Therapeutic Drug Monitoring And Meta-analysis Of Tigecycline In The Treatment Of Multi-drug Resistance Bacteria Pneumonia

OBJECTIVE: Tigecycline(TGC)is an important antibacterial agent for the treatment of multi-drug resistance(MDR)infection,but its efficacy and safety in the treatment of pneumonia are still controversial.This paper will study from two aspects: on the one hand,this paper will establish a TGC therapeutic concentration monitoring method to meet the needs of clinical individualized medication;on the other hand,this paper will conduct systematic evaluation and meta-analysis of the efficacy and safety of TGC treatment of MDR bacterial pneumonia,providing evidence for clinical treatment.METHODS: The concentration of TGC in human plasma was determined by high performance liquid chromatography tandem mass spectrometry.After plasma samples were treated with acetonitrile precipitation protein,ZORBAX SB-C8 column(2.1 mm × 50 mm,3.5 μm)was used combined with 2 mmol/L ammonium formate(Polycarboxylic acid adjusted pH=2)-Methanol was used as the mobile phase,to conduct gradient elution.Electrospray ionization source was used to detect TGC and internal standard compounds under multi-reaction monitoring mode with negative ion scanning,and guided by in vivo drug quantitative analysis method.Methodological confirmation was carried out according to the guiding principle of quantitative drug analysis methods in vivo.Then,plasma samples from patients with MDR bacteria pneumonia who had used TGC were collected,and the steady-state plasma concentration of TGC was measured.The literature that have been published in these Chinese or English databases including PuMed,EMbase,The Cochrane Library,CNKI,Wanfang and Weipu as of December 2018 were searched.Quality evaluations of included randomized controlled trials were performed using the Cochrane bias risk assessment tool.TGC single-drug treatment or combined with other antibacterial drugs for the treatment of MDR pneumonia as the experimental group,other antibiotics(excluding TGC)monotherapy or combination therapy for MDR pneumonia as the control group,meta-analysis was used to evaluate the two groups’ clinical efficacy,microbiology efficacy,incidence of adverse drug reactions,death rate,and gap in clinical symptom improvement time.RESULTS: The TGC plasma standard curve was linear in the range of 25-1600 ng/ml;the intra-day accuracy was 90.63%~100.18%,inter-day accuracy was 89.94%~ 102.28%;intra-day precision was 5.20%~8.09%,and inter-day precision was 4.18%~9.03%;the absolute recovery rate,matrix effect and various stability tests of TGC and internal standard TGC-d9 met the requirements of analysis in vivo.The TGC plasma concentration was 5620 ng/ml in one patient who received conventional dose of TGC(first dose 200 mg,maintenance doses 100 mg,q12 h,ivgtt),and 16100 ng/ml in the other patient who received large doses of TGC(first dose 200 mg,maintenance doses 100 mg,q12 h,ivgtt).A total of 986 related articles were collected,and 18 articles were finally included,with a total of 1347 patients(675 patients in the experimental group,and 672 patients in the control group).The study showed that the clinical effective rate of the experimental group was higher than that of the control group(P<0.05);the bacterial clearance rate of the experimental group was higher than that of the control group(P<0.05);the gap in incidence of adverse drug reactions between the two groups has no statistical significance(P>0.05);the death rate of the experimental group was lower than that of the control group(P<0.05).In term of clinical symptoms and signs improvement,the time for recovery to normal temperature,for disappearance of lung voice,recovery of white blood cell and Creactive protein of the experiment group were shorter than those of the control group(P<0.05).The time of disappearance of chest radiograph was not statistically significant compared with the control group(P>0.05).CONCLUSION: In the aspect of therapeutic concentration monitoring,the high performance liquid chromatography tandem mass spectrometry method established in this study is featured by short analysis time,high accuracy,high sensitivity,strong specificity,good stability,and small matrix effect.It can be used in clinical TGC therapeutic drug monitoring to meet the needs of clinical individualized medication.In terms of evidence-based medicine,compared with other antibacterial drugs,TGC is more effective in treating MDR bacteria pneumonia while the safety risk has not increased.