Staphylococcus keratitis

Cornea

Effectiveness of ciprofloxacin, levofloxacin, or moxifloxacin for treatment of experimental Staphylococcus aureus keratitis

Antimicrob Agents Chemother

Comparative in vitro and in vivo activity of the C-8 methoxy quinolone moxifloxacin and the C-8 chlorine quinolone BAY y 3118

Clin Infect Dis

In vitro activity of BAY 12-8039, a new 8-methoxyquinolone

Chemotherapy

Increasing resistance of Staphylococcus aureus to ciprofloxacin

Antimicrob Agents Chemother

Effect of fluoroquinolone concentration on selection of resistant mutants of Mycobacterium bovis BCG and Staphylococcus aureus