美罗培南治疗药物监测的HPLC方法探索及其临床采样流程建立

目的：建立HPLC法测定人血浆中美罗培南的血药浓度，结合其稳定性研究制定临床采样流程，并应用到治疗药物监测个体化给药方案设计。方法：血浆样品经甲醇沉淀蛋白，取上清加水稀释后进样分析；色谱柱为Venusil HILIC（4.6 mm×250 mm，5.0 μm）；流动相为50 mmol·L^-1磷酸二氢钾含0.05%甲酸-乙腈（30：70，V/V）；流速0.8 mL·min^-1；检测波长为299 nm；柱温40℃；分别考察美罗培南全血、溶血样本在不同温度、不同采血管等条件下的稳定性。结果：美罗培南在0.38~71.30 μg·mL^-1范围内线性关系良好（r=0.999 9），定量下限为0.38 μg·mL^-1，低、中、高浓度的萃取回收率在101.87%~107.89%，日内、日间RSD均小于2.81%；以EDTA-K2为最佳的临床采血管，EDTA-K2管和肝素钠管中的美罗培南能在室温（19~22℃）下稳定4 h；溶血样本在2~6℃冰箱存放7 h稳定，但相对于EDTA-K2管和血浆质控，肝素钠管会使美罗培南检出率偏高；血浆样本在室温（19~22℃）、2~6℃冰箱内6 h、-40℃冻存20 d、-40℃反复冻融3次均稳定。结论：建立的TDM临床采样流程充分考虑了临床采样的实际情况并能确保美罗培南药物的稳定性及分析检测结果的准确性，可满足临床血药浓度监测需求。     

Meropenem and Vaborbactam: Stepping up the Battle against Carbapenem‐resistant Enterobacteriaceae

Vaborbactam (VAB; formerly RPX7009) is a novel beta‐lactamase inhibitor based on a cyclic boronic acid pharmacophore with potent inhibitory activity against Ambler class A and C beta‐lactamases. It has been co‐formulated with meropenem to restore its activity against Klebsiella pneumoniae carbapenemases (KPC). VAB does not inhibit class B or D carbapenemases, nor does it improve the activity of meropenem against multidrug‐resistant nonfermenting gram‐negative bacilli, notably Acinetobacter spp. and Pseudomonas aeruginosa. The purpose of this article is to review existing data pertaining to the biochemistry, mechanism of action, pharmacokinetics/pharmacodynamics, in vitro activity, and current progress in clinical trials of meropenem and VAB (MV). Phase 1 studies have demonstrated single and multiple doses of VAB up to 2000 mg, alone or in combination with meropenem 2000 mg administered as a prolonged infusion over 3 hours, are well tolerated with an adverse effect profile similar to that of meropenem monotherapy. The available data suggest preexisting resistance among KPC‐producing isolates is rare. Strains with elevated MICs have been characterized by multiple resistance determinants including porin defects, increased drug efflux, and increased blaKPC expression. It remains uncertain whether multifactorial resistance will emerge during MV treatment and with more widespread use. Early data are positive for complicated urinary tract infections and MV compared with best available therapy in patients with serious carbapenem‐resistant Enterobacteriaciae (CRE) infections. As clinicians contemplate how to incorporate MV into CRE treatment strategies, it will be important to track and understand resistance, discern the role, if any, of combination therapy in enhancing efficacy and/or preserving activity, and define the specific therapeutic niche of MV among the expanding anti‐CRE armamentarium.     

基于血药浓度监测的美罗培南药物利用评价探索与实践

目的:建立美罗培南药物利用评价方法,评价治疗药物监测(therapeutic drug monitoring,TDM)对临床用药的影响。方法:依据国家卫健委2018版《碳青霉烯类抗菌药物临床应用评价细则》及相关资料,制定美罗培南临床应用评价标准。采用层次分析法(AHP)评估各项评价指标的重要性,并运用逼近理想解排序法(TOPSIS)进行数据处理。对厦门大学附属中山医院2020年6月至10月未开展美罗培南TDM的病例(对照组)和2021年6月至10月开展TDM的病例(监测组)进行对比评价。比较2组临床有效率和细菌学有效率、合理性指标符合率和改善情况以及与最优方案的相对接近度(C_i)。结果:监测组中,ICU患者的血药浓度达标率为70.2%,非ICU患者的血药浓度达标率为42.7%。与对照组相比,监测组临床有效率、细菌学有效率、合理性指标符合率均显著提高(P＜0.05);临床用药不合理(C_i＜0.6)的病例数显著减少(P＜0.05),达到用药基本合理以上水平的病例数增加(C_i≥0.6)。结论:应用TDM有助于提高美罗培南用药的合理性和有效性。     

基于加权TOPSIS 法对儿科美罗培南的利用评价

目的:探讨儿科美罗培南使用评价体系,为儿科美罗培南合理应用提供参考。方法:构建儿科美罗培南药物利用评价 (DUE)标准,采用加权逼近理想解排序(TOPSIS)法对2020 年10 月至2021 年3 月我院儿科使用美罗培南的患儿临床资料进行 评价。结果:共纳入130 例合格病例,根据其与最佳解的相对接近程度Ci 值进行划分,Ci ≥0. 8 的合理病例38 例(29. 23%), 0. 6≤Ci <0. 8 的基本合理病例60 例(46. 15%),Ci <0. 6 的不合理病例32 例(24. 62%)。结论:采用加权TOPSIS 法评估儿科美 罗培南的合理应用是切实可行的,我院美罗培南的应用仍存在问题,应加强管理,促进美罗培南在儿科患者中的合理应用。     

2012—2015年1380株肝移植术后感染病原菌的分布及耐药性分析

目的了解江苏省人民医院肝移植术后感染病原菌的分布及耐药性,为临床合理用药提供参考。方法对2012年1月—2015年1月江苏省人民医院肝移植术后感染病原菌的分布及耐药性进行统计分析。结果共分离出病原菌1 380株,主要来源于痰液标本。病原菌分布以革兰阴性菌为主,占69.57%,革兰阳性菌和真菌分别占20.07%、10.36%;其中革兰阴性菌以鲍曼不动杆菌、肺炎克雷伯菌为主,革兰阳性菌以溶血葡萄球菌为主;革兰阴性菌对美罗培南、阿米卡星、亚胺培南较为敏感,耐药率均低于30%,对头孢曲松、氨曲南等的耐药率均较高;革兰阳性菌对万古霉素、利奈唑胺、替考拉宁较为敏感,耐药率均低于20%,对氨苄西林、诺氟沙星等耐药率均较高。结论肝移植术后感染病原菌的构成主要是鲍曼不动杆菌、肺炎克雷伯菌和溶血葡萄球菌,临床选择抗菌药物时建议选用病原菌表现较低耐药性的美罗培南、阿米卡星、万古霉素、利奈唑胺等药物。     

MEROPENEM IN THE TREATMENT OF FEBRILE NEUTROPENIC CHILDREN

The aim of this retrospective study was to evaluate the clinical effectiveness of meropenem in immunocompromised children. Between January 1998 and December 2002 in the hemato-oncological units of our hospital meropenem was used in 87 febrile events diagnosed in 55 patients, and 328 bacterial cultures were evaluated. Microorganisms were detected and identified in 64 of the 328 hemocultures; there was a predominance of gram-positive strains (67%). In 49.4% the infection was documented microbiologically. In 16 additional cases the infection was proven clinically and 32.2% of the episodes were considered to be fever of unknown origin. The success rate of the meropenem therapy—excluding the proven fungal or coagulase-negative Staphylococcus infections—was 72.9% and for the whole cohort 49.4%. The results demonstrate that meropenem is effective and well-tolerated when used for the treatment of neutropenic cancer children.     

美罗培南配合免疫球蛋白治疗新生儿败血症的疗效及其对炎症因子的影响

目的?探讨新生儿败血症患儿实施美罗培南配合免疫球蛋白治疗的疗效及炎症水平变化。方法?选取2016年4月—2018年4月海南医学院第二附属医院收治的新生儿败血症患儿100例,以挂号就诊单病案号单、双数为基准,分为研究组和对照组。治疗组采用美罗培南+免疫球蛋白治疗,对照组采用美罗培南治疗,对比两组临床症状改善时间、临床疗效、炎症水平及临床指标。结果?研究组拒奶改善时间、体温改善时间、神经系统症状改善时间、血培养转阴时间及住院时间低于对照组（P?<0.05）,研究组总有效率高于对照组（P?<0.05）,研究组治疗前后白细胞介素-6、白细胞介素-1、高敏感C反应蛋白及肿瘤坏死因子-α的差值高于对照组（P?<0.05）,研究组治疗前后分化抗原3、分化抗原8、免疫球蛋白G及免疫球蛋白M的差值高于对照组（P?<0.05）。结论?新生儿败血症患儿实施美罗培南配合免疫球蛋白治疗的临床疗效显著,可明显改善机体炎症水平,值得借鉴。     

不同条件下CIM试验检测耐碳青霉烯类肠杆菌科细菌的评价

目的评估不同底物、不同孵育时间下碳青霉烯类抑制法(CIM)对肠杆菌科细菌碳青霉烯酶表型筛选能力的差异。方法分别用亚胺培南、美罗培南、厄他培南作为指示底物对120株耐碳青霉烯类肠杆菌科细菌(CRE)进行CIM试验,再以美罗培南为指示底物,分别孵育0.5、1、2、4h进行CIM试验,并采用PCR及测序技术检测菌株是否携带碳青霉烯酶相关基因。结果碳青霉烯酶耐药基因PCR检测结果显示,120株CRE中,阳性93株,阴性27株。以亚胺培南作为底物,阳性95株,阴性25株;以美罗培南作为底物,阳性87株,阴性33株;以厄他培南作为底物,阳性68株,阴性52株。与PCR结果相比,三者的灵敏度分别是98.9%(92/93),90.3%(84/93),69.9%(65/93),差异有统计学意义(χ~2=18.43,P<0.01);三者的特异度均为88.9%(24/27)。3种底物的一致率分别为96.7%,90.0%,74.2%,Kappa值分别是0.90,0.73,0.44。在4个不同孵育时间下,灵敏度分别为46.2%(43/93)、58.1%(54/93)、90.3%(84/93)和90.3%(84/93),孵育2h和0.5、1h结果相比差异有统计学意义(χ~2=27.31,P<0.05)。结论亚胺培南、美罗培南CIM试验灵敏度和一致率均高于厄他培南,可作为合适的底物,同时2h为最佳孵育时间。     

Meta-analysis: combination of meropenem vs ceftazidime and amikacin for empirical treatment of cancer patients with febrile neutropenia

Background:Meropenem monotherapy vs ceftazidime plus amikacin have been approved for use against febrile neutropenia. To assess the effectiveness and safety of them for empirical treatment of cancer patients with febrile neutropenia, we conducted a meta-analysis of randomized controlled trial.Methods:Randomized controlled trials on ceftazidime plus amikacin, or/and monotherapy with meropenem for the treatment of cancer patients with febrile neutropenia were identified by searching Cochrane Library, PubMed, Science Direct, Wiley Online, Science Citation Index, Google (scholar), National Center for Biotechnology Information, and China National Knowledge Infrastructure. Data on interventions, participants’ characteristics and the outcomes of therapy, were extracted for statistical analysis. Seven trials fulfilled the inclusion criteria.Result:The treatment with ceftazidime plus amikacin was more effective than meropenem (OR = 1.17; 95% CI 0.93–1.46; 1270 participants). However, the treatment effects of the 2 therapy methods were almost parallel in adults (OR = 1.15; 95% CI 0.91–1.46; 1130 participants older than 16). Drug-related adverse effects afflicted more patients treated with ceftazidime plus amikacin (OR = 0.78; 95% CI 0.52–1.15; 1445 participants). The common responses were nausea, diarrhea, rash, and increased in serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase and bilirubin.Conclusion:Ceftazidime plus amikacin should be the first choice for empirical treatment of cancer patients with febrile neutropenia, and meropenem may be chosen as a last defense against pathogenic bacteria.     

美罗培南个体化治疗慢性阻塞性肺病并发铜绿假单胞菌感染患者的研究

目的：探讨美罗培南个体化治疗慢性阻塞性肺疾病（COPD）并发铜绿假单胞菌感染患者的效果及安全性。方法将COPD并发铜绿假单胞菌感染的患者分成2组（个体化剂量组、标准剂量组）进行治疗,统计分析美罗培南对2组患者的疗效及安全性。结果个体化剂量组患者的美罗培南平均剂量为每12 h（0．86±0．09）g,低于标准剂量组;个体化剂量组治疗的有效率为81．3％,2组间有效率的差异无统计学意义（P＞0．05）。个体化剂量组患者不良反应的发生率低于标准剂量组（P＜0．05）,标准剂量治疗对肾功能有一定损伤,而个体化剂量能减轻美罗培南对肾功能的损伤。结论美罗培南的个体化给药不仅能在保证疗效的前提下提高治疗的安全性,还能降低对肾功能的损害。