頭孢喹肟對Ⅱ型豬鏈球菌在感染小鼠體內(nèi)的藥動藥效模型研究
發(fā)布時間：2019-06-03 17:38
【摘要】：豬鏈球菌是人畜共患菌,給養(yǎng)豬業(yè)及公共衛(wèi)生安全構(gòu)成了嚴(yán)重的威脅。其中Ⅱ型豬鏈球菌是流行最廣,致病性最強,危害最大的血清型。β-內(nèi)酰胺類藥物是治療Ⅱ型豬鏈球菌感染首選藥物,頭孢喹肟對Ⅱ型豬鏈球菌極其敏感,是治療Ⅱ型豬鏈球菌感染理想選擇。目前有關(guān)Ⅱ型豬鏈球菌藥動藥效研究還未見報道,因此無法為治療Ⅱ型豬鏈球菌感染提供科學(xué)依據(jù)。為此本文開展頭孢喹肟對Ⅱ型豬鏈球菌的體外藥效和體內(nèi)藥動藥效同步模型的相關(guān)研究。本文主要通過體內(nèi)頭孢喹肟對Ⅱ型豬鏈球菌PK/PD參數(shù)、抗菌后效應(yīng)和菌量效應(yīng)研究,得到的數(shù)據(jù)通過蒙特克羅模擬推薦臨床豬感染Ⅱ型豬鏈球菌的治療方案。1.頭孢喹肟對Ⅱ型豬鏈球菌的體外抗菌活性測定頭孢喹肟對不同初始菌量(正常菌量:106log10CFU和高菌量:108log10CFU)的MIC和體外殺菌曲線,結(jié)果顯示無論正常菌量還是高菌量MIC值差異不顯著。體外殺菌曲線顯示高菌量抑制頭孢喹肟的殺菌效果,呈現(xiàn)菌量效應(yīng)。對防突變濃度的測定結(jié)果顯示,防突變濃度為0.12μg/m L,耐藥選擇突變窗為0.03~0.12μg/m L,選擇指數(shù)為4,比值較低。體外實驗表明:菌量變化對MIC影響不明顯,但影響體外殺菌效果;選擇突變窗窄表明不容易選擇出耐藥突變株。2.頭孢喹肟在感染小鼠體內(nèi)的藥代動力學(xué)研究建立免疫缺陷小鼠大腿局部感染模型,按4倍增加的劑量治療,于給藥前和給藥后從小鼠眼框靜脈叢穿刺間隔采血,利用LC-MS/MS方法測定藥物濃度,Win Nonlin5.2.1藥動學(xué)軟件對血藥濃度-時間數(shù)據(jù)進行處理。結(jié)果顯示:頭孢喹肟在感染小鼠體內(nèi)的藥動學(xué)符合一級吸收一室模型。頭孢喹肟的峰濃度為1.96~606.71μg/m L;藥時曲線下面積為1.58~551.4μg.h/m L;達(dá)峰時間為0.25~0.28 h;消除半衰期為0.32~0.38 h,為后續(xù)藥效學(xué)奠定基礎(chǔ)。3.頭孢喹肟對Ⅱ型豬鏈球菌的抗菌后效應(yīng)為了減少雜菌干擾,本文優(yōu)化和制定選擇性培養(yǎng)基:萘啶酸:多粘菌素B(60:30,μg/m L:μg/m L)用于體內(nèi)藥效研究。應(yīng)用免疫缺陷小鼠大腿局部感染模型,進行體內(nèi)抗菌后效應(yīng)(PAE)實驗。結(jié)果顯示:2.5mg/kg和40 mg/kg產(chǎn)生的PAE分別為2.45 h和8.55 h,具有濃度依賴性。結(jié)果表明,頭孢喹肟對Ⅱ型豬鏈球菌可產(chǎn)生長PAE,相對于產(chǎn)生短PAE的細(xì)菌,治療Ⅱ型豬鏈球菌時可相對延長給藥間隔,此為首次在體內(nèi)揭示β-內(nèi)酰胺類藥物對Ⅱ型豬鏈球菌可產(chǎn)生長的PAE。4.小鼠大腿局部感染模型的藥動/藥效同步模型研究應(yīng)用免疫缺陷小鼠大腿局部感染正常菌量和高菌量制作感染模型,進行藥動藥效學(xué)研究。通過劑量分配法評價最相關(guān)的PK/PD指數(shù)、指數(shù)范圍并考察是否存在菌量效應(yīng)。結(jié)果顯示:頭孢喹肟對Ⅱ型豬鏈球菌在兩種菌量下體內(nèi)抗菌活性與PK/PD指數(shù)(%?TMIC)的相關(guān)性最強;指數(shù)范圍:兩個菌量達(dá)到靜態(tài)效應(yīng)所需的%?TMIC沒有差異而達(dá)到1-log殺菌效時,感染高菌量所需的%?TMIC比正常菌量高1.2倍;根據(jù)劑量比例,高菌量達(dá)到靜態(tài)效應(yīng)和1-log殺菌效應(yīng)所需的給藥劑量與正常菌量的比例為1.59和4.47倍,結(jié)果表明,頭孢喹肟藥效受感染菌量的影響。接著結(jié)合頭孢喹肟在豬體內(nèi)的藥動數(shù)據(jù),通過蒙特卡羅分析,推出治療臨床上豬感染Ⅱ型豬鏈球菌的推薦給藥劑量為:當(dāng)MIC≤0.12μg/m L時,推薦給藥劑量為2mg/kg/24h i.m.,當(dāng)MIC=0.24μg/m L時,推薦給藥劑量為2mg/kg/12h i.m。以上結(jié)果表明,頭孢喹肟用于臨床治療Ⅱ型豬鏈球菌感染時,需要根據(jù)MIC值和感染程度調(diào)整給藥方案。5.小鼠敗血癥模型藥動/藥效同步模型研究由于Ⅱ型豬鏈球菌引起豬和人類的感染主要為敗血癥,因此建立小鼠敗血癥模型進一步評價藥效。給予4倍增加的5個藥物劑量,間隔6h給藥,24h治療,以生存率作為判斷標(biāo)準(zhǔn),結(jié)果顯示:藥物半數(shù)有效量為2.87mg/kg,%TMIC為22.5%~42.5%,表明頭孢喹肟在感染敗血癥的小鼠模型中也能達(dá)到很好的治療效果。本研究利用體外藥效和小鼠體內(nèi)PK/PD模型,研究頭孢喹肟對Ⅱ型豬鏈球菌的抗菌活性,確定了與抗菌效應(yīng)最相關(guān)的PK/PD參數(shù),計算不同感染菌量達(dá)到不同抗菌效應(yīng)所需的PK/PD參數(shù)值,結(jié)合頭孢喹肟在豬體內(nèi)的藥動數(shù)據(jù)通過蒙特卡羅分析推薦臨床治療豬感染Ⅱ型豬鏈球菌最佳治療方案,為臨床經(jīng)驗治療提供科學(xué)依據(jù)。
[Abstract]:Streptococcus suis is a common animal, and poses a serious threat to the pig industry and public health. The second type of Streptococcus suis is the most popular and most highly pathogenic serotype. The present invention relates to a method for treating type II streptococcus suis infection, and is an ideal choice for treating type II streptococcus suis infection. At present, the study on the drug effect of type II streptococcus suis has not been reported, so it is not possible to provide scientific basis for the treatment of type II streptococcus suis infection. In this paper, the effect of cefixime on the in vitro and in vivo drug effect of Streptococcus suis is studied in this paper. The results of the study on the PK/ PD parameters, the post-antibiotic effect and the amount of the bacteria in the second type of Streptococcus suis were studied by cefammoximes in vivo. The results of the study were as follows:1. The results showed that the MIC and in vitro bactericidal curves of cefixime to different initial bacteria (normal bacterial amount:106 log10CFU and high colony:108 log10CFU) were not significant, and the results showed that the difference of the MIC between the normal and high strains was not significant. The in vitro sterilization curve shows that the high-bacteria amount inhibits the sterilization effect of the cefixime, and the effect of the fungus quantity is present. The result of the determination of the anti-mutation concentration showed that the anti-mutation concentration was 0.12 & mu; g/ m L, the mutation window of drug resistance was 0.03-0.12 & mu; g/ m L, the selection index was 4, and the ratio was low. In vitro experiments show that the effect of the change of the amount of the bacteria on the MIC is not obvious, but the in vitro sterilization effect is influenced; and the selection of the mutant window indicates that the resistant mutant is not easy to be selected. The pharmacokinetics of cefixime in mice infected with infected mice were studied to establish a local infection model of the thigh of an immune-deficient mouse, which was treated at a dose of 4-fold, and the concentration of the drug was measured by the LC-MS/ MS method before and after administration and after the puncture interval of the vein of the mouse eye frame. The plasma concentration-time data was processed by the pharmacokinetic software of Win Nonlin5.2.1. The results showed that the pharmacokinetics of cefixime in the infected mice were in accordance with the first-order absorption of one-compartment model. The peak concentration of cemedoxime is 1.96-606.71. mu. g/ m L, the area under the curve is 1.58-551.4. m u.g. h/ m L, the peak time is 0.25-0.28 h, the elimination half-life is 0.32-0.38h, and the foundation is laid for the follow-up pharmacodynamics. In order to reduce the interference of the complex bacteria, the antibacterial effect of the cefixime on the type II streptococcus suis is optimized and the selective culture medium is prepared in this paper: polymyxin B (60:30,. mu.g/ m L:. mu.g/ m L) is used in the in vivo efficacy study. An in vivo anti-bacterial effect (PAE) experiment was carried out using an immune-deficient mouse thigh local infection model. The results showed that PAE from 2.5 mg/ kg and 40 mg/ kg was 2.45 h and 8.55 h, respectively, with a concentration-dependent manner. The results show that cefammoximes can be used to produce long PAE in type II Streptococcus suis, and can be used for the treatment of Streptococcus suis with short PAE. This is the first time to reveal the long PAE of the class II Streptococcus suis in vivo, which is the first to reveal the long PAE.4 of the class II Streptococcus suis. The model of local infection in the thigh of mice was studied by the model of drug action/ drug effect of the local infection model of the thigh, and the infection model was made with the normal amount of the local infection and the amount of high bacteria in the thigh of the mouse. The most relevant PK/ PD index, the index range, and the presence of a bacterial volume effect were evaluated by the dose distribution method. The results showed that the antibacterial activity and PK/ PD index (%) of cefammoximes in the two strains of Streptococcus suis were measured. The strongest correlation between the TMICs; the exponential range: the% required to achieve the static effect of two bacterial amounts? When the TMIC does not differ to achieve a 1-log sterilization effect, the% of the amount of high-bacteria infection is infected? TMIC is 1.2 times higher than that of normal bacteria; according to the proportion of the dosage, the proportion of the dose to the static effect and the 1-log sterilization effect is 1.59 and 4.47 times the amount of the normal bacteria, and the result shows that the effect of the ceftrioxime is affected by the amount of the infected bacteria. and then combined with the medicinal kinetic data of the cefixime in the pig body, and through the Monte Carlo analysis, the recommended dosage of the therapeutic clinical pig-infected type II streptococcus suis is as follows: when the MIC is 0.12 & mu; g/ m L, the recommended dose is 2 mg/ kg/24 h i.m., when the MIC is 0.24. mu. g/ m L, The recommended administration dose is 2 mg/ kg/12 h i.m. The results indicated above indicate that Ceftrioxime is used in the clinical treatment of type II swine streptococcal infection, and the dosing protocol should be adjusted according to the MIC value and the degree of infection. The drug action/ drug effect synchronization model of the mouse sepsis model studies the infection of the pigs and the human being caused by the type II streptococcus suis mainly to be septicemia, and therefore, the mice septicemia model is established to further evaluate the drug effect. The results showed that the effective amount of the drug was 2.87 mg/ kg and the% of TMIC was 22.5% ~ 42.5%. It was shown that the Ceftdoxime can also achieve a good therapeutic effect in the model of mice infected with septicemia. In this study, in vitro and in vivo PK/ PD model of mice, the antibacterial activity of cefammoximes on type II swine streptococci was studied, and the most relevant PK/ PD parameters were determined, and the PK/ PD parameter values required for different antibacterial effects were calculated. In order to provide scientific basis for clinical experience treatment, the best treatment plan of swine-infected type II streptococcus suis is recommended by Monte-Carlo analysis in combination with the drug-moving data of cefixime in pig.
【學(xué)位授予單位】：華南農(nóng)業(yè)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：S859.7
[Abstract]:Streptococcus suis is a common animal, and poses a serious threat to the pig industry and public health. The second type of Streptococcus suis is the most popular and most highly pathogenic serotype. The present invention relates to a method for treating type II streptococcus suis infection, and is an ideal choice for treating type II streptococcus suis infection. At present, the study on the drug effect of type II streptococcus suis has not been reported, so it is not possible to provide scientific basis for the treatment of type II streptococcus suis infection. In this paper, the effect of cefixime on the in vitro and in vivo drug effect of Streptococcus suis is studied in this paper. The results of the study on the PK/ PD parameters, the post-antibiotic effect and the amount of the bacteria in the second type of Streptococcus suis were studied by cefammoximes in vivo. The results of the study were as follows:1. The results showed that the MIC and in vitro bactericidal curves of cefixime to different initial bacteria (normal bacterial amount:106 log10CFU and high colony:108 log10CFU) were not significant, and the results showed that the difference of the MIC between the normal and high strains was not significant. The in vitro sterilization curve shows that the high-bacteria amount inhibits the sterilization effect of the cefixime, and the effect of the fungus quantity is present. The result of the determination of the anti-mutation concentration showed that the anti-mutation concentration was 0.12 & mu; g/ m L, the mutation window of drug resistance was 0.03-0.12 & mu; g/ m L, the selection index was 4, and the ratio was low. In vitro experiments show that the effect of the change of the amount of the bacteria on the MIC is not obvious, but the in vitro sterilization effect is influenced; and the selection of the mutant window indicates that the resistant mutant is not easy to be selected. The pharmacokinetics of cefixime in mice infected with infected mice were studied to establish a local infection model of the thigh of an immune-deficient mouse, which was treated at a dose of 4-fold, and the concentration of the drug was measured by the LC-MS/ MS method before and after administration and after the puncture interval of the vein of the mouse eye frame. The plasma concentration-time data was processed by the pharmacokinetic software of Win Nonlin5.2.1. The results showed that the pharmacokinetics of cefixime in the infected mice were in accordance with the first-order absorption of one-compartment model. The peak concentration of cemedoxime is 1.96-606.71. mu. g/ m L, the area under the curve is 1.58-551.4. m u.g. h/ m L, the peak time is 0.25-0.28 h, the elimination half-life is 0.32-0.38h, and the foundation is laid for the follow-up pharmacodynamics. In order to reduce the interference of the complex bacteria, the antibacterial effect of the cefixime on the type II streptococcus suis is optimized and the selective culture medium is prepared in this paper: polymyxin B (60:30,. mu.g/ m L:. mu.g/ m L) is used in the in vivo efficacy study. An in vivo anti-bacterial effect (PAE) experiment was carried out using an immune-deficient mouse thigh local infection model. The results showed that PAE from 2.5 mg/ kg and 40 mg/ kg was 2.45 h and 8.55 h, respectively, with a concentration-dependent manner. The results show that cefammoximes can be used to produce long PAE in type II Streptococcus suis, and can be used for the treatment of Streptococcus suis with short PAE. This is the first time to reveal the long PAE of the class II Streptococcus suis in vivo, which is the first to reveal the long PAE.4 of the class II Streptococcus suis. The model of local infection in the thigh of mice was studied by the model of drug action/ drug effect of the local infection model of the thigh, and the infection model was made with the normal amount of the local infection and the amount of high bacteria in the thigh of the mouse. The most relevant PK/ PD index, the index range, and the presence of a bacterial volume effect were evaluated by the dose distribution method. The results showed that the antibacterial activity and PK/ PD index (%) of cefammoximes in the two strains of Streptococcus suis were measured. The strongest correlation between the TMICs; the exponential range: the% required to achieve the static effect of two bacterial amounts? When the TMIC does not differ to achieve a 1-log sterilization effect, the% of the amount of high-bacteria infection is infected? TMIC is 1.2 times higher than that of normal bacteria; according to the proportion of the dosage, the proportion of the dose to the static effect and the 1-log sterilization effect is 1.59 and 4.47 times the amount of the normal bacteria, and the result shows that the effect of the ceftrioxime is affected by the amount of the infected bacteria. and then combined with the medicinal kinetic data of the cefixime in the pig body, and through the Monte Carlo analysis, the recommended dosage of the therapeutic clinical pig-infected type II streptococcus suis is as follows: when the MIC is 0.12 & mu; g/ m L, the recommended dose is 2 mg/ kg/24 h i.m., when the MIC is 0.24. mu. g/ m L, The recommended administration dose is 2 mg/ kg/12 h i.m. The results indicated above indicate that Ceftrioxime is used in the clinical treatment of type II swine streptococcal infection, and the dosing protocol should be adjusted according to the MIC value and the degree of infection. The drug action/ drug effect synchronization model of the mouse sepsis model studies the infection of the pigs and the human being caused by the type II streptococcus suis mainly to be septicemia, and therefore, the mice septicemia model is established to further evaluate the drug effect. The results showed that the effective amount of the drug was 2.87 mg/ kg and the% of TMIC was 22.5% ~ 42.5%. It was shown that the Ceftdoxime can also achieve a good therapeutic effect in the model of mice infected with septicemia. In this study, in vitro and in vivo PK/ PD model of mice, the antibacterial activity of cefammoximes on type II swine streptococci was studied, and the most relevant PK/ PD parameters were determined, and the PK/ PD parameter values required for different antibacterial effects were calculated. In order to provide scientific basis for clinical experience treatment, the best treatment plan of swine-infected type II streptococcus suis is recommended by Monte-Carlo analysis in combination with the drug-moving data of cefixime in pig.
【學(xué)位授予單位】：華南農(nóng)業(yè)大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：S859.7
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相關(guān)期刊論文 前8條
1 廖雪玲;張炳旭;丁煥中;;基于防突變濃度的新型藥動學(xué)-藥效學(xué)-突變選擇窗同步模型在臨床用藥上的指導(dǎo)作用[J];中國畜牧獸醫(yī);2013年01期
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