【摘要】 目的评估美罗培南15种给药方案的有效性与耐药风险。方法运用药动学/药效学模型和蒙特卡洛模拟,结合非重症监护室（ICU）与ICU中微生物菌种和最低抑菌浓度（MIC）分布,评估美罗培南对大肠埃希菌（EC）、肺炎克雷伯菌（KP）、铜绿假单胞菌（PA）及鲍曼不动杆菌（AB）共计15种给药方案的有效性[非危重患者以给药间隔内游离血药浓度超过致病菌MIC的时间(%T_>MIC)>40%,危重患者以%T_>MIC>100%、%T_>4MIC>50%为目标靶值]与抑制耐药突变能力(非危重和危重患者均以%T_>4MIC>100%为目标靶值)的达标概率和累积反应分数（CFR）。结果非危重患者以%T_>MIC>40%作为有效性目标靶值,对于EC和KP,除0.5 g、q12 h之外,其余14种方案的CFR均>90%。对于PA,只有2 g、q6 h和3 g、q6 h的CFR能达到90%。对于AB,只有3 g、q6 h的CFR能达到90%。危重患者分别以%T_>MIC>100%和%T_>4MIC>50%作为有效性目标靶值,结果相似。对于EC和KP,只有部分方案CFR能达到90%。而对于PA和AB,所有方案CFR均不能达到90%,即使是3 g、q6 h的方案,对PA的CFR也仅能达到62.6%,对AB的CFR亦仅能达到11.2%。若制定更为严苛的目标靶值(即T_>4MIC>100%)来评估抑制耐药突变能力,非危重、危重患者都很难达标,只有危重患者3 g、q6 h方案对EC和KP目标治疗的CFR能达到90%。结论美罗培南目前的传统给药模式是美罗培南耐药性蔓延的重要因素。需要进一步优化当前的用药模式,在提高治疗有效性的同时将用药引起的耐药突变风险最小化。更多还原

【Abstract】 Objective To evaluate the germicidal effectiveness and resistance risk for 15 kinds of meropenem dosage regimens. Methods We used PK/PD model, Monte Carlo simulation, and MIC distribution in intensive care unit（ICU）and non-ICU,to evaluate the probability of target attainment and cumulative fraction of response（CFR）of 15 kinds of dosage regimens for Escherichia coli（EC）,Klebsiella pneumonia（KP）,Pseudomonas aeruginosa（PA）and Acinetobacter baumannii（AB）in effectiveness and the ability to suppress resistance mutation.(%T_>MIC>40% in non-ICU,%T_>MIC>100%,%T_{>4 MIC}>50% in ICU as target threshold, %T_{>4 MIC}>100% both in non-ICU and ICU as target threshold.) Results For non-critical patients, %T _>MIC >40% was taken as the target threshold of effectiveness.For EC and KP,with the exception of 0.5 g, q12 h, the CFR of all the other regimens were greater than 90%.For PA,only 2 g q6 h and 3 g q6 h could achieve 90% for CFR.For AB,only 3 g q6 h could reach 90%.For the critical patients, whether %T_>MIC >100% or %T_{>4 MIC} >50% was taken as the target threshold of effectiveness, the results were similar.For EC and KP,only part of the regimen CFR could reach 90%.For PA and AB,the CFR of all regimens couldn’t reach 90%,even if the 3 g q6 h regimen could only reach 62.6% for PA,and for AB could only reach 11.2%.In order to achieve the purpose of inhibiting drug-resistant mutations, a more stringent target threshold(i.e.,T_{>4 MIC} >100%)was formulated.According to the MCS results, it was difficult to reach the standard for non-critical patients and critical patients.Only the 3 g q6 h regimen in critical patients could achieve 90% CFR for target treatment against EC and KP. Conclusion The current pattern of meropenem use is an important factor contributing to the spread of meropenem resistance.It is need to further optimize the current infusion pattern in order to improve the treatment effectiveness and minimize the risk of drug resistance mutations.更多还原