Pharmacokinetic/Pharmacodynamic Analysis Of High-dose Tigecycline In Plasma And Sputum Of Patients With Hospital-acquired Pneumonia

Objective:The study of the pharmacokinetic/pharmacodynamic（PK/PD）of high-dose tigecycline in plasma and sputum of patients with hospital-acquired pneumonia（HAP）,and the clinical efficacy of tigecycline,provides a basis for clinical treatment of multidrug-resistant bacteria（MDRB）infection with HAP and optimises individualized treatment regimens.Methods:Twelve HAP patients with MDRB infection requiring tigecycline treatment were given a high-dose of tigecycline 200 mg as the first dose and 100 mg as the maintenance dose for q12 h.Plasma and sputum specimens were drawn at the start of the seventh dose of the drug at steady state at the time points 0,0.25,0.5,1,2,4,6,8 and 12 h after the start of the infusion.The time points for blood specimens were 0,0.25,0.5,1,2,4,6,8,12 h and for sputum specimens were 0,1,2,4,6,12 h.After centrifugation of all specimens,the concentration of tigecycline was determined by High-performance liquid chromatography（HLPC）and the concentration-time curve was plotted.PK parameters were estimated using a non-atrial model using Win Nonlin 6.2 software.According to two reference standards(AUC_0-12h/MIC≥4.5,AUC_0-12h×V/MIC≥100),Monte Carlo Simulation（MCS）was carried out using Crystal Ball software to calculate the probability of target attainments（PTAs）at different minimum inhibitory concentrations（MICs）（0.25-16μg/m L）.At the same time,the patients’clinical indicators（Temperature,White blood cells,Neutrophil ratio,C-reactive protein）before and after treatment with high-dose tigecycline were statistically analyzed by normality test,one-factor ANOVA and Wilcoxon signed-rank test.Results:Based on the assay results,in plasma,the maximum concentration(C_max)and area under the concentration-time curve(AUC_0-12h)of tigecycline in plasma were 2.21±0.17μg/m L and 15.29±1.13 h·μg/m L,respectively.In sputum,the C_max was 2.48±0.21μg/m L and the AUC_0-12h was 19.46±1.82 h·μg/m L.The AUC0-12h was 19.46±1.82 h·μg/m L.The mean lung permeability was calculated from the AUC_0-12h ratio in lung to plasma and was 127.27%.At the MIC≤4μg/m L,PTAs in both plasma and sputum was 100.00%.When MIC increased to 8μg/m L,using AUC_0-12h/MIC≥4.5 as the reference standard,PTAs in both plasma and sputum was<90.00%,1.10%and 77.70%,respectively,and when AUC_0-12h×V/MIC≥100 was used as the reference standard,the plasma PTAs was 94.61%,while the PTAs of sputum was 84.19%.Meanwhile,Wilcoxon signed-rank test using Spss.26 showed that all inflammatory factors（Temperature,White Blood Cell,Neutrophil ratio,C-reactive protein）decreased significantly after treatment and all P values were<0.05,indicating that the changes in each of these indicators were statistically significant.Conclusion:In the study,high-dose tigecycline was found to be effective in anti-infective treatment of patients with MDRB-induced HAP with the MIC≤4μg/m L from a PK/PD perspective,while the MIC of≥8μg/m L,antimicrobial agents may need to be adjusted to achieve better clinical outcomes.The sputum was found to be similar to alveolar epithelial lining fluid（AELF）,which is a good indicator of PK/PD in the lungs,and clinical inflammatory factors were significantly improved with high-dose tigecycline treatment.At the same time,monitoring the concentration of antibacterial drugs when they are used in clinical treatment can help to understand the efficacy of anti-infective drugs and to adjust the type or concentration of antibacterial drugs in time to achieve individualized treatment.