InVitro and In Vivo Antibacterial Activities of DK-507k, aNovelFluoroquinolone

Abstract

The antibacterial activities of DK-507k, a novel quinolone, were compared with those of other quinolones: ciprofloxacin, gatifloxacin, levofloxacin, moxifloxacin, sitafloxacin, and garenoxacin (BMS284756). DK-507k was as active as sitafloxacin and was as active as or up to eightfold more active than gatifloxacin, moxifloxacin, and garenoxacin against Streptococcus pneumoniae, methicillin-susceptible and methicillin-resistant Staphylococcus aureus, and coagulase-negative staphylococci. DK-507k was as active as or 4-fold more active than garenoxacin and 2-to 16-fold more active than gatifloxacin and moxifloxacin against ciprofloxacin-resistant strains of S. pneumoniae, including clinical isolates and in vitro-selected mutants with known mutations. DK-507k inhibited all ciprofloxacin-resistant strains of S. pneumoniae at 1 g/ml. A time-kill assay with S. pneumoniae showed that DK-507k was more bactericidal than gatifloxacin and moxifloxacin. The activities of DK-507k against most members of the family Enterobacteriaceae were comparable to those of ciprofloxacin and equal to or up to 32-fold higher than those of gatifloxacin, levofloxacin, moxifloxacin, and garenoxacin. DK-507k was fourfold less active than sitafloxacin and ciprofloxacin against Pseudomonas aeruginosa, while it was two to four times more potent than levofloxacin, gatifloxacin, moxifloxacin, and garenoxacin against P. aeruginosa. In vivo, intravenous treatment with DK-507k was more effective than that with gatifloxacin and moxifloxacin against systemic infections caused by S. aureus, S. pneumoniae, and P. aeruginosa in mice. In a mouse model of pneumonia due to penicillin-resistant S. pneumoniae, DK-507k administered subcutaneously showed dose-dependent efficacy and eliminated the bacteria from the lungs, whereas gatifloxacin and moxifloxacin had no significant efficacy. Oral treatment with DK-507k was slightly more effective than that with ciprofloxacin in a rat model of foreign body-associated urinary tract infection caused by a P. aeruginosa isolate for which the MIC of DK-507k was fourfold higher than that of ciprofloxacin. Oral administration of DK-507k to rats achieved higher peak concentrations in serum and higher concentrations in cumulative urine than those achieved with ciprofloxacin. These data indicate the potential advantages of DK-507k over other quinolones for the treatment of a wide range of community-acquired infections.

Noninvasive Biophotonic Imaging for Monitoring of Catheter-Associated Urinary Tract Infections and Therapy in Mice

“…Microscopically, both pathogens were seen to grow as a biofilm on the inside and the outside of the catheter, and it is likely that this mode of growth in some way impeded the effectiveness of the drug, although the exact mechanism behind this impedance was not identified. The therapeutic efficacy of ciprofloxacin against UTI including foreign body-associated UTI caused by several uropathogens has been shown previously (13,39,46). Our results are consistent with previous observations.…”

“…Our results are consistent with previous observations. However, the relapse of infection in catheterized mice following cessation of treatment shown in the present study has not been reported in studies conducted with conventional ex vivo methods (39). These methods require the sacrificing of animals for sampling and therefore will not permit longitudinal monitoring of infection in the same animal.…”

“…A number of these studies were conducted to investigate the pathogenesis of various uropathogens and for the evaluation of different antibiotics for UTIs in laboratory animals (2,8,11,12,17,23,33,39,40,43,46). However, monitoring the infections in these animal models using conventional methods is cumbersome, laborious, and time consuming.…”

“…Treatment of animals with catheter-associated infection commenced 2 days after bacterial challenge with a dose of 30 mg/kg of body weight ciprofloxacin given orally in 0.2 ml of water twice daily for four consecutive days. This dose of ciprofloxacin was previously shown to have bactericidal effect against several uropathogens in mouse models of experimental UTI (13,39,46). A second group of animals served as an untreated infection control group by being implanted with infected catheters and treated with saline.…”

Treatment prospects of Helicobacter pylori infection

“…Skuteczność takiego schematu eradykacyjnego oceniano odpowiednio na 100% i 91,6%. Badania in vitro pokazują, że najnowsze fluorochinolony (sitafloksacyna i garenoksacyna) charakteryzują się wyższą aktywnością przeciwbakteryjną ocenianą na podstawie wartości minimalnego stężenia hamującego (minimal inhibitory concentration -MIC) w porównaniu z gatifloksacyną i LEV [19].…”