Study On The Effect Of Nemofloxacin On The Anti-MRSA Activity And Anti-bacterial Resistance Mutation Ability Of Vancomycin Based On PK/P

Objective Vancomycin is the first-line drug for methicillin resistance staphylococcus aureus(MRSA)infection.When the minimum inhibitory concentration(MIC)of vancomycin>1 μg/mL,it is difficult to achieve the ideal pharmacokinetic/pharmacodynamics(PK/PD)target value under the conventional administration(1g q12h IVGTT),which increases the risk of treatment failure.At the same time,the MIC value of vancomycin has drifted to a certain extent.Vancomycin intermediate staphylococcus aureus(VISA)and vancomycin resistance staphylococcus aureus(VRSA)have been reported.Based on this,55 strains of vancomycin MIC>1 μg/mL identified by VITEK 2 compact and selected in this study.Objective to study of the nemonoxacin on vancomycin’s antibacterial activity and anti-resistant mutation ability in vitro,the expression of resistance gene locus of nemonoxacin,and nemonoxacin on vancomycin’s antibacterial activity and anti-resistant mutation ability in dynamic PK/PD model vitro.So as to provide the basis for the rational application of vancomycin.Methods 1.The clinical MRSA strains with MIC>1 μg/mL of vancomycin identified by VITEK 2 compact were collected.The MIC and mutant prevention concentration(MPC)of vancomycin,nemonoxacin and vancomycin combined with nemonoxacin were determined by agar dilution method,were used to evaluate the antibacterial activity and anti-mutation ability of the two drugs in vitro.2.The expression of parC,parE,gyrA,gyrB,NorA,NorB and NorC were detected by qPCR,and the correlation between the expression of drug-resistant genes and the results of nemonoxacin drug sensitivity was analyzed.3.2D-LC and HPLC methods were established to determine the concentrations of vancomycin and nemonoxacin in broth,and established vancomycin single drug,nemonoxacin single drug and vancomycin combined with nemonoxacin in vitro dynamic PK/PD model.The bactericidal effects of MRSA04,MRSA23 and MRSA25 were studied,and the antimutagenic effects of MRSA04,MRSA23 and MRSA24 were studied.Objective to study of the nemonoxacin on vancomycin’s antibacterial activity and anti-resistant mutation ability.Result 1.In vitro static drug sensitivity study showed that the combined effect of vancomycin and nemonoxacin was partially synergistic(50.91%),additive(14.55%)or irrelevant(34.54%),and the MIC and MPC of vancomycin were significantly decreased after combination(P<0.0001,P<0.0001).2.qPCR analysis of drug resistance genes showed that over expression of DNA gyrase,topoisomerase Ⅳ and efflux pump genes in fluoroquinolones resistant mutant sites reduced the sensitivity of MRSA to nemonoxacin,and the combination of overexpression would lead to higher drug resistance.3.While the combination of vancomycin and nemonoxacin showed partial synergistic and additive effects in vitro static experiments,the combination of vancomycinl gq12h and nemonoxacin0.5gqd showed synergistic bactericidal effect in the bactericidal PK/PD model.And it’s still had additive bactericidal effect after vancomycin half dose.5.The strain of which the MPC value of vancomycin was reduced by 2～8 times in the static test,can improve the inhibition and killing ability of vancomycin to spontaneous mutants.Conclusion nemonoxacin can improve vancomycin of bactericidal effect and the ability to prevent drug-resistant mutation...