舒巴坦聯(lián)合美羅培南不同給藥方案抑制鮑曼不動桿菌耐藥突變的研究
發(fā)布時間：2018-11-10 16:57
【摘要】：目的：在體外PK/PD模型中,探討舒巴坦聯(lián)合美羅培南的不同給藥方案對鮑曼不動桿菌耐藥突變的抑制作用。 方法：紙片擴散法測定抗菌藥物單藥對鮑曼不動桿菌45791的MIC值；微量肉湯稀釋法和瓊脂法測定美羅培南和舒巴坦單藥及聯(lián)合時對該菌的MIC、MPC值和兩藥的相互作用。建立體外藥代動力學/藥效學(PK/PD)模型,模擬2種美羅培南單藥給藥方案(1.030min Q8h,1.03h Q8h);6種舒巴坦單藥給藥方案,即1.030min Q8h、2.030min Q8h、3.030min Q8h及1.03h Q8h、2.03h Q8h、3.03h Q8h;6種聯(lián)合方案,即美羅培南1.030min Q8h分別與舒巴坦1.030min Q8h、2.030min Q8h、3.030min Q8h,美羅培南1.03h Q8h分別與舒巴坦1.03h Q8h、2.03h Q8h、3.03h Q8h。各方案均持續(xù)給藥7天,在相應的時間點測定模型中總細菌數(shù)、耐藥突變菌數(shù),并用高效液相色譜法(HPLC)測定美羅培南的濃度,用高效液相色譜串聯(lián)質譜法(HPLC-MS/MS)測定肉湯中舒巴坦的濃度。 結果：美羅培南對該菌的MIC為2μg·mL-1,MPC為28.μg·mL-1,舒巴坦的MIC為128μg·mL-1,MPC為128μg·mL-1,該菌對青霉素類、喹諾酮類、氨基糖苷類、頭孢菌素類、含β內(nèi)酰胺酶的復合制劑類耐藥。棋盤法表明,聯(lián)合的MIC顯示有協(xié)同作用,聯(lián)合后美羅培南和舒巴坦的MPC值各降至8ug/mL和32ug/mL。6種舒巴坦單藥方案中,168h內(nèi)細菌總量均未見減少。美羅培南1.030min Q8h及1.03hQ8h單藥方案中,總細菌量在72h及24h內(nèi)持續(xù)下降,下降約103cfu/mL,之后分別在144h和96h內(nèi)維持基本不變,最后穩(wěn)定生長,最終濃度超過106cfu/mL;耐藥突變菌于72h富集生長。6種聯(lián)合方案均不能防止耐藥菌產(chǎn)生,美羅培南1.030min Q8h與舒巴坦1.030min Q8h、2.030min Q8h、3.030minQ8h的聯(lián)合方案中,各聯(lián)方案之間無差異；總細菌數(shù)持續(xù)下降,下降約105cfu/mL,耐藥突變菌于144h富集生長。美羅培南1.03h Q8h與舒巴坦1.03h Q8h、2.03h Q8h、3.03h Q8h聯(lián)合方案中,各聯(lián)方案之間亦無差異；總細菌數(shù)持續(xù)下降,下降約106cfu/mL,未出現(xiàn)耐藥菌富集生長。上述14種方案,在時間為168h時系統(tǒng)中的細菌均全部為耐藥菌。 結論：對于本研究的實驗菌株,舒巴坦和美羅培南聯(lián)合可以明顯縮小美羅培南的突變選擇窗口。舒巴坦與美羅培南聯(lián)合后,可明顯延緩耐藥突變菌的富集速度。3小時靜脈滴注的聯(lián)合給藥方案比30min靜脈滴注的聯(lián)合給藥方案效果更明顯,能在168小時內(nèi)抑制耐藥菌的富集。美羅培南與舒巴坦的聯(lián)合中,增加舒巴坦的劑量不能提高殺菌效果和抑制耐藥突變。
[Abstract]:Aim: to investigate the inhibitory effect of sulbactam combined with meropenem on resistant mutation of Acinetobacter baumannii in vitro PK/PD model. Methods: the MIC value of single antimicrobial drug against Acinetobacter baumannii 45791 was determined by disk diffusion method, and the MIC,MPC value and the interaction between the two drugs were determined by broth dilution method and Agar method. In vitro pharmacokinetics / pharmacodynamics (PK/PD) model was established to simulate two meropenem single drug administration regimens (1.030min Q8h 1.03h Q8h). Six sulbactam single drug administration regimens, namely 1.030min Q8H 2.030min, Q8h 3.030min Q8h and 1.03h Q8hU 2.03h Q8hU 3.03hQ8h; Six combined schemes, meropenem 1.030min Q8h and sulbactam 1.030min Q8hU 2.030min Q8h, meropenem 1.03h Q8h and sulbactam 1.03h Q8h respectively and sulbactam 1.030min Q8hU 2.030min Q8hU 3.030min Q8h respectively. The total number of bacteria and the number of resistant mutant bacteria in the model were determined at the corresponding time points. The concentration of meropenem was determined by high performance liquid chromatography (HPLC) (HPLC). The concentration of sulbactam in broth was determined by high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Results: the MIC of meropenem to this strain was 2 渭 g mL-1,MPC = 28. 0 渭 g mL-1, sulbactam, and the MIC of meropenem was 128 渭 g mL-1,MPC and 128 渭 g mL-1,. The bacteria had penicillin, quinolones, aminoglycosides, cephalosporins, penicillin, quinolones, aminoglycosides and cephalosporins. Complex preparations containing 尾-lactamases were resistant to drugs. Chessboard method showed that the combined MIC showed synergistic effect, and the MPC values of meropenem and sulbactam decreased respectively to 8ug/mL and 32ug/mL.6 sulbactam monopharmaceuticals, and the total amount of bacteria did not decrease within 168h. In meropenem 1.030min Q8h and 1.03hQ8h single drug regimen, the total bacterial count decreased continuously in 72 h and 24 h, decreased about 103 cfur / mL, then remained basically unchanged for 144 h and 96 h, and finally grew stably, and the final concentration was over 106 cfur / mL; The drug resistant mutant bacteria were enriched and grown at 72 h. All of the six combination protocols could not prevent the production of resistant bacteria, but there was no difference between the two combinations of meropenem 1.030min Q8h and sulbactam 1.030min Q8h 2.030min Q8hU 3.030minQ8h. The total bacterial count continued to decrease, about 105 cfur / mL, and the drug-resistant mutant bacteria enriched and grew at 144h. In the combination regimen of meropenem 1.03h Q8h and sulbactam 1.03h Q8hU 2.03h Q8hU 3.03h Q8h, there was no difference between the two schemes, and the total bacterial count decreased by 106cfu-mL. there was no enrichment growth of drug-resistant bacteria. All the bacteria in the system were drug-resistant when the time was 168h. Conclusion: the combination of sulbactam and meropenem can significantly reduce the mutation window of meropenem. After combination of sulbactam and meropenem, the enrichment rate of resistant mutant bacteria was significantly delayed. The combined administration regimen of 3 hours intravenous drip was more effective than that of 30min intravenous drip regimen, and could inhibit the enrichment of resistant bacteria within 168h. In the combination of meropenem and sulbactam, increasing the dosage of sulbactam did not improve bactericidal efficacy and inhibit drug-resistant mutation.
【學位授予單位】：中南大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R96
本文編號：2323031
[Abstract]:Aim: to investigate the inhibitory effect of sulbactam combined with meropenem on resistant mutation of Acinetobacter baumannii in vitro PK/PD model. Methods: the MIC value of single antimicrobial drug against Acinetobacter baumannii 45791 was determined by disk diffusion method, and the MIC,MPC value and the interaction between the two drugs were determined by broth dilution method and Agar method. In vitro pharmacokinetics / pharmacodynamics (PK/PD) model was established to simulate two meropenem single drug administration regimens (1.030min Q8h 1.03h Q8h). Six sulbactam single drug administration regimens, namely 1.030min Q8H 2.030min, Q8h 3.030min Q8h and 1.03h Q8hU 2.03h Q8hU 3.03hQ8h; Six combined schemes, meropenem 1.030min Q8h and sulbactam 1.030min Q8hU 2.030min Q8h, meropenem 1.03h Q8h and sulbactam 1.03h Q8h respectively and sulbactam 1.030min Q8hU 2.030min Q8hU 3.030min Q8h respectively. The total number of bacteria and the number of resistant mutant bacteria in the model were determined at the corresponding time points. The concentration of meropenem was determined by high performance liquid chromatography (HPLC) (HPLC). The concentration of sulbactam in broth was determined by high performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS). Results: the MIC of meropenem to this strain was 2 渭 g mL-1,MPC = 28. 0 渭 g mL-1, sulbactam, and the MIC of meropenem was 128 渭 g mL-1,MPC and 128 渭 g mL-1,. The bacteria had penicillin, quinolones, aminoglycosides, cephalosporins, penicillin, quinolones, aminoglycosides and cephalosporins. Complex preparations containing 尾-lactamases were resistant to drugs. Chessboard method showed that the combined MIC showed synergistic effect, and the MPC values of meropenem and sulbactam decreased respectively to 8ug/mL and 32ug/mL.6 sulbactam monopharmaceuticals, and the total amount of bacteria did not decrease within 168h. In meropenem 1.030min Q8h and 1.03hQ8h single drug regimen, the total bacterial count decreased continuously in 72 h and 24 h, decreased about 103 cfur / mL, then remained basically unchanged for 144 h and 96 h, and finally grew stably, and the final concentration was over 106 cfur / mL; The drug resistant mutant bacteria were enriched and grown at 72 h. All of the six combination protocols could not prevent the production of resistant bacteria, but there was no difference between the two combinations of meropenem 1.030min Q8h and sulbactam 1.030min Q8h 2.030min Q8hU 3.030minQ8h. The total bacterial count continued to decrease, about 105 cfur / mL, and the drug-resistant mutant bacteria enriched and grew at 144h. In the combination regimen of meropenem 1.03h Q8h and sulbactam 1.03h Q8hU 2.03h Q8hU 3.03h Q8h, there was no difference between the two schemes, and the total bacterial count decreased by 106cfu-mL. there was no enrichment growth of drug-resistant bacteria. All the bacteria in the system were drug-resistant when the time was 168h. Conclusion: the combination of sulbactam and meropenem can significantly reduce the mutation window of meropenem. After combination of sulbactam and meropenem, the enrichment rate of resistant mutant bacteria was significantly delayed. The combined administration regimen of 3 hours intravenous drip was more effective than that of 30min intravenous drip regimen, and could inhibit the enrichment of resistant bacteria within 168h. In the combination of meropenem and sulbactam, increasing the dosage of sulbactam did not improve bactericidal efficacy and inhibit drug-resistant mutation.
【學位授予單位】：中南大學
【學位級別】：碩士
【學位授予年份】：2014
【分類號】：R96
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