| Infectious diseases seriously threaten human health and social stability. Infections indu ced by resistant bacteria is an urgent problem for clinical antimicrobial therapy. The alarming increase of resistance mainly caused by misuse and abuse of antibiotics. The typical clinical resistant bacteria include Methicillin-resistant Staphylococcus aureus (MRSA), Methicillin-resistant Staphylococcus epidermidis (MRSE), Penicillin-resistant Streptococcus pneumoniae (PRSP), Vancomycin-resistant Enterococci (VRE), Multi-drug resistant Pseudomonas aeruginosa (MDR-PA) and Pan-resistant Acinetobacter baumannii (PDR-AB). MRSA is associated with high morbidity and mortality rates, and is one of the mose important pathogens in hospital-acquired infection. MRSA, togethor with Hepatitis B and AIDS are the three most difficult infections to treat worldwide.Drug-resistance is a big challenge to the development of antimicrobial drugs.The targets of antibiotics are exogenous pathogens rather than the host. Pharmacodynamics reflects the effect of inhibiton or elimination of pathogens, the outcome is the results of complex interactions between the three elements:the host, the microorganism, and the antibiotics. The PK/PD analysis of antibiotics reveals the dynamic process of elimination of pathogens at the target site, clarifies the pattern of antimicrobial activity, determines the PK/PD parameters which can best describe the antibiotic efficacy and the corresponding PK/PD target values to aquire clinical outcomes, PK/PD analysis integrates all this information, and contributes to determination of the optimal antibiotic and dosing regimen for clinical research. U.S. FDA and China CFDA advocated that the concentration of antibiotics at the target site and the PK/PD properties need to be determined before the approval of drugs to new indications.Gemifloxacin, a new-generation quinolone, exerts a strong antibacterial activity against a broad spectrum of pathogens, and the antimicrobial activity against Gram-positive bacteria is higher than other quinolones. The objective of this research is to clarify the in vivo and in vitro antimicrobial activity of gemifloxacin mesylate injection, determine the plasma and thigh concentrations based on MD-LC-MS/MS, clarify PK parameters, and analyze PK/PD properties of gemifloxacin.The pharmacodynamic results demostrated that gemifloxacin exerted a strong antibacterial activity against a broad spectrum of pathogens. Gemifloxacin showed high antimicrobial activity against Gram-positive isolates than Moxifloxacin, ciprofloxacin, levofloxacin, clarithromycin, cefuroxime, ampicillin and meropenem. The in vitro activity of gemifloxacin against Gram-negtive bacteria was similar to moxifoxacin and lecofoxacin, lower than ciprofloxacin and meropenem, significantly better than clarithromycin, cefuroxime and ampicillin. Gemifloxacin showed strong in vivo activity in mouse systemic infection model caused by Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, Escherichia coli, Klebsiella pneumoniae. The in vivo activity of gemifloxacin against Gram-positive bacteria (Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes) was significantly higher than moxifloxacin, levofloxacin, ciprofloxacin. While the in vivo activity against Gram-negative bacteria (Escherichia coli and Klebsiella pneumoniae) was higher than moxifloxacin and similar to levofloxacin and ciprofloxacin.The rat PK results demonstrated that the MD sampling and LC-MS/MS analysis methods were founded and can be used for the following research. The gemifloxacin concentrations in rat plasma and thigh after i.v. administration (9mg/kg,18mg/kg and 72mg/kg) were determined, and the pharmacikinetic parameters were characterized by noncompartment model. The pharmacokinetic parameters for doses 9mg/kg,18mg/kg and 72mg/kg were as follows:the values of plasma AUCo-24hwere 3090.96±979.81,7939.30± 2157.81 and 32930±12880.48 h*ng/mL, plasma Cmax were 1583.37±573.78,4866.83± 738.09 and 13966.68±3883.80 ng/mL, T1/2 were 2.15±0.74,2.40±0.41 and 2.61±0.95h; the values of thigh AUC0-24hwere 1402.82±877.71,5005.21±3115.87 and 27588.99± 12750.61 h*ng/mL, Cmax were 462.77±353.47,1905.66±978.54 and 6046.72±2635.94 ng/mL, T1/2 were 2.25±0.67,2.79±0.47 and 3.78±1.80h, respetively.The PK/PD results in rat thigh infection model demestrated, that the MRSA-induced rat thigh infection model was successfully established, After i.v. single administration of gemifloxacin at different dose levels of 9mg/kg,18mg/kg and 72mg/kg, the plasma f AUC0-24/ MIC were 98.91,254.06 and 1053.76,f Cmax/MIC were 50.67,155.74 and 446.93,f%T>MIC were 0.44,0.50 and 1; the thigh f AUC0-24h/MIC were 44.89,160.17 and 882.85,f Cmax/MIC were 14.80,60.98 and 193.50,f %T>Mic were 0.36,0.58 and 0.77, respectively. The plasma f AUC0-24MIC and thigh fAUC0-24h/MIC correlated best with change in Log CFU/thigh (r2= 0.9939), suggesting concentration-dependent killing. The target PK/PD values for a 3 Log unit reduction of the bacterial burdern 24 ours after administration were 215.83 and 130.55 plasma f AUC0-24h/MIC and/Cmax/MIC,128.44 for thigh f AUC0-24h/MIC, respectively.In summary, gemifloxacin exerted a strong antibacterial activity against a broad spectrum of pathogens, the activity against Gram-positive bacteria was higher than the control agents. Plasma and thigh concentrations of gemifloxacin were determined simultaneously based on MD and LC-MS/MS method, hence the informations of dynamic plasma and thigh concentrations of the same rat can be aquired. The PK characteristics of gemifloxacin were evaluated. The PK/PD results in thigh infection rat model suggested concentration-dependent killing of gemifloxacin. The target PK/PD values for a 3 Log reduction of the bacerial burdern 24 hours after administration were 215.83 and 130.55 plasma f AUC0-24h/MIC and f Cmax/MIC,128.44 for thigh f AUC0-24h/MIC, respectively.Tuberculosis (TB) is a serious respiratory disease endangering health. It is included in the statutory major infectious disease in China. The World Health Organization estimated that the number of annual incidence of TB in China was second largest in the world. Since the 1980s, with the increasing incidence of drug-resistant TB, TB has become a major global public health and social problems. However, in the past 40 years, almost no novel anti-TB drug was approved for marketing.A2 and A6 are novel anti-TB compounds which are developed by our institute, and has prospects for research and development. The purpose of this research was to study the PK profile of A2 and A6 in rats, and the evaluation of toxicity.First, we established LC-MS/MS analysis method of A2 and A6 in plasma, and the methodology was validated to lay the foundation for the following research.Next, we studied the plasma pharmacokinetic after 25mg/kg oral dose A2 or A6. The pharmacokinetic properties of A2 and A6 were characterized by noncompartment model, and T1/2 values were 0.43±0.09 h and 1.120±0.38 h, AUC0-24values were 452.65±254.34 and 214.46±89.20, respetively. The plasma concentration 6 h follow oral dose A2 or A6 were below LLOQ.The research on toxicity of A2 and A6 has not showed significant toxic. Death were observed in all groups following oral dose 2000mg/kg A2 or A6. Compare the number of deaths from animals,we included that toxicity was A2> A6, more informations are needed for further study.In summary, we studied pharmacokinetic parameters and toxicity of A2 and A6, the results show that A2 and A6 have short half-life, which indicted poor drugability, further structural optimization may be needed. |
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