Gemifloxacin MICs Research Articles

Relative Potential for Selection of Quinolone-Resistance- Determining-Region Mutations in Streptococcus pneumoniae by Gemifloxacin, Gatifloxacin and Moxifloxacin

Serial passage of a clinical isolate of Streptococcus pneumoniae, in the presence of moxifloxacin, gatifloxacin or gemifloxacin, gave rise to resistant isolates. Non-susceptibility as defined by Clinical and Laboratory Standards Institute (CLSI, formerly NCCLS) breakpoints arose on Days 10, 11, and 12 with gatifloxacin, gemifloxacin, and moxifloxacin respectively. Moxifloxacin and gatifloxacin selected for a single step quinolone-resistant-determining-region (QRDR) mutation in DNA gyrase (GyrA) on Day 4 and 7 respectively, whereas gemifloxacin selected simultaneously for multi-step mutations in gyrase and topoisomerase IV (ParC) on Day 17 and activated a non-reserpine inhibited efflux mechanism by Day 4. As found in clinical isolates, mutations included Ser-81-Phe and Glu-85-Lys in GyrA and Ser-79- Phe or Asp-83-Tyr in ParC. At high MICs, moxifloxacin showed a previously unreported 4 amino-acid deletion in GyrB as well as a more unusual substitution Ser-79-Leu/Ile in ParC. Gemifloxacin showed a 2- to 16-fold greater activity than moxifloxacin or gatifloxacin against strains with two or more QRDR mutations, however, its potency did not translate to nonsusceptibility and gemifloxacin MIC values were either at or well above the CLSI nonsusceptible breakpoint concentration.

In vitro activity of gemifloxacin and contemporary oral antimicrobial agents against 27,247 Gram-positive and Gram-negative aerobic isolates: a global surveillance study

This study was a multi-centre, multi-country surveillance of 27,247 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>levofloxacin>ciprofloxacin against the Gram-positive aerobes and shared comparable Gram-negative activity with ciprofloxacin and levofloxacin.

Mechanism of fluoroquinolone resistance is an important factor in determining the antimicrobial effect of gemifloxacin against Streptococcus pneumoniae in an in vitro pharmacokinetic model.

Antibacterial effect and emergence of resistance to gemifloxacin and levofloxacin were studied in an in vitro pharmacokinetic model of infection. A panel of Streptococcus pneumoniae strains with known mechanisms of resistance were used; two strains had no known resistance mechanism, two had efflux pumps, three had gyrA plus parC mutations, and one had only a parC mutation. Gemifloxacin MICs were in the range of 0.016 to 0.25 mg/liter, and levofloxacin MICs ranged from 1 to 16 mg/liter. Antimicrobial effect was measured by area under the bacterial-kill curve up to 72 h, and emergence of resistance was determined by population analysis profile before and during drug exposure. The area under the curve (AUC)/MIC ratios for gemifloxacin and levofloxacin were 35 to 544 and 3 to 48, respectively. As expected on the basis of these AUC/MIC ratio differences, antibacterial effect was much greater for gemifloxacin than levofloxacin. In the gemifloxacin simulations, mechanism of resistance as well as MIC determined the antibacterial effect, as indicated by gemifloxacin's greater effect against efflux strains compared to those with gyrA or parC mutations despite similar MICs. This was not true of levofloxacin. Emergence of resistance was not easily demonstrated with either agent, and mechanism of resistance did not have any impact on it.

Activities of new fluoroquinolones, ketolides, and other antimicrobials against blood culture isolates of viridans group streptococci from across Canada, 2000.

The rates of nonsusceptibility to penicillin, erythromycin, and clindamycin of 191 blood culture isolates of viridans group streptococci collected from across Canada in 2000 were 36, 42, and 10%, respectively. Although 8% of the strains were resistant to ciprofloxacin (MIC >or= 4 microg/ml), the MICs of gemifloxacin, BMS 284756, telithromycin, and ABT 773 at which 90% of the strains were inhibited were 0.06, 0.06, 0.12, and 0.03 microg/ml, respectively.

Development of gemifloxacin in vitro susceptibility test methods for gonococci including quality control guidelines

Gemifloxacin (formerly SB-265805 or LB20304a) is a new fluoronapthyridone with documented activity against Gram-positive and -negative organisms. The activity of gemifloxacin was tested against 150 Neisseria gonorrhoeae strains, using reference agar dilution, standardized disk diffusion, and Etest (AB BIODISK, Solna, Sweden) methods. Gemifloxacin was very potent against ciprofloxacin (CIPRO)-susceptible strains (MIC 90, 0.008 μg/ml) but was significantly less active against the CIPRO-resistant gonococci (MIC 90, 0.12 μg/ml). Etest and reference agar dilution MIC results showed excellent correlation ( r = 0.96), and 98.7% MICs were within ± one log 2 dilution. Agar dilution MICs were also compared to zone diameters obtained using gemifloxacin 5-μg disks; and complete intermethod categorical agreement (100%) was achieved applying breakpoints proposed as follows: ≤0.25 μg/ml (zone, ≥ 25 mm) for susceptible and ≥1 μg/ml (zone, ≤21 mm) for resistant. Gemifloxacin MIC and disk diffusion test quality control (QC) ranges were established for N. gonorrhoeae ATCC 49226. Data were collected from ≥ seven laboratories, three GC agar medium lots for both agar MICs and disk methods, and two lots each of the 5- and 10-μg disks. The proposed MIC QC range was 0.002 to 0.016 μg/ml and the calculated mm zone ranges (median ± 0.5× average mm range) for both disks were similar, but contained only 88.1 to 91.9% of participant results. To achieve the acceptable ≥ 95% of all study results within range, a 43 to 54 mm limits (5-μg disks) were necessary. The excellent broad-spectrum activity and a low reported adverse effects profile of gemifloxacin shows a potential for treatment of fluoroquinolone-resistant gonorrhea.

In vitro activity of gemifloxacin and other antimicrobial agents against isolates of Bordetella pertussis and Bordetella parapertussis.

We investigated the activity of the novel quinolone agent gemifloxacin (SB-265805) and a panel of comparator agents against Bordetella pertussis and Bordetella parapertussis. Erythromycin, azithromycin, ciprofloxacin and gemifloxacin were consistently active against both species. An azithromycin- and erythromycin-resistant B. pertussis isolate was not resistant to any of the other agents tested (gemifloxacin MIC < or =0.008 mg/L; ciprofloxacin, 0.015 mg/L; ampicillin, 2.0 mg/L; trimethoprim-sulphamethoxazole, 4.0 mg/L). The potency of ampicillin, azithromycin, erythromycin, ciprofloxacin and trimethoprim-sulphamethoxazole recorded against B. pertussis and B. parapertussis in this study was comparable to that noted in previous studies. However, MICs were generally higher than those noted in other trials; this may reflect the different methods used. Although in vitro data on the potency of gemifloxacin against B. pertussis and B. parapertussis have not previously been reported, these results are comparable to the potency of other quinolones against these pathogens. Should gemifloxacin achieve similar concentrations within the respiratory tract as other quinolones, this, coupled with its high in vitro potency, suggests that gemifloxacin has potential clinical efficacy in pertussis.