A Preliminary Pharmacokinetic/Pharmacodyna-Mic Study Of Meropenem In Elderly Patients With Severe Community-Acquired Pneumonia

Objective:Severe community-acquired pneumonia（s CAP）is one of the most life-threatening diseases in the elderly,and meropenem is widely used in s CAP.In this study,the pharmacokinetic（PK）parameters of meropenem in plasma and sputum under the dosing regimen of 1g q8h with a 2-h infusion was explored,then the Monte Carlo simulation combined with pharmacodynamic（PD）parameters was performed to investigate the probability of target attainments（PTAs）for this dosing regimen in elderly s CAP.Methods:Elderly patients（age≥65 years）admitted to the emergency intensive care unit（EICU）and diagnosed with s CAP were enrolled.Meropenem（2-h infusion of 1g every 8 h）was injected by using an infusion pump.Blood and sputum samples were collected at 0.0,0.5,1.0,2.0,3.0,4.0,6.0,and 8.0 h after the first administration,respectively.After protein removal,the concentrations of meropenem in plasma and sputum at different time points were determined by high performance liquid chromatography（HPLC）.Then Win Nonlin software was used to calculate the PK parameters.The Monte Carlo simulation was performed to calculate the PTAs when drug concentrations above the minimum inhibitory concentration（%T>MIC）at different minimum inhibitory concentrations（MICs）.At the same time,the patients’clinical indicators（Temperature,White Blood Cell Count,Neutrophil ratio,C-reactive protein）before and after the treatment were statistically analyzed by normality test,one-factor ANOVA and Wilcoxon signed-rank test.Results:A total of 11 patients were included in this study.1.PK/PD parameters:（1）In plasma,the time maximum concentration(T_max),elimination half-time(t_1/2),peak concentration(C_max),the mean area under the curve from0 to 8 h(AUC₀–_8h),the total body clearance（CL）,and volume of distribution（Vd）were2.00±0.00 h,2.98±1.14 h,12.71±2.15μg/m L,49.11±9.65 h·μg/m L,18.37±5.41 L/h,81.12±20.74 L,respectively.（2）In sputum,T_max,t_1/2,C_max,AUC₀–_{8 h} were 2.5±0.93 h,3.1±0.92 h,6.42±1.36μg/m L,31.99±5.87 h·μg/m L,respectively.The mean percent lung penetration was 50.51%and 65.14%in terms of C_max and AUC₀–_{8 h}.2.Monte Carlo simulation:（1）In plasma,when MIC≤1μg/m L,the PTA of 40%T>MIC,60%T>MIC,80%T>MIC,and 100%T>MIC were all above 90%;when MIC increased to 2μg/m L,the PTA of 40%T>MIC,60%T>MIC,and 80%T>MIC in plasma were above 90%,while the PTA of 100%T>MIC was 85.34%;at the MIC of 4μg/m L,only 40%T>MIC obtained PTA>90%;when MIC≥8μg/m L,all%T>MIC failed to meet the standard of PTA>90%.（2）In sputum,when MIC≤1μg/m L,the PTA of 40%T>MIC,60%T>MIC,80%T>MIC,and 100%T>MIC were above 90%;at the MIC of2μg/m L,only 40%T>MIC and 60%T>MIC observed PTA>90%;at MIC≥4μg/m L,all%T>MIC observed PTA<90%,indicating that it was difficult to achieve better antibacterial effect for s CAP.3.Wilcoxon signed-rank test using Spss.26 showed that all inflammatory factors（Temperature,White Blood Cell Count,Neutrophil ratio,C-reactive protein）decreased significantly after treatment,P values were<0.05 except for White Blood Cell Count,indicating that the changes in each of these indicators were statistically significant.Conclusions:In this study,the PK/PD parameters of meropenem in elderly patients with s CAP were studied,and the following conclusions were drawn:（1）Two ways were adopted to calculate the mean percent lung penetration:C_max（50.51%）and AUC₀–_8h（65.14%）,suggesting that the distribution of meropenem in the lungs is less than that in the blood;（2）When MIC≤2.0μg/m L,the current dosing regimen is expected to achieve a good therapeutic effect.For pathogens with higher MICs,it may be necessary to increase the single dosage,increase the infusion frequency or extend the infusion time to improve the therapeutic effect.