应用Monte Carlo模拟优化抗菌药物莫西沙星的临床给药方案

发布时间：2018-03-28 12:54

本文选题：莫西沙星　切入点：药物不良反应　出处：《郑州大学》2017年硕士论文

【摘要】：目的:结合莫西沙星药物不良反应,应用Monte Carlo模拟优化抗菌药物莫西沙星的临床给药方案。方法:1.收集2000-2017年国内公开发表的有关莫西沙星药物不良反应的中文期刊、会议报道,运用计算机辅助工具,对检索资料逐篇进行筛选、分析,提出临床用药的合理建议;2.采用微量肉汤二倍稀释法测定莫西沙星对9种1011株临床主要分离菌株的体外MIC值,并同步建立粒细胞减少小鼠大腿感染模型评价其体内抗菌效果,为下一阶段研究奠定基础;3.基于PK/PD理论,使用Crystal ball软件进行Monte Carlo模拟,模拟10000次,计算莫西沙星临床常用给药方案(即400mg qd、800mg qd和1200mg qd)的累计反应分数CRF和达标概率PTA。以AUIC≥125作为需住院病人预期可获得满意临床疗效的靶值,以AUIC≥30作为门诊病人预期可获满意临床疗效的靶值,并将获得的CRF≥90%或能达到最高PTA作为抗菌药物经验治疗的合理选择,即最佳的临床治疗给药方案。结果:1.莫西沙星药物不良反应主要包括血液和淋巴系统反应、消化系统反应、神经系统反应、全身性损害、皮肤反应、呼吸系统反应及其他。在不良反应发生相关因素分析中,性别与不良反应发生无关。而在年龄方面,年龄≥50岁的患者共56例(72.72%),药物不良反应发生率明显高于其他年龄段。静脉给药所致不良反应发生率(50.65%)高于口服给药(35.06%),联合用药不良反应发生率(61.04%)高于单独用药(38.96%)。2.1011株临床主要分离菌株对莫西沙星具有较好的敏感性,敏感率为9.7%-100%。莫西沙星的主要药效学参数为:对MSSA,MIC50、MIC90和MICrange分别为0.12、1和≤0.03-2μg/ml;对MRSA,MIC50、MIC90和MICrange分别为2、2和0.06-4μg/ml;对PSSP,MIC50、MIC90和MICrange分别为0.06、0.25和≤0.03-4μg/ml;对PISP,MIC50、MIC90和MICrange分别为0.12、0.5和≤0.03-8μg/ml;对H.inf,MIC50、MIC90和MICrange分别为≤0.03、0.12和≤0.03-1μg/ml;对KPN,MIC50、MIC90和MICrange分别为0.5、2和≤0.03-8μg/ml;对M.cata,MIC50、MIC90和MICrange分别为≤0.03、0.12和≤0.03-0.12μg/ml;对E.coli,MIC50、MIC90和MICrange分别为0.12、0.5和≤0.03-8μg/ml;对ENT,MIC50、MIC90和MICrange分别为0.12、0.25和≤0.03-2μg/m。体内抗菌实验结果显示,莫西沙星治疗24h后,除甲氧西林耐药金黄色葡萄球菌和肺炎克雷伯菌未被显著清除外,大腿肌肉中的其他感染细菌几乎被完全清除,这与体外抗菌实验结果一致。3.对于AUIC≥125,400mg qd对H.inf和M.cata的CRF90%,对其他菌株的CRF均90%;800mg qd对H.inf、M.cata和ENT的CRF90%,对其他菌株的CRF均90%;1200mg qd对MSSA、MRSA和KPN的CRF90%,对其他菌株的CRF90%。PTA结果显示,当MIC≤0.125μg/mL,三种给药方案的PTA均大于90%及以上;对于AUIC≥30,400mg qd对MSSA、MRSA和KPN的CRF90%,对其他菌株的CRF90%;800mg qd除对MRSA的CRF90%外,对其他菌株的CRF90%;1200mg qd对所有菌株的CRF90%。当MIC≤0.5μg/mL,三种给药方案的PTA均大于90%及以上。结论:针对需住院治疗患者,为达到满意的临床疗效并降低细菌耐药性的产生,莫西沙星对流感嗜血杆菌和卡他莫拉菌感染,可采用400mg qd给药方案;肠球菌属感染,可采用800mg qd给药方案;青霉素敏感肺炎链球菌、青霉素中介肺炎链球菌和大肠埃希菌感染,可采用1200mg qd给药方案或联合用药;甲氧西林敏感金黄色葡萄球菌、甲氧西林耐药金黄色葡萄球菌和肺炎克雷伯菌需考虑联合用药。针对门诊患者,为达到满意的临床疗效并降低细菌耐药性的产生,莫西沙星对青霉素敏感肺炎链球菌、青霉素中介肺炎链球菌、流感嗜血杆菌、卡他莫拉菌、大肠埃希菌和肠球菌属感染,可采用400mg qd给药方案;甲氧西林敏感金黄色葡萄球菌和肺炎克雷伯菌,可采用800mg qd给药方案;甲氧西林耐药金黄色葡萄球菌可采用1200mg qd给药方案或联合用药。此外,在调整优化给药方案的同时,临床上应对莫西沙星的不良反应引起一定重视,规范合理用药。
[Abstract]:Objective: the adverse reactions of moxifloxacin, application of Monte Carlo simulation and optimization of clinical antibiotics moxifloxacin regimen. Methods: Chinese journal, 1. collection of moxifloxacin 2000-2017 adverse drug reactions published conference reports, using computer aided tools, analysis of information retrieval of articles for screening, clinical, and puts forward the reasonable suggestion medication; 2. by broth dilution method for determination of moxifloxacin on two 9 1011 strains of clinical isolates in vitro mainly MIC, and synchronize the establishment of neutropenic mouse thigh infection model to evaluate the in vivo antibacterial effect, lay the foundation for the next phase of the study; the 3. is based on the PK/PD theory, Monte Carlo simulation using Crystal ball 10000 times of simulation, calculation software, commonly used in clinical dosage regimen of moxifloxacin (400mg QD, 800mg QD and 1200mg QD) the total score of CRF and the reaction of The probability PTA. to AUIC over 125 as required patients can obtain satisfactory clinical curative effect of the expected target value, with AUIC = 30 as outpatients are expected to be satisfied with the clinical effect of the target value, and will get the CRF = 90% or PTA can reach the highest as reasonable drug treatment experience, which is the best clinical treatment dosing regimens. Results: 1. adverse reactions of moxifloxacin include blood and lymphatic system, digestive system, nervous system reactions, systemic damage, skin reactions, respiratory system reactions and other adverse reactions occurred. In the analysis of the related factors, and adverse reactions of gender. In terms of age, age 50 the age of patients with a total of 56 cases (72.72%), the incidence of adverse reaction was significantly higher than that of other age groups. Intravenous drug induced adverse reaction incidence rate (50.65%) higher than that of oral administration (35.06%), combined drug adverse reaction Should the incidence rate (61.04%) higher than that of single drug (38.96%).2.1011 strains of clinical isolates mainly has good sensitivity to moxifloxacin, the sensitivity rate was the main pharmacodynamics of moxifloxacin 9.7%-100%. parameters for MSSA, MIC50, MIC90 and MICrange were 0.12,1 and g/ml = 0.03-2; MRSA, MIC50, MIC90 and MICrange respectively. 2,2 and 0.06-4 of PSSP, MIC50, g/ml; MIC90 and MICrange were 0.06,0.25 and 0.03-4 g/ml; MIC50, MIC90 and PISP, MICrange and 0.12,0.5 respectively than 0.03-8 g/ml; on H.inf, MIC50, MIC90 and MICrange were less than 0.03,0.12 and less than 0.03-1 g/ml; on KPN, MIC50, MIC90 0.5,2 and MICrange were less than 0.03-8 and g/ml; M.cata, MIC50, MIC90 and MICrange were less than 0.03,0.12 and less than 0.03-0.12 g/ml; on E.coli, MIC50, MIC90 and MICrange were 0.12,0.5 and g/ml = 0.03-8; ENT, MIC50, MIC90 and MICrange respectively. For 0.12,0.25 and less than 0.03-2 g/m. in vivo antibacterial experiments showed that moxifloxacin in the treatment of 24h, in addition to methicillin resistant Staphylococcus aureus and Klebsiella pneumoniae were not significantly clear, other bacterial infections in the thigh muscles was almost completely removed, and the in vitro antibacterial experimental results for AUIC = 125400mg QD.3. the H.inf and M.cata CRF90%, on the other strains of CRF was 90%; 800mg QD of H.inf, M.cata and ENT CRF90%, on the other strains of CRF 90%; 1200mg QD of MSSA, MRSA and KPN CRF90%, on the other strains of CRF90%.PTA results showed that when MIC is less than or equal to 0.125 g/mL, to three regimen of PTA was greater than 90% and above; for more than 30400mg AUIC QD on MSSA, MRSA and KPN CRF90%, the others were CRF90%; in addition to the 800mg QD MRSA CRF90%, on the other strains of CRF90%; 1200mg QD of all strains of the CRF90%. when the MIC is less than or equal to 0.5 g/mL, three Regimens of PTA was greater than 90% and above. Conclusion: for hospitalized patients, to achieve satisfactory clinical efficacy and reduce the emergence of drug resistance of bacteria, bacillus and moxifloxacin on Haemophilus influenzae infection catarrhal bacteria Mora, can use 400mg QD regimen; enterococcus infection, can be used 800mg QD regimen penicillin; penicillin sensitive Streptococcus pneumoniae, intermediate Streptococcus pneumoniae and Escherichia coli infection, can adopt 1200mg QD regimen or combination of drugs; methicillin sensitive Staphylococcus aureus, methicillin resistant Staphylococcus aureus and Klebsiella pneumonia should be considered in combination. According to the clinical curative effect of outpatients. Satisfaction and reduce bacterial drug resistance and moxifloxacin against penicillin sensitive Streptococcus pneumoniae, penicillin intermediate Streptococcus pneumoniae, Haemophilus influenzae, Moraxella Mora bacteria, Escherichia coli and intestinal Staphylococcus aureus infection, can adopt 400mg QD regimen; methicillin sensitive Staphylococcus aureus and Klebsiella pneumoniae with 800mg QD regimen; methicillin resistant Staphylococcus aureus can adopt 1200mg QD regimen or combined with medication. In addition, on the adjustment and optimization of the dosing regimen at the same time clinical adverse effects with moxifloxacin, some attention, standard and reasonable medication.

【学位授予单位】：郑州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R969

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