Antibacterial Pharmacodynamics Of A New Fluoroquinolone Chinfloxacin

Quinolone antibiotics are important kind of medicines dealing with clinical infectious diseases in China, which are broad-spectrum, highly potent and have good pharmacokinetics parameters, especially the fluoroquinolones which are more effective. Since the discovery of the quinolones, there are several scores of ones with new structure being used in clinical. Ciprofloxacin, ofloxacin, levofloxacin and moxifioxaxin are enssential in the treatment of infection. Chinfloxacin is a Class I new quinolone drug developed by our country, which is the difluoride substitution of moxifloxacin in the 8-methoxy group, and it shows broad-spectrum activities against bacteria in vitro and in vivo.In the first part of this work, the in vitro pharmacodynamics characteristics of Chinfloxacin were studied to 1756 clinical isolates and standard isolates, including the MICs, MBC, KCs, incubation conditions'effects, cytotoxic and inhibition test against DNA gyrase and topoisomerase IV. The result demonstrated that Chinfloxacin had good antibacterial activity against both Gram-positive and Gram-negative organisms, notablely the antibacterial activity against S. pneumoniae, H. influenzae were extremely good, MIC90S were 0.25μg/mL,0.03μg/mL, which were equal to or better than moxifloxacin. Besides, the MIC50S of Chinfloxacin against the other frequent clinical isolates such as S. aureus, S. epidermidis, S. pyogenes, E. faecalis and K. pneumoniae were between 0.06μg/mL to 0.5μg/mL, showed good activities too. Chinfloxacin had relatively good antibacterial activity to clinical drug-resistant isolates. The MIC50S against MRSA, CR-MRSA, MRSE, CR-MRSE, PISP and PRSP were from 0.125μg/mL to 4μg/mL. The activities of Chinfloxacin against ESBL- E. coli and ESBL-K. pneumonia were slightly week, but still equal to that of moxifloxacin. The susceptible rates of Chinfloxacin to S. aureus, S. pneumoniae, H. influenzae and H. parainfluenzae were quite high, which were 52.3%,97.8%,100% and 86.5%, showed good potential. MBC experiment and KCs experiment revealed that Chinfloxacin was an effective bactericidal agent against S. aureus, S. pyogenes, S. pneumoniae, E. coli and K. pneumoniae. The activities of Chinfloxacin against S. aureus, S. pneumoniae, E. coli and K. pneumoniae were concentration dependent, but were time dependent against S. pyogenes, which should be studied later. The pH, inoculum size and serum concentration had no apparent effects on the activity of Chinfloxacin.The cytotoxicity experiment showed that Chinfloxacin was safe to human adenocarcinoma lung cell A549, with IC50 551.04μg/mL (more than 1000μM), which was similar to the other quinolones usually used in clinical.The inhibition test of Chinfloxacin against DNA gyrase and topoisomerase IV, the target of the quinolone, revealed that the IC50 of Chinfloxacin in the supercoling inhibition test is 1.05μM, a little weak than moxifloxacin, but equal to ciprofloxacin. The IC50 of Chinfloxacin in the decatenation inhibition test is 2.25μM, which is inferior than moxifloxacin and ciprofloxacin. Then the IC50 of Chinfloxacin in the relaxation inhibition test is 0.79μM, which is superior than moxifloxacin and ciprofloxacin.Besides, to do some further research, we express the topoisomeraseⅣof S. aureus, one of the target of quinolones. We purified the two submits of the enzyme, quantitate the concentration and then determined the activity of the enzyme, to do the groundwork for the further research of the mechanism of action.In the second part of this work, the in vivo pharmacodynamics of Chinfloxacin was studied. In the mouse systemic infection model, Chinfloxacin showed the same therapeutic efficacy with moxifloxacin by oral administration, which is better than levofloxacin against Gram-positive bacteria, and is inferior than levofloxacin against Gram-negative bacteria. Chinfloxacin showed good efficacy against S. aureus, S. pneumoniae, E. coli and K. pneumoniae, with ED50s 1.25 mg/kg to 8.28 mg/kg, and showed weaker efficacy against E. faecalis in vivo, with ED50 25.02 mg/kg.Meanwhile the pharmacokinetics of Chinfloxacin in mouse was studied. The Cmax, T1/2, AUC0-24h were 1085ng/mL,1.425h,1101.31h*ng/mL respectively calculated by the pharmacokinetics parameters of mouse after oral administration of Chinfloxacin. On the basis of the MIC in vitro, we obtained the Cmax/MIC50 of S. aureus, S. pneumoniae, K. pneumoniae, H. influenzae and H. parainfluenzae which were 18.08,8.68,4.3,135.625,31.17 respectively, and the T>MIC50 of S. pyogenes was 2.03h. The results demonstrate that Chinfloxacin had good pharmacokinetics performance, and revealed the good antibacterial potential in vivo.