A critical review of the fluoroquinolones: focus on respiratory infections.

The new fluoroquinolones (clinafloxacin, gatifloxacin, gemifloxacin, grepafloxacin, levofloxacin, moxifloxacin, sitafloxacin, sparfloxacin and trovafloxacin) offer excellent activity against Gram-negative bacilli and improved Gram-positive activity (e.g. against Streptococcus pneumoniae and Staphylococcus aureus) over ciprofloxacin. Ciprofloxacin still maintains the best in vitro activity against Pseudomonas aeruginosa. Clinafloxacin, gatifloxacin, moxifloxacin, sitafloxacin, sparfloxacin and trovafloxacin display improved activity against anaerobes (e.g. Bacteroides fragilis) versus ciprofloxacin. All of the new fluoroquinolones display excellent bioavailability and have longer serum half-lives than ciprofloxacin allowing for once daily dose administration. Clinical trials comparing the new fluoroquinolones to each other or to standard therapy have demonstrated good efficacy in a variety of community-acquired respiratory infections (e.g. pneumonia, acute exacerbations of chronic bronchitis and acute sinusitis). Limited data suggest that the new fluoroquinolones as a class may lead to better outcomes in community-acquired pneumonia and acute exacerbations of chronic bronchitis versus comparators. Several of these agents have either been withdrawn from the market, had their use severely restricted because of adverse effects (clinafloxacin because of phototoxicity and hypoglycaemia; grepafloxacin because of prolongation of the QTc and resultant torsades de pointes; sparfloxacin because of phototoxicity; and trovafloxacin because of hepatotoxicity), or were discontinued during developmental phases. The remaining fluoroquinolones such as gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin have adverse effect profiles similar to ciprofloxacin. Extensive post-marketing safety surveillance data (as are available with ciprofloxacin and levofloxacin) are required for all new fluoroquinolones before safety can be definitively established. Drug interactions are limited; however, all fluoroquinolones interact with metal ion containing drugs (eg. antacids). The new fluoroquinolones (gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin) offer several advantages over ciprofloxacin and are emerging as important therapeutic agents in the treatment of community-acquired respiratory infections. Their broad spectrum of activity which includes respiratory pathogens such as penicillin and macrolide resistant S. pneumoniae, favourable pharmacokinetic parameters, good bacteriological and clinical efficacy will lead to growing use of these agents in the treatment of community-acquired pneumonia, acute exacerbations of chronic bronchitis and acute sinusitis. These agents may result in cost savings especially in situations where, because of their potent broad-spectrum activity and excellent bioavailability, they may be used orally in place of intravenous antibacterials. Prudent use of the new fluoroquinolones will be required to minimise the development of resistance to these agents.     

In vitro activity of sitafloxacin compared with several fluoroquinolones against Streptococcus anginosus and Streptococcus constellatus

The in vitro activities of sitafloxacin and seven other fluoroquinolones a (ciprofloxacin, tosufloxacin, sparfloxacin, levofloxacin, T-3811ME, moxifloxacin and trovafloxacin) were examined by the microdilution method against 79 clinically isolated 'Streptococcus milleri' group (SMG) microorganisms. No statistically significant differences were found between the minimum inhibitory concentrations (MIC(50) and MIC(90)) against Streptococcus anginosus and Streptococcus constellatus. Sitafloxacin was the most active agent of the eight fluoroquinolones tested against SMG, with a MIC(90) of 0.06 microg/mL, which was 8 times more active than ciprofloxacin and 16 times more active than levofloxacin. Although none of the SMG strains showed high resistance to any of the fluoroquinolones tested, three agents (trovafloxacin, sitafloxacin and T-3811ME) had low MICs against 23 SMG strains against which levofloxacin had a MIC> 1 microg/mL. In conclusion, several fluoroquinolones have low MICs against SMG, but sitafloxacin has the lowest.     

Fluoroquinolones, the cornerstone of treatment of drug-resistant tuberculosis: a pharmacokinetic and pharmacodynamic approach

Fluoroquinolones (FQs) are important drugs to treat drug-resistant tuberculosis. In this review we integrated pharmacokinetic properties (PK) and microbiological susceptibility against M. tuberculosis and eventually evaluated the pharmcodynamic (PD) properties, as well as the influence of co-administered agents on these characteristics, for the currently used FQs (ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin and moxifloxacin) in TB treatment. Future FQs that are being developed may overcome the problems with FQs that are used in daily practice. Therefore PK and pharmacodynamic (PD) properties of novel FQs (clinafloxacin, garenoxacin, lomefloxacin, sitafloxacin, sparfloxacin, trovafloxacin, gemifloxacin, grepafloxacin and DC-159a) were evaluated in TB treatment as well. Integrating both excellent PK and PD properties, moxifloxacin, possibly at a higher dosage, may fulfil a far more important role in the treatment of multi-drug and early-generation FQ resistant TB than proposed in the current WHO guideline. Sparfloxacin, trovafloxacin and sitafloxacin are upcoming novel FQs that may be useful for drug-resistant TB based on their favourable PK properties or microbiological susceptibility against M. tuberculosis. Finally, the 8-methoxy moiety, as present in the chemical structure of MFX, will possibly provide DC- 159a with promising PK/PD characteristics and consequently this FQ may develop into a key FQ in future drug resistant TB treatment.     

Comparative activity of quinolones, macrolides and ketolides against Legionella species using in vitro broth dilution and intracellular susceptibility testing

The comparative in vitro activity of quinolones (trovafloxacin, gemifloxacin, levofloxacin, ciprofloxacin, moxifloxacin and grepafloxacin), ketolides (ABT-773 and telithromycin) and macrolides (clarithromycin, azithromycin and erythromycin) were evaluated against Legionella pneumophila by broth dilution and an HL-60 intracellular model. The MIC90 of the quinolones, clarithromycin and ABT-773 were more than eight times lower than for erythromycin. Telithromycin, ABT-773 and azithromycin had significantly greater intracellular activity against L. pneumophila than erythromycin at 1xMIC and 8xMIC. The rank order of intracellular activity against L. pneumophila serogroup 1 was quinolones>ketolides>macrolides. Clinical trials to determine the clinical efficacy of ketolides for the treatment of Legionnaires' disease are warranted.     

Mutagenesis induced by 12 quinolone antibacterial agents in Escherichia coli WP2uvrA/pKM101.

The mutagenic potential of 12 quinolone antibacterial agents (quinolones) was examined at concentrations of 3.91-1000 ng/plate with or without S9 mix in Escherichia coli WP2uvrA/pKM101. All quinolones showed mutagenic potential in the strain: the maximum numbers of revertant colonies were observed at 7.81 ng/plate for clinafloxacin and sitafloxacin; 15.63 ng/plate for ciprofloxacin, gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin, and trovafloxacin; and 31.25-500 ng/plate for enoxacin, lomefloxacin, norfloxacin and ofloxacin. The numbers for all quinolones were comparable between the groups with and without S9 mix. In all quinolones, bactericidal effects were observed at one or two higher concentrations than their mutagenic concentrations except for enoxacin without S9 mix. From these results, the WP2uvrA/pKM101 strain is proved to be highly sensitive to quinolones.     

Comparative in vitro activity of gatifloxacin, grepafloxacin, levofloxacin, moxifloxacin and trovafloxacin against 4151 Gram-negative and Gram-positive organisms

Gatifloxacin, grepafloxacin, moxifloxacin and trovafloxacin are fluoroquinolones with enhanced Gram-positive activity while retaining broad-spectrum activity against Gram-negative pathogens. Levofloxacin and ciprofloxacin are older quinolones with broad activity against Gram-negative pathogens and borderline activity against some Gram-positive organisms. We compared the in vitro activity of these compounds against 4151 Gram-negative and -positive organisms. Gatifloxacin, grepafloxacin, moxifloxacin and trovafloxacin were highly active against penicillin sensitive and resistant Streptococcus pneumoniae, Staphylococcus aureus, Streptococcus pyogenes and Streptococcus agalactiae. Ciprofloxacin and levofloxacin were active but less potent. All compounds were highly active (overall) against Gram-negative pathogens with ciprofloxacin being the most active agent against Pseudomonas aeruginosa. Our data indicate that the advanced fluoroquinolones will be important compounds for treating infections caused by Gram-positive and Gram-negative pathogens.     

In vitro activity of gemifloxacin against clinical isolates of Neisseria gonorrhoeae with and without mutations in the gyrA gene

The MIC of gemifloxacin and five other quinolones was tested against 31 clinical isolates of Neisseria gonorrhoeae; strains were analyzed for the presence of mutations in both the gyrA and parC genes. Only seven strains were resistant to nalidixic acid due to a mutation in the gyrA gene but not in the parC gene, with six and two considered intermediate to ciprofloxacin and levofloxacin, respectively. The activity of gemifloxacin was similar to that of trovafloxacin and moxifloxacin, but was more active than nalidixic acid, ciprofloxacin or levofloxacin against the gyrA mutant strains. Gemifloxacin is a valid therapeutic alternative to treat infections with N. gonorrhoeae, retaining its activity against strains already presenting a mutation in gyrA.     

Effects of sparfloxacin, grepafloxacin, moxifloxacin, and ciprofloxacin on cardiac action potential duration

Fluoroquinolone antibiotics have been associated with QT prolongation following administration to humans. This study compares the effects of four fluoroquinolones, sparfloxacin, grepafloxacin, moxifloxacin and ciprofloxacin on action potential duration recorded from canine isolated cardiac Purkinje fibres. Left and right ventricular Purkinje fibres were isolated from canine hearts and continuously superfused with physiological salt solution. Action potential duration at 90% repolarization was recorded via intracellular microelectrodes. Sparfloxacin, grepafloxacin, moxifloxacin and ciprofloxacin prolonged action potential duration in a concentration dependent manner. Mean concentrations causing a 15% prolongation of action potential duration recorded at a stimulation frequency of 1 Hz were: sparfloxacin 4.2+/-0.7 microg/ml; grepafloxacin 9.3+/-0.9 microg/ml; moxifloxacin 9.9+/-1.6 microg/ml and ciprofloxacin 72.8+/-26.4 microg/ml. Prolongation was inverse frequency dependent with larger increases in action potential duration occurring when the stimulation frequency was reduced to 0.5 Hz. These results indicate that effects on action potential duration vary within this class of compound. Rank order of potency was sparfloxacin > grepafloxacin = moxifloxacin > ciprofloxacin.     

Activity of moxifloxacin and other quinolones against pneumococci resistant to first-line agents, or with high-level ciprofloxacin resistance

The activity of moxifloxacin and other quinolones was assessed against 288 epidemiologically diverse isolates of Streptococcus pneumoniae, many of them resistant to one or more first-line agents and/or with increased ciprofloxacin resistance (minimum inhibitory concentrations, MICs 16- > 64 mg/l compared with 1-2 mg/l for most isolates). Moxifloxacin and grepafloxacin were the most active quinolone analogues, inhibiting about 90% of the isolates at < or = 1 mg/l, whereas levofloxacin inhibited 64% of isolates at < = 1 mg/l and ciprofloxacin inhibited 42%. Moxifloxacin also was the most active agent against isolates with elevated ciprofloxacin resistance (MIC 16- > 64 mg/l): moxifloxacin MICs of around 4 mg/l were seen for most such isolates, compared with 16-32 mg for levofloxacin and grepafloxacin. The activity of moxifloxacin against pneumococci resistant to one or more first-line agent suggests it will have a useful therapeutic role, although its activity against highly ciprofloxacin resistant isolates seems marginal.     

In vivo activity of gemifloxacin, moxifloxacin and levofloxacin against pneumococci with gyrA and parC point mutations in a sepsis mouse model measured with the all or nothing mortality end-point

A dose-decreasing immunocompetent sepsis mouse model was used to evaluate the in vivo effect of levofloxacin, moxifloxacin and gemifloxacin, using a ciprofloxacin/levofloxacin susceptible serotype 6B strain (ciprofloxacin MIC: 1 mg/l) and two resistant serotype 14 and 19F strains with gyrA and parC point mutations (ciprofloxacin MICs of 32 and 64 mg/l, respectively). Significant higher in vivo activity was found for moxifloxacin and gemifloxacin than for levofloxacin against strains 1 and 2, and for gemifloxacin versus moxifloxacin or levofloxacin against strain 3. Gemifloxacin treatment resulted in 100% survival against strains 1 and 2(AUC0-24 h/MIC of 30 and 62) but against strain 3, survival was 60-80% (AUC0-24 h/MIC of 93). Similar AUC0-24 h/MIC values produced different therapeutic results suggesting that in vitro parameters other than the MIC could influence efficacy predictions based on in vitro susceptibility tests (MICs) or pharmacodynamic parameters (AUC0-24 h/MIC).     

Electrophysiological safety of novel fluoroquinolone antibiotic agents gemifloxacin and balofloxacin

Some fluoroquinolones have been reported to induce QT interval prolongation associated with the onset of torsades de pointes (TdP), resulting in a life-threatening ventricular arrhythmia. We investigated the cardiac electrophysiological effects of two new fluoroquinolones, gemifloxacin and balofloxacin, by using conventional microelectrode recording techniques in isolated rabbit Purkinje fiber and whole-cell patch-clamp techniques in human ether-á-go-go related gene (hERG)-transient transfected CHO cells. Gemifloxacin had no significant effects on the resting membrane potential, total amplitude, action potential, and Vmax of phase 0 depolarization at concentrations up to 30 microM, but gemifloxacin at 100 microM significantly decreased total amplitude (p < 0.01). These values of gemifloxacin (30 and 100 microM) were approximately 25- and 83-fold more than the free plasma concentration of 1.2 microM in a single therapeutic injection in humans. For I(hERG), the IC(50) value was about 300 microM. Balofloxacin had also no significant effects on the resting membrane potential, total amplitude, action potential duration, and Vmax of phase 0 depolarization at concentrations up to 30 microM, but balofloxacin at 100 microM significantly (p < 0.01) prolonged action potentials at both 50% repolarization (APD(50)) and 90% repolarization (APD(90)). These values of balofloxacin (30 and 100 microM) were approximately 6.8- and 23-fold more than the free plasma concentration of 4.4 microM in a single therapeutic injection in humans. For I(hERG), the IC(50) value was 214 +/- 14 microM. Therefore, our data suggested that in the electrophysiological aspect, gemifloxacin and balofloxacin may have no torsadogenic potenties up to 30 microM.     

In vitro activity of gemifloxacin and contemporary oral antimicrobial agents against 27247 Gram-positive and Gram-negative aerobic isolates: a global surveillance study

This study was a multi-centre, multi-country surveillance of 27247 Gram-positive and Gram-negative isolates collected from 131 study centres in 44 countries from 1997 to 2000. MICs of gemifloxacin were compared with penicillin, amoxicillin-clavulanic acid, cefuroxime, azithromycin, clarithromycin, trimethoprim-sulphamethoxazole, ciprofloxacin, grepafloxacin and levofloxacin by broth microdilution. Penicillin resistance in Streptococcus pneumoniae was extremely high in the Middle East (65.6%), Africa (64.0%) and Asia (60.4%) and lower in North America (40.3%), Europe (36.9%) and the South Pacific (31.8%). Macrolide resistance in S. pneumoniae was highest in Asia (51.7%) but varied widely between laboratories in Europe (26.0%), North America (21.6%), the Middle East (13.7%), the South Pacific (10.6%) and Africa (10.0%). All the study quinolones were highly active against penicillin-resistant and macrolide-resistant S. pneumoniae. Overall, gemifloxacin had the lowest MIC(90) at 0.06 mg/l with MICs 4-64-fold lower than ciprofloxacin, levofloxacin and grepafloxacin against S. pneumoniae. Gemifloxacin MICs were more potent than grepafloxacin > levoflaxacin > ciproflaxin against the Gram-positive aerobes and shared comparable Gram-negative activity with ciprofloxacin and levofloxacin.     

In vitro activity of gatifloxacin compared with gemifloxacin, moxifloxacin, trovafloxacin, ciprofloxacin and ofloxacin against uropathogens cultured from patients with complicated urinary tract infections

Minimum inhibitory concentrations (MICs) of gatifloxacin were compared with those of gemifloxacin, moxifloxacin, trovafloxacin, ciprofloxacin and ofloxacin using an agar dilution method for 400 uropathogens cultured from the urine of urological patients with complicated and/or hospital-acquired urinary tract infections (UTI). The collection of strains was made up of Enterobacteriaceae (34.5%), enterococci (31.5%), staphylococci (21.2%) and non-fermenting bacteria (12.8%). The antibacterial activity of the three newer fluoroquinolones, gatifloxacin, gemifloxacin, and moxifloxacin, were similar, but showed some drug specific differences. Gemifloxacin was most active against Escherichia coli, but less so against Proteus mirabilis. In this series all isolates of E. coli were inhibited at a MIC of 0.25 mg/l gatifloxacin and moxifloxacin and by 0.125 mg/l gemifloxacin. The MIC distribution of all fluoroquinolones showed a bimodal distribution for staphylococci, enterococci and Pseudomonas aeruginosa. The two modes for P. aeruginosa were 1 and 64 mg/l for gemifloxacin and moxifloxacin and 0.5 and 64 mg/l for gatifloxacin. For staphylococci the two modes were 0.125 and 2 mg/l for gatifloxacin, 0.03 and 4 mg/l for gemifloxacin, and 0.03 and 2 mg/l for moxifloxacin; for enterococci, 0.25 and 16 mg/l for gatifloxacin, 0.06 and 2 mg/l for gemifloxacin, and 0.25 and 8 mg/l for moxifloxacin. Compared with trovafloxacin the MICs were similar, but the newer fluoroquinolones were more active than ciprofloxacin and ofloxacin against Gram-positive bacteria. Of the newer fluoroquinolones gatifloxacin had the highest rate of renal excretion and could be considered a promising alternative fluoroquinolone agent for the treatment of UTI.     

Measurement of the bactericidal activity of fluoroquinolones against Streptococcus pneumoniae using the bactericidal index method

Kill curve analysis alone showed trovafloxacin to be more bactericidal than levofloxacin, grepafloxacin and moxifloxacin against four isolates of Streptococcus pneumoniae. However, using the bactericidal index (BI) method, levofloxacin was the most bactericidal fluoroquinolone using serum or lung biopsy concentration levels against the ofloxacin-susceptible strains and trovafloxacin was the most bactericidal against the ofloxacin-intermediate strain. None of the fluoroquinolones was bactericidal against the ofloxacin-resistant strain. With BIs using epithelial lining fluid or alveolar macrophage concentration levels, trovafloxacin or grepafloxacin was most bactericidal, respectively. These data illustrate that simple analysis of traditional kill curves may not be adequate in the evaluation of fluoroquinolone bactericidal activity. The results of this study suggest a need for further investigation to assess the role of tissue concentration and bactericidal activity in antimicrobial efficacy.     

Effect of pazufloxacin mesilate, a new quinolone antibacterial agent, for intravenous use on QT interval

The potential for QT interval prolongation of pazufloxacin mesilate (PZFX mesilate), a new quinolone antibacterial agent for intravenous use, was investigated by in vitro and in vivo electrophysiology studies. Following results were obtained. In vitro electrophysiology study using guinea pig papillary muscles: PZFX mesilate (30-300 microM) had no effects on resting membrane potential (RMP), action potential amplitude (APA) and action potential duration (APD). Reference quinolones, sparfloxacin (3-30 microM) and moxifloxacin (10-100 microM), had no effects on RMP and APA, but significantly prolonged APD at more than 3 and 10 microM, respectively, while ciprofloxacin (10-100 microM) had no effect on each parameter. In vivo electrophysiology study using anesthetized dogs: PZFX mesilate had no effects on electrocardiograph parameter (PR interval, QRS interval, QT interval and QTc) after intravenous administration of 3-30 mg/kg. These results suggest that PZFX mesilate has low potential for QT interval prolongation.     

In vitro activities of mutant prevention concentration-targeted concentrations of fluoroquinolones against Staphylococcus aureus in a pharmacodynamic model

To test the validity of the mutant selection window, we simulated mutant prevention concentration-targeted fluoroquinolone concentrations using an in vitro model with infected fibrin clots. Therapeutic ciprofloxacin (peak 5 microg/mL; t(1/2) 4 h), gatifloxacin (3.5 microg/mL; 8h), gemifloxacin (1.25 microg/mL; 8 h), levofloxacin (6 microg/mL; 6 h) and moxifloxacin (4.5 microg/mL; 12 h) were tested against methicillin-susceptible and -resistant Staphylococcus aureus, as were mutant prevention concentration (MPC)-targeted regimens achieving a trough of 1/4x or 2x MPC. MIC/MPC for MSSA K553 were 0.125/2, 0.03/0.125, 0.03/0.063, 0.125/1 and 0.015/0.25 microg/mL for ciprofloxacin, gatifloxacin, gemifloxacin, levofloxacin and moxifloxacin, respectively. Corresponding values for MRSA 494 were 0.125/1, 0.063/0.125, 0.03/0.063, 0.125/0.5 and 0.063/0.125 microg/mL. All regimens produced efflux mutants of MSSA K553. For MRSA 494, therapeutic and 1/4x MPC levofloxacin regimens produced resistance, whereas only 1/4x MPC regimens of gatifloxacin, gemifloxacin, and moxifloxacin produced resistance. All ciprofloxacin regimens produced resistance. Ciprofloxacin 1/4x MPC and therapeutic levofloxacin caused outgrowth of GrlA mutants (S80Y amino acid substitution); efflux mutants were isolated in all other cases. Overall, gatifloxacin, gemifloxacin, and moxifloxacin displayed a lesser propensity to select resistant isolates of S. aureus than ciprofloxacin and levofloxacin. The mutant selection window premise appeared valid for MRSA only. Additional studies are necessary to define the applicability of the MPC.     

Antibacterial activity of tosufloxacin against major organisms detected from patients with respiratory infections

We determined the susceptibility of bacteria which were isolated from the patients with respiratory infections between January and October 2005, to tosufloxacin and other fluoroquinolones. A total of 900 isolate including 300 Streptococcus pneumoniae, 100 Streptococcus pyogenes, 100 Moraxella catarrhalis, 200 Haemophilus influenzae, 100 Klebsiella pneumoniae and 100 Pseudomonas aeruginosa were tested. Tosufloxacin, gatifloxacin, levofloxacin, moxifloxacin, ciprofloxacin and prulifloxacin were used as the test antimicrobials. Tosufloxacin, gatifloxacin and moxifloxacin were potent antibiotics tested for the antibacterial activity against Streptococcus including penicillin-resistant S. pneumoniae; the MIC90 were 0.12-0.5/ micromL. Fluoroquinolones exerted the potent antibacterial activity against M. catarrhalis and H. influenzae; the MIC90 of fluoroquinolones tested were < or =0.06 microg/mL. Tosufloxacin, ciprofloxacin and prulifloxacin showed to be more active against K. pneumoniae and P. aeruginosa, but parts of some strains were resistant. These results indicate that tosufloxacin has the potent antibacterial activity against major organisms detected from patients with respiratory infections. Since it was approved in 1990, tosufloxacin was considered to be useful as a therapeutic antimicrobial for the treatment of respiratory infections.     

In vitro susceptibility of 4903 bacterial isolates to gemifloxacin--an advanced fluoroquinolone

The in vitro activity of gemifloxacin against over 4900 bacterial isolates was determined by microbroth dilution with interpretation in accordance with NCCLS guidelines. Susceptibility results were compared with those for ciprofloxacin, gatifloxacin, levofloxacin and moxifloxacin. Gemifloxacin and the other fluoroquinolones were not affected by either beta-lactamase production or penicillin-resistance in Streptococcus pneumoniae. The MIC90 values for gemifloxacin were: S. pneumoniae 0.063 mg/l; Haemophilus influenzae 0.016 mg/l; Moraxella catarrhalis 0.008 mg/l, methicillin-susceptible Staphylococcus aureus 0.063 mg/l; methicillin-susceptible Streptococcus pyogenes 0.031 mg/l; Enterobacteriaceae 0.031-0.16 mg/l; Pseudomonas aeruginosa 4 mg/l; Neisseria meningitidis 0.008 mg/l. The MIC90 for gemifloxacin was lower than those for the other quinolones tested against S. pneumoniae (ciprofloxacin 2-4 mg/l, gatifloxacin 0.5 mg/l, levofloxacin 1-2 mg/l, moxifloxacin 0.25 mg/l). This study confirms the enhanced potent activity of gemifloxacin against Gram-positive pathogens, its broad-spectrum, Gram-negative activity and indicates that gemifloxacin is likely to have an important role in treating patients with Gram-positive and/or Gram-negative infections.     

New fluoroquinolone antibiotics

In 1993, we reviewed three fluoroquinolone antibiotics (ciprofloxacin, norfloxacin and ofloxacin). Since then, four more fluoroquinolones have been awarded marketing authorisations. Here we review the clinical evidence and discuss the place of two of these drugs, grepafloxacin (Raxar-GlaxoWellcome) and levofloxacin (Tavanic-Hoechst Marion Roussel). Sparfloxacin and trovafloxacin are not considered, as they are not yet commercially available.     

In vivo experimental approach for the risk assessment of fluoroquinolone antibacterial agents-induced long QT syndrome

The proarrhythmic effects of fluoroquinolone antibacterial agents, sitafloxacin, gatifloxacin and moxifloxacin, were compared using three in vivo models. In the halothane-anesthetized dogs (n=5), intravenous 10-min infusion of gatifloxacin and moxifloxacin (1-3 mg/kg) prolonged the ventricular effective refractory period and the repolarization period to a similar extent, whereas sitafloxacin (1-3 mg/kg) prolonged the former only. No significant change was detected in other cardiovascular parameters. In the chronic complete atrioventricular block dogs (n=4), oral administration of 100 mg/kg of gatifloxacin (2 of 4) and moxifloxacin (3 of 4) induced torsades de pointes, which was not observed by sitafloxacin. In the alpha-chloralose-anesthetized rabbits (n=5), intravenous 20-min infusion of 60 mg/kg of gatifloxacin induced torsades de pointes (1 of 5) in the presence of methoxamine infusion, which was not observed by sitafloxacin or moxifloxacin. Thus, the halothane-anesthetized model is suitable for assessing QT prolongation, whereas the chronic complete atrioventricular block model is sensitive for detecting torsadogenic action of drugs. The alpha-chloralose-anesthetized model is the simplest and least expensive method, but its sensitivity to detect proarrhythmic action may be less great.