| Objective:We use the Monte Carlo pharmacokinetic pharmacodynamic(PK/PD) model in this subject to simulate and compare the probability of target attainment(PTA) achieved by effective treatment of critical patients using different Biapenem dosage regimens in anti-infection treatment. The subject offers help to clinic for the development of rational dosage regimens.Methods:1.The HPLC methodology of detecting the concentration of Biapenem in human plasma is established. The method will be applied to the analysis of Biapenem plasma concentration of the 36 cases healthy volunteers and 30 cases critical patients. The pharmacokinetic parameters of critically ill patients are calculated using the population pharmacokinetic model established by NONMEM software. The results are analyzed and compared with healthy volunteers.2.The MIC of 8 kinds of common pathogenic bacteria strains obtained from two medical institutions is determined by agar dilution method. The in vitro antibacterial activity of Biapenem to the 8 strains is compared and analyzed.3.Monte Carlo model is applied to simulate the PTA and CFA of MIC50 and MIC90 by the antibacterial effect of different Biapenem dosage regimens used for resisting 8 kinds of common bacteria. Moreover, we will evaluate the effectiveness of the different Biapenem dosage regimen used in anti-infection treatment for critical patients.Results:1.The HPLC method established for detecting Biapenem concentration in human plasma can be used for sample analysis with high sensitivity and accuracy. Standard curve linear range of 0.1-50μg?m L-1, Minimum quantitative lower concentration of 0.1μg?m L-1, Between batch and batch variation are less than 11%, Average extraction recovery rate is 102.35%, 97.94% and 94.64% respectively, Stability test results showed that sample stability after treatment by the regulation.2.The Biapenem pharmacokinetic parameters of healthy volunteers are T1/2=1.11±0.08(h) 、 Cl=12.43±1.31(L/h) 、 Vd=19.45±2.45(L) 、 Tmax=0.51±0.06(h) 、Cmax=18.31±1.91( mg/L) 、 AUC0-t =22.57±1.91(mg·h/L); The pharmacokinetics parameters show great difference between critical patients and healthy volunteers. Tmax is consistent(( P > 0.05);Cmax=6.66±2.93( mg/L) 、 AUC0-8=13.14±9.92(mg·h/L),Cmax and AUC0-8 of critical patients are lower than healthy people, and T1/2=2.06±1.93、Cl=20.9±17.4(L/h)、Vd=46.43±3.5(L),T1/2, Cl, Vd are higher than healthy people.3. Biapenem has different sensitive rate in vitro antimicrobial activity from the two hospitals, for non-enzyme producing Enterobacteriaceae and sensitive S. aureus, MIC90 range in tertiary hospital a is 0.064-0.5 mg/L,MIC90 range in tertiary hospital b is 0.25-0.5 mg/L,but they have an over 90% sensitive rate.Besides, for multiple drug resistance of acinetobacter baumannii and pseudomonas aeruginosa, MIC90 range in tertiary hospital a and tertiary hospital b are 32-64 mg/L、16-64 mg/L,Biapenem has lower than 30% sensitive rate towards. And at the same rate of medical institutions in different clinical departments of sensitive data also have differences.4. PTA and cumulative fraction of response(CFR) of different dosage regimens applied to critical patients are simulated and compared by Monte Carlo models. Under four different dosage regimen of critically ill patients and healthy volunteers CFR significant differences(P < 0.01); Four kinds of dosage regimen in healthy crowd CFR difference is not big, But in critical patients difference is obvious(P < 0.01), 300 mg dose group with dosing frequency q6 h, q8 h, q12 h gradually reduce, PTA, CFR result is a downward trend.In 300 and 600 mg q12 h group is no obvious difference. As a result, we find that 300 mg q8 h and 300 mg q6 h Biapenem treatment for effective antiinfection are better than 300 q12 h mg and 600 mg q12 h dosage regimens.Conclusion:1.The resistant rate of common bacteria of medical institutions, especially the proportion of extended-spectrum enzyme producing bacteria and multi-resistant bacteria is increasing year by year. Although carbapenem antibiotics such as Biapenem are highly sensitive to Enterobacteriaceae and sensitive S. aureus, the antibacterial effect of them to multiple drug resistance bacteria such as acinetobacter baumannii and pseudomonas aeruginosa is very limited.2.Due to the special pathophysiological changes of severe patients, the in vivo pharmacokinetic parameters of them are very different from healthy people. When making their anti-infection dosage regimens, we should combine the patient’s own special cases with economic capacity and the result of drug sensitivity test to formulate reasonable solutions to fight infection.3.Application of Monte Carlo simulation(MCS) the pharmacokinetic/pharmacodynamic(PK/PD) models, analysis and evaluation of antimicrobial agents pharmacodynamics index of different dosage regimen for drug pharmacokinetic and pharmacodynamic research provides a new method, for antimicrobial treatment and individualized treatment of experience to provide rational dosage regimen. |
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