Anti-pneumococcal activity of gatifloxacin compared with other quinolone and non-quinolone agents

Agar dilution MIC determination was used to compare the activity of DK-507k with those of ciprofloxacin, levofloxacin, gatifloxacin, moxifloxacin, sitafloxacin, amoxicillin, cefuroxime, erythromycin, azithromycin, and clarithromycin against 113 penicillin-susceptible, 81 penicillin-intermediate, and 67 penicillin-resistant pneumococci (all quinolone susceptible). DK-507k and sitafloxacin had the lowest MICs of all quinolones against quinolone-susceptible strains (MIC at which 50% of isolates were inhibited [MIC 50 ] and MIC 90 of both, 0.06 and 0.125 g/ml, respectively), followed by moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. MICs of ␤-lactams and macrolides rose with those of penicillin G. Against 26 quinolone-resistant pneumococci with known resistance mechanisms, DK-507k and sitafloxacin were also the most active quinolones (MICs, 0.125 to 1.0 g/ml), followed by moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. Mutations in quinolone resistance-determining regions of quinolone-resistant strains were in the usual regions of the parC and gyrA genes. Time-kill testing showed that both DK-507k and sitafloxacin were bactericidal against all 12 quinolonesusceptible and -resistant strains tested at twice the MIC at 24 h. Serial broth passages in subinhibitory concentrations of 10 strains for a minimum of 14 days showed that development of resistant mutants (fourfold or greater increase in the original MIC) occurred most rapidly for ciprofloxacin, followed by moxifloxacin, DK-507k, gatifloxacin, sitafloxacin, and levofloxacin. All parent strains demonstrated a fourfold or greater increase in initial MIC in <50 days. MICs of DK-507k against resistant mutants were lowest, followed by those of sitafloxacin, moxifloxacin, gatifloxacin, ciprofloxacin, and levofloxacin. Four strains were subcultured in subinhibitory concentrations of each drug for 50 days: MICs of DK-507k against resistant mutants were lowest, followed by those of sitafloxacin, moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. Exposure to DK-507k and sitafloxacin resulted in mutations, mostly in gyrA.The incidence of pneumococci resistant to penicillin G and other ␤-lactam and non-␤-lactam compounds has increased worldwide, including the United States, at an alarming rate. Major foci of infections currently include South Africa, Spain, and Central and eastern Europe (1,14,15). In the United States a recent survey has shown an increase in resistance to penicillin from Ͻ5% before 1989 (including Ͻ0.02% of isolates for which the MICs were Ն2.0 g/ml) to 6.6% in 1991 to 1992 (including 1.3% of isolates for which MICs were Ն2.0 g/ml) (3). In another more recent survey, 50.4% of 1,476 clinically significant pneumococcal isolates were not susceptible to penicillin (16). It is also important to note the high rates of isolation of penicillin-intermediate and -resistant pneumococci (approximately 30%) in middle ear fluids from patients with refractory otitis media, compared to the rates for other isolation sites (2). The problem...

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Antipneumococcal Activity of DK-507k, a New Quinolone,Compared with the Activities of 10 OtherAgents

Browne¹,

Bozdoğan

Clark

et al. 2003

“…Gatifloxacin contains a methoxy substituent at position 8 of the quinolone ring that has been associated in some bacteria with increased bacteriostatic and bactericidal activity as well as decreased selection of resistant mutants (7,27,53,54). Although gatifloxacin has been studied in S. pneumoniae (6,13,17,21,22,33,38) and Escherichia coli (27), there have been few studies of gatifloxacin action and resistance in S. aureus (14,15,22). We thus undertook to define the effects of established resistance mechanisms on gatifloxacin activity, to characterize gatifloxacin-selected mutants, and to compare the bactericidal activity of gatifloxacin with its desmethoxy derivative AM-1121.…”

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confidence: 99%

Mechanisms and Frequency of Resistance to Gatifloxacin in Comparison to AM-1121 and Ciprofloxacin in Staphylococcus aureus

İnce

Hooper

2001

Gatifloxacin, an 8-methoxyfluoroquinolone, was found to be two-to fourfold more active against wild-type Staphylococcus aureus ISP794 than its desmethoxy derivative, AM-1121, and ciprofloxacin, another desmethoxy fluoroquinolone. Single grlBA mutations caused two-to fourfold increases in the MIC of gatifloxacin, and a single gyrase mutation was silent. Double mutations in gyrA and grlA or grlB caused a 32-fold increase in the MIC of gatifloxacin, in contrast to a 128-fold increase for ciprofloxacin and AM-1121. Overexpression of the NorA efflux pump had minimal effect on the MIC of gatifloxacin. The bactericidal activity of the three quinolones at four times the MIC differed only for a double mutant, with gatifloxacin exhibiting a killing pattern similar to that for ISP794, whereas ciprofloxacin and AM-1121 failed to show any killing. With gatifloxacin, selection of resistant mutants at twice the MIC was 100-to 1,000-fold less frequent than with the comparison quinolones, and mutants could rarely be selected at four times the MIC. The limit resistance in ISP74 was 512 times the MIC of gatifloxacin and 1,024 times the MICs of ciprofloxacin and AM-1121. Novel mutations in topoisomerase IV were selected in five of the six single-step mutants, three of which were shown to cause quinolone resistance by genetic studies. In conclusion, topoisomerase IV is the primary target of gatifloxacin. In contrast to comparison quinolones, mutations in both topoisomerase IV and gyrase are required for resistance to gatifloxacin by clinical breakpoints and do not abolish bactericidal effect, further supporting the benefit of the 8-methoxy substituent in gatifloxacin.

“…For all 12 pneumococcal strains to show a 3 log 10 decrease in cell counts, the quinolones required 12 h of contact, while the ␤-lactams needed 24 h for an equal effect (7). In summary, these results indicate that the rate of killing by fluoroquinolones is bacterial group dependent.…”

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confidence: 74%

Comparative Killing Rates of Fluoroquinolones and Cell Wall-Active Agents

Fung‐Tomc

Gradelski

Valera

et al. 2000

Killing rates of fluoroquinolones, ␤-lactams, and vancomycin were compared against Enterobacteriaceae, Staphylococcus aureus, pneumococci, streptococci, and Enterococcus faecalis. The times required for fluoroquinolones to decrease viability by 3 log 10 were 1.5 h for Enterobacteriaceae, 4 to 6 h for staphylococci, and >6 h for streptococci and enterococci. Thus, the rate of killing by fluoroquinolones is organism group dependent; overall, they killed more rapidly than ␤-lactams and vancomycin.The ability of an antibiotic to kill bacteria may be important in some clinical settings, such as the management of bacterial endocarditis or the treatment of bacteremia in granulocytopenic patients. Members of the primary antimicrobial classes showing bactericidal properties that are used therapeutically as single agents are the quinolones and the cell wall-active agents, specifically ␤-lactams and the glycopeptide vancomycin.Quinolones exhibit concentration-dependent killing kinetics, with maximum killing rates achieved at the optimum bactericidal concentration (12), which for more recently developed fluoroquinolones occurs close to eight times their MICs (E. Gradelski, B. Kolek, D. Bonner, and J. Fung-Tomc, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. E-182, 1998). On the other hand, ␤-lactam antibiotics and vancomycin exhibit time-dependent kinetics (8), with little difference in killing rates at concentrations above their MICs.In this study, we compared the killing rates of three fluoroquinolones (trovafloxacin, levofloxacin, and gatifloxacin) to those of cell wall-active agents commonly used in the treatment of infections involving specific bacterial species.Bacterial strains used in this study were clinical isolates: four members of the family Enterobacteriaceae, four Staphylococcus aureus isolates (two methicillin susceptible and two methicillin resistant), four streptococci (two alpha-hemolytic and two beta-hemolytic streptococci), nine Streptococcus pneumoniae isolates (with various penicillin susceptibilities), and five Enterococcus faecalis isolates. The strains were chosen because their quinolone MICs were close to the respective quinolone-bacterial species modal MICs.Gatifloxacin was from Kyorin Pharmaceutical Co. (Tochigi, Japan), methicillin was from Bristol-Myers Squibb Co. MICs were determined by the agar dilution method withMueller-Hinton agar (supplemented with 5% sheep blood for pneumococci) according to standardized methods (13). The MIC is defined as the lowest concentration of antibiotic that inhibited all visible growth. Time-kill kinetics were conducted at drug concentrations equal to 10 times the MIC of that drug for a bacterial strain. The optimal bactericidal concentrations of quinolones are close to eight times their MICs. The maximum killing rates of seven ␤-lactams and vancomycin for seven strains used in this study were determined (data not shown); maximum killing occurred at four to eight times the MIC of a drug, and this rate was maintained up to 16 times the MIC. The...