左氧氟沙星耐药小鼠模型的建立
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摘要
目的检测低浓度左氧氟沙星对铜绿假单胞菌(PA)感染小鼠肺炎模型的影响,探索左氧氟沙星耐药产生的方法。方法采用PA感染小鼠致肺炎模型,各实验中小鼠按体重随机分组,以不同的菌液浓度、感染次数、给药方法,以小鼠体重变化规律、小鼠肺指数为评价指标,分析左氧氟沙星的治疗效果,探讨模型建立的可行性。结果低浓度左氧氟沙星对PA(1×109cfu/m L)单次感染小鼠,模型组1、模型组2肺指数与正常组比较均有显著性差异(P<0. 01);左氧氟沙星组2与模型组2比较无显著性差异。低浓度左氧氟沙星对PA(1×1010cfu/m L)单次感染小鼠,模型组1和模型组2与正常组比较,均有显著性差异(P<0. 01)。左氧氟沙星组3与模型组2比较,结果无显著性差异。左氧氟沙星组1、2均能显著性降低模型组肺指数; PA重复感染小鼠实验中,模型组1和模型组2与正常组比较,均有显著性差异(P<0. 01)。左氧氟沙星组2与模型组2比较,无显著性差异。各实验中,小鼠感染后第二天,体重较正常组降低,结果无显著性差异。结论实验条件下,低浓度左氧氟沙星对PA(1×1010cfu/m L)单次感染小鼠、低浓度左氧氟沙星对PA重复感染小鼠中,动物模型可在一定程度上模拟临床中耐药产生的现象。
Objective To explore the method of establishing a mouse model of levofloxacin resistance by infection with Pseudomonas aeruginosa( PA) in combination with a low-dose levofloxacin administration. Methods The model of pneumonia was induced by infecting mice with a PA standard strain. Different concentrations of bacterial suspension,times of infection and lerofloxacin administration method were analyzed. The therapeutic effect of levofloxacin was analyzed and the feasibility of establishing the model was determined by measuring body weight changes and lung index of the mice.Results There were significant differences in lung indexes between the model groups 1 and 2 and normal group( P <0. 01),and there was no significant difference between levofloxacin group 2 and model group 2 after single infection of PA( 1×109 cfu/m L) in mice treated with low-dose levofloxacin. In the experiment of single infection of PA( 1× 1010 cfu/m L)plus low-dose levofloxacin,there were significant differences between the model groups 1 and 2 and the normal group( P<0. 01),and there was no significant difference between levofloxacin group 3 and model group 2. Levofloxacin groups 1 and2 significantly reduced the lung index in model group. In the experiment of repeated infection of PA in mice,there were significant differences between model groups 1 and 2 and normal group( P < 0. 01). There was no significant difference between the levofloxacin group 2 and model group 2. In each experiment,the body weight of mice in the experimental groups was lower than that of the normal group on the second day after infection,although this was not significantly different. Conclusions Under the experimental conditions used in our study,this animal model can simulate the phenomenon of drug resistance to a certain extent generated by PA( 1 × 1010 cfu/ml) single infection and PA repetitive infection combined with administration of a low-dose levofloxacin.
Objective To explore the method of establishing a mouse model of levofloxacin resistance by infection with Pseudomonas aeruginosa( PA) in combination with a low-dose levofloxacin administration. Methods The model of pneumonia was induced by infecting mice with a PA standard strain. Different concentrations of bacterial suspension,times of infection and lerofloxacin administration method were analyzed. The therapeutic effect of levofloxacin was analyzed and the feasibility of establishing the model was determined by measuring body weight changes and lung index of the mice.Results There were significant differences in lung indexes between the model groups 1 and 2 and normal group( P <0. 01),and there was no significant difference between levofloxacin group 2 and model group 2 after single infection of PA( 1×109 cfu/m L) in mice treated with low-dose levofloxacin. In the experiment of single infection of PA( 1× 1010 cfu/m L)plus low-dose levofloxacin,there were significant differences between the model groups 1 and 2 and the normal group( P<0. 01),and there was no significant difference between levofloxacin group 3 and model group 2. Levofloxacin groups 1 and2 significantly reduced the lung index in model group. In the experiment of repeated infection of PA in mice,there were significant differences between model groups 1 and 2 and normal group( P < 0. 01). There was no significant difference between the levofloxacin group 2 and model group 2. In each experiment,the body weight of mice in the experimental groups was lower than that of the normal group on the second day after infection,although this was not significantly different. Conclusions Under the experimental conditions used in our study,this animal model can simulate the phenomenon of drug resistance to a certain extent generated by PA( 1 × 1010 cfu/ml) single infection and PA repetitive infection combined with administration of a low-dose levofloxacin.
引文
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[2] Yayan J,Ghebremedhin B,Rasche K. Antibiotic resistance of pseudomonas aeruginosa in pneumonia at a single university hospital center in Germany over a 10-year period[J]. PLoS One,2015; 10(10):e0139836.
[3]刘国星.铜绿假单胞菌肺炎证候特点及扶正解毒化瘀方对MDRPA体外抑菌实验研究[D].北京:北京中医药大学,2018.
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[9]丁军颖,高翔,洪燕英,等.不同感染途径致大鼠肺炎模型制备的比较[J].中国实验动物学报,2017,25(6):600-604.
[10]巫俊琴,程曦.2014-2016年某院铜绿假单胞菌耐药性监测[J].中国微生态学杂志,2017,29(11):1285-1288.
[11]辛大平,彭彬,庹田,等.帕珠沙星与左氧氟沙星治疗院内铜绿假单胞菌肺炎的临床研究[J].湖南中医药大学学报,2012,32(12):26,28.
[12]侯芳,吕媛.不容忽视的细菌耐药[J].中国抗生素杂志,2017,42(03):203-206.
[13] Moradali MF,Ghods S,Rehm BH. Pseudomonas aeruginosa lifestyle:a paradigm for adaptation,survival,and persistence[J]. Front Cell Infect Microbiol,2017; 7:39.
[14]左虹.铜绿假单胞菌医院感染现状及耐药性分析[J].检验医学与临床,2013,10(2):159-160.
[15]李绪定.碳青霉烯类治疗铜绿假单胞菌肺炎的临床效果分析[J].医学信息,2018,31(13):134-136.
[16]魏建新,杨青.多重耐药铜绿假单胞菌不同药物治疗疗效的比较[J].中国现代药物应用,2015,9(18):118-119.
[17]李浩.左氧氟沙星联合头孢哌酮舒巴坦对老年肺炎临床疗效[J].北方药学,2018,15(09):108-109.
[18]王良.2012-2016年某院铜绿假单胞菌感染情况及耐药性分析[J].中国医院统计,2017,24(3):228-231.
[19] Segatore B,Setacci D,Perilli M, et al. Italian survey on comparative levofloxacin susceptibility in 334 clinical isolates of Pseudomonas aeruginosa[J]. Antimicrob Agents Chemother,1999; 43(2):428-431.
[20]菅凌燕,何晓静,于莹.黄芩苷联合左氧氟沙星对铜绿假单胞菌生物膜的影响及相关机制[J].中国医院药学杂志,2012,32(14):1097-1100.
[21] Stockmann C,Sherwin CM,Ampofo K,et al. Development of levofloxacin inhalation solution to treat Pseudomonas aeruginosa in patients with cystic fibrosis[J]. Ther Adv Respir Dis,2014; 8(1):13-21.
[22]陈建安,周静,张丽华,等.2006至2010年铜绿假单胞菌分布及耐药性分析[J].实验与检验医学,2011,29(5):539-540+542.
[23]高雅婷.环丙沙星体外诱导对铜绿假单胞菌QS基因调控影响的研究[D].太原:山西医科大学,2018.
[24]张智琪.氟喹诺酮药物诱导铜绿假单胞菌生物膜及耐药机制研究[D].太原:山西医科大学,2018.
[25] Papaioannou E,Utari PD,Quax WJ. Choosing an appropriate infection model to study quorum sensing inhibition in pseudomonas infections[J]. Int J Mol Sci. 2013; 14(9):19309-19340.
[2] Yayan J,Ghebremedhin B,Rasche K. Antibiotic resistance of pseudomonas aeruginosa in pneumonia at a single university hospital center in Germany over a 10-year period[J]. PLoS One,2015; 10(10):e0139836.
[3]刘国星.铜绿假单胞菌肺炎证候特点及扶正解毒化瘀方对MDRPA体外抑菌实验研究[D].北京:北京中医药大学,2018.
[4] Lavoie EG, Wangdi T, Kazmierczak BI. Innate immune responses to Pseudomonas aeruginosa infection[J]. Microbes Infect,2011; 13(14-15):1133-1145.
[5] Cash HA,Woods DE,Mc Cullough B,et al. A rat model of chronic respiratory infection with Pseudomonas aeruginosa[J].Am Rev Respir Dis,1979,119(3):453-459.
[6]童明庆,戴传箴,赵旺胜,等.小鼠细菌性支气管肺炎模型的建立[J].南京医学院学报,1994,38(1):1-4.
[7]李建生,张艳霞,周红艳等.细菌性肺炎痰热证模型的建立与评价[J].中医杂志,2009,50(9):822-825.
[8] Takashima K,Tateda K,Matsumoto T,et al. Establishment of a model of penicillin-resistant Streptococcus pneumoniae pneumoni-a in healthy CBA/J mice[J]. J Med Microbiol,1996,45(5):319-322.
[9]丁军颖,高翔,洪燕英,等.不同感染途径致大鼠肺炎模型制备的比较[J].中国实验动物学报,2017,25(6):600-604.
[10]巫俊琴,程曦.2014-2016年某院铜绿假单胞菌耐药性监测[J].中国微生态学杂志,2017,29(11):1285-1288.
[11]辛大平,彭彬,庹田,等.帕珠沙星与左氧氟沙星治疗院内铜绿假单胞菌肺炎的临床研究[J].湖南中医药大学学报,2012,32(12):26,28.
[12]侯芳,吕媛.不容忽视的细菌耐药[J].中国抗生素杂志,2017,42(03):203-206.
[13] Moradali MF,Ghods S,Rehm BH. Pseudomonas aeruginosa lifestyle:a paradigm for adaptation,survival,and persistence[J]. Front Cell Infect Microbiol,2017; 7:39.
[14]左虹.铜绿假单胞菌医院感染现状及耐药性分析[J].检验医学与临床,2013,10(2):159-160.
[15]李绪定.碳青霉烯类治疗铜绿假单胞菌肺炎的临床效果分析[J].医学信息,2018,31(13):134-136.
[16]魏建新,杨青.多重耐药铜绿假单胞菌不同药物治疗疗效的比较[J].中国现代药物应用,2015,9(18):118-119.
[17]李浩.左氧氟沙星联合头孢哌酮舒巴坦对老年肺炎临床疗效[J].北方药学,2018,15(09):108-109.
[18]王良.2012-2016年某院铜绿假单胞菌感染情况及耐药性分析[J].中国医院统计,2017,24(3):228-231.
[19] Segatore B,Setacci D,Perilli M, et al. Italian survey on comparative levofloxacin susceptibility in 334 clinical isolates of Pseudomonas aeruginosa[J]. Antimicrob Agents Chemother,1999; 43(2):428-431.
[20]菅凌燕,何晓静,于莹.黄芩苷联合左氧氟沙星对铜绿假单胞菌生物膜的影响及相关机制[J].中国医院药学杂志,2012,32(14):1097-1100.
[21] Stockmann C,Sherwin CM,Ampofo K,et al. Development of levofloxacin inhalation solution to treat Pseudomonas aeruginosa in patients with cystic fibrosis[J]. Ther Adv Respir Dis,2014; 8(1):13-21.
[22]陈建安,周静,张丽华,等.2006至2010年铜绿假单胞菌分布及耐药性分析[J].实验与检验医学,2011,29(5):539-540+542.
[23]高雅婷.环丙沙星体外诱导对铜绿假单胞菌QS基因调控影响的研究[D].太原:山西医科大学,2018.
[24]张智琪.氟喹诺酮药物诱导铜绿假单胞菌生物膜及耐药机制研究[D].太原:山西医科大学,2018.
[25] Papaioannou E,Utari PD,Quax WJ. Choosing an appropriate infection model to study quorum sensing inhibition in pseudomonas infections[J]. Int J Mol Sci. 2013; 14(9):19309-19340.