| OBJECTIVE: To study the pharmacokinetics and pharmacodynamics of gatifloxacin and investigate the mechanism of postantibiotic effect on E. coli. We also assessed the potential drug interactions between gatifloxacin and other drugs by studying the effects of gatifloxacin on mice hepatic microsomal enzymes(CYP450). These will offer theorial data for dosage regimen. METHODS: Minimal Inhibitory Concentrations (MIC) were determined by agar dilution method. The combination of flow cytomtry and fluorescent probes method allows several physiological parameters such as sizes, nucleic acid contents, membrane patency and membrane potential of Escherichia coli ATCC25922 following gatifloxacin exposure to be measured. The effects of gatifloxacin on mice hepatic microsomal enzymes(CYP450) were study by spectrophotometer. The pharmacokinetics of gatifloxacin was examined in healthy male volunteers after the administration of a single dose of 100, 200, 400mg and multiple doses of 400mg once daily for 14 days. In 8 volunteers who received a single intravenous 400mg dose of gatifloxacin serum bactericidal activity were tested. RESULTS: Gatifloxain shows high antibacterial activity against common clinical isolates such as Staphylococcus aureus, Strepetococcus pneumoniae, Hamophilas influenzae, M.Catarrhalis and Klebsiella pneumoniae(with 70.8%~100% susceptible rate) except Escherichia coli. The killing curves of gatifloxacin are characterized by concentration-dependent killing over a range of concentrations. At 1 MIC, 2 MIC, 4xMIC, gatifloxacin showed postantibiotic effects 1.12, 1.69, 2.37h against Escherichia coli ATCC25922. The PAE phase characterized by filament formation after exposure to gatifloxacin as seen through fluorescence microscopy and atomic force microscope. The flow cytometry showed similar results: a profound increase on Escherichia coli ATCC25922 size and nucleic acid after exposure to gatifloxacin , this morphological alteration was characterized by an apparently dose-dependent manner and did not appear until after drug removal for 6h, yet smaller changes were observed inmembrane potential and membrane potency. The FCM also showed that chloramphenicol and rifampicin significantly inhibited changes in size and nucleic acid.Gatifloxacin did not inhibit activity of a number of hepatic enzymes (cytochrome b5, NADPH-cytochrome C reductase, aminopyrine-N-demethylase, erytheomycin-N-demethylase, Coumarin 7-hydroxylation), which suggests a low potential for interaction with agents that are biotransformed by these enzymes.Throughout the whole pharmacokinetics study , gatifloxacin was well tolerated in every subject. In the single-dose study, the concentration in serum reached a peak between 0.5 and 2h(Tmax), and the Qvalues were 1.09^ 2.1?.329, 3.14?.473 mg-U1, the elimination half-life was 7.4~8.5h, independently of the doses. The unchanged drug was excreted mainly in the urine, with 43 .08% to 5 1 .33% of the dose appearing for 48h. In the multiple-doses study, gatifloxacin was tolerated well by heathy subjects.The percentage of Cmax-SBT with gatifloxacin against Staphylococcus aureus, Staphylococcus epidermidic, K.pneumoniae, E.faecalis was >1:8, The percentage of Cmin- SET with gatifloxacin against Staphylococcus aureus, Staphylococcus epidermidic, K.pneumoniae, E.coli was >1:2 except E.faecalis, Pseudomonas aeruginosa.CONCLUSION: Gatifloxacin has an extended spectrum of antibacterial activity compared with earlier fluoroquinolones. The killing curves and postantibiotic effect of gatifloxacin are characterized by concentration-dependent killing. Gatifloxacin exposure leads to induction of the SOS response(the process requires RNA and protein systhesis), resulted in the increasing of size and nucleic acid,but the membrance potential and menbrance patency did not change.Gatifloxacin was well tolerated, the elimination half-life was 7.4-8. 5h, independently of the doses and the unchanged drug was excreted mainly in urine. The serum bactericidal activity of gatifloxacin showed 400mg... |
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