Evaluation Of PK/PD Of Levofloxacin And Ceftazidime In The Treatment Of Pseudomonas Aeruginosa In The Hollow-fiber Infection Model Simulating Abnormal Renal Function In Critically Ill Patients

Objective:To evaluate the efficacy of bacterial kill of levofloxacin(LVF)and ceftazidime(CAZ)in the treatment of Pseudomonas aeruginosa(PA)infection in patients with severe abnormal renal function by using the hollow fiber infection model(HFIM)to simulate the PK/PD process.The effect of inhibiting the amplification of drug-resistant bacteria can provide reference for clinical rational drug use.Methods:The minimum inhibitory concentration(MIC)and mutation preventive concentration(MPC)of PA standard strain(ATCC27853)were measured,and the fractional inhibitory concentration(FIC)was calculated.The standard strain was cultured overnight and diluted to 1-2×10~7cfu/mL,and then inoculated into HFIM,simulating the commonly used clinical drug administration,i.e.LVF500 mgqd,LVF750 mgqd,CAZ1 gq8 h,LVF500 mgqd combined with CAZ1 gq8h and LVF750 mgqd combined with CAZ1 gq8 h.In addition,according to the drug instruction and the National guidelines for antimicrobial therapy(2nd Edition),the drug delivery scheme for patients with severe abnormal renal function(CCR of16-20 mL/min)was simulated,namely LVF125 mgqd,LVF187.5 mgqd,CAZ1 gqd,LVF125mgqd combined with CAZ1 gqd and LVF187.5 mgqd combined with CAZ1 gqd.The drug concentration was determined by HPLC and the drug time curve was drawn.Take the bacterial solution at different time points,count and culture on plates,and draw the time sterilization curve.According to the characteristics of PK/PD,the drug administration were evaluated.Results:In vitro static determination of pharmacodynamic parameters of PA,MIC to LVF=0.5?g/mL,MPC=5.1?g/m L,MIC to CAZ=1?g/m L,MPC=82?g/m L,FIC to LVF and CAZ=1,indicating that the two drugs are additive.HFIM was successfully constructed,which was proved to be similar to the known pharmacokinetic parameters.LVF500mg:AUC0-24h/MIC=136.91,Cmax/MIC=15.82;LVF750mg:AUC0-24h/MIC=252.1,Cmax/MIC=25.94;LVF125mg:AUC0-24h/MIC=71.66,Cmax/MIC=8.1;LVF187.5mg:AUC0-24h/MIC=111.85,Cmax/MIC=12.38;CAZ:%T>MIC=100%.Each experimental group had good bacterial kill efficacy,and the efficacy of the combination administration was better than that of single administration.In LVF administration in patients with normal renal function,drug-resistant bacteria increased after 6 h,and in combination administration,drug-resistant bacteria increased after 16 h.The amount of drug-resistant bacteria in CAZ administration in patients with normal renal function and each administration in patients with abnormal renal function increased at 0 h,but the drug-resistant bacteria in the combination administration in patients with abnormal renal function decreased at 8 h.In the resistant bacterial inhibition,combination administration showed better effect than single administration.Conclusion:Compared with the single administration,the combination administration had better bactericidal effect.The combination of LVF and CAZ can not only enhance the bactericidal activity of PA,but also delay the drug resistance and inhibit the proliferation of drug-resistant bacteria.The combination administration can be used for clinical reference and has certain significance for promoting rational use of drugs.