Quantification of Structurally Alert Mutagenic Impurities in Meropenem Trihydrate Drug Substance by Liquid Chromatography with High Resolution Mass Spectrometer (LC-HRMS)

Potential mutagenic impurities in Active Pharmaceutical Ingredient, Meropenem Trihydrate were assessed and a novel analytical method for their quantification was developed and validated. This Liquid Chromatographic method using High Resolution Mass Spectrometer (LC-HRMS) technique is proved to be suitable for simultaneous quantification of all ten identified impurities with required specificity, sensitivity, resolution, precision, accuracy, and other method characteristics as per ICH Guidelines. The acceptable limit of less than 2.9 μg/g was considered for evaluations, based on drug substance dosage and duration of treatment. The method stands most sensitive with a Limit of Detection of 0.35 μg/g, considering the challenge full acceptance criteria as per current regulatory standards.

Meropenem一个新的碳青霉烯类抗生素

美洛培南是一个新的碳青霉烯类抗生素。它对需氧菌及厌氧菌都有很好的杀菌活性，虽然对葡萄球菌属的抗菌活性较弱，但它对绿脓杆菌、肠杆菌属、流感嗜血杆菌及厌氧菌的抗菌活性强。美洛培南对ｇｒｏｕｐ１和ｇｒｏｕｐ２丝氨酸酶及能水解三代头孢菌素的β－内酰胺酶稳定。它对金属酶的稳定性不如亚胺培南，但对碳青霉烯酶Ｓｍｅ－１的稳定性强于亚胺培南，并且对金黄色葡萄球菌、大肠杆菌、绿脓杆菌的青霉素结合蛋白的亲和力强。临床试验结果表明美洛培南用于治疗慢性支气管炎急性恶化、下呼吸道感染、泌尿系感染、腹腔感染、细菌性脑膜炎及败血症是安全有效的。药代动力学研究表明美洛培南能迅速分布于组织间隙产生临床治疗浓度。美洛培南的药物不良反应发生率与对照药相似，常见的为腹泻、皮肤红斑、恶心呕吐、及肝功改变。

Meropenem as an Alternative Antibiotic Agent for Suppression of Agrobacterium in Genetic Transformation of Orchid

A case of Meropenem as a novel antibacterial agent to suppress and eliminate Agrobacterium tumefaciens in the Agrobacterium-mediated transformation of orchid protocorm-like bodies （PLBs） has been reported in this article. The in vitro activities of meropenem and four comparator antibacterial agents against three Agrobacterium tumefaciens strains, LBA4404, EHA101, and GV3101, were assessed. In addition, the effect of meropenem on the growth of Dendrobium phalaenopsis PLBs was determined. Compared with other commonly used antibiotics （including ampicillin, carbenicillin, cefotaxime, and cefoperazone）, meropenem showed the highest activity in suppressing all tested A. tumefaciens strains （minimum inhibitory concentration [MIC] 〈 0.5 mg L^-1, which is equal to minimum bactericidal concentration [MBC]）. Meropenem, at all tested concentrations, except for 10 mg L^-1 concentration, had little negative effect on the growth of orchid tissues. The A. tumefaciens strain EHA101 in genetic transformation with vector plG121Hm in infected PLBs of the orchid was visually undetectable after a two-month subculture in 1/2 MS medium with 50 mg L^-1 meropenem and 25 mg L^-1 hygromacin. The expression and incorporation of the transgenes were confirmed by GUS histochemical assay and PCR analysis. Meropenem may be an alternative antibiotic for the effective suppression of A. tumefaciens in genetic transformation.

Meropenem的临床药物动力学

Meropenem(MRP)是新开发的一种类似亚胺培南(imipenem)的碳青霉烯类抗生素,体外具有广谱抗革兰阳性和阴性菌作用,包括铜绿假单胞菌和厌氧菌。与亚胺培南相比,其优点在于MRP不易被肾脱氢肽酶Ⅰ(DPH-I)水解,比较稳定,因此不必与DHP-I抑制剂(如西司他丁)同用,且其肾及神经毒性较亚胺培南低。本文重点介绍MRP的药物动力学特征及其药物动力学和药效学参数的相关性。

碳青霉烯类抗生素 Meropenem 的开发

碳青霉烯类抗生素的研究,以1976年的硫霉素(Thienamycin)(1)的发现为开端,现在已经过去了15年。硫霉素不仅具有优良的广谱抗菌活性,而且含有前人未曾发现的独特化学结构,从而引起众多研究者的注目,广泛地开展了各方面的研究。迄今已分离得到40多种同一类结构的碳青霉烯类天然化合物。

Possible Factors Involved in Oral Inactivity of Meropenem, a Carbapenem Antibiotic

Meropenem, a carbapenem antibiotic, is inactive after oral administration and administered exclusively by injection. In this study, in order to address the factors involved in the oral inactivity of meropenem, in vitro permeation characteristics across rat ileal segments was investigated using diffusion cells. Moreover, stability of meropenem was evaluated in the Japanese Pharmacopoeia (JP) 1st and 2nd fluid for disintegration test. Cefotaxime, ceftibuten, and faropenem were used for comparison. The permeation of meropenem across rat ileal segments was approximately 5-fold greater in secretory direction than in absorptive direction. The secretory-oriented transport of meropenem markedly diminished by replacement of D-glucose in the experimental medium with unmetabolizing 3-O-methyl-D-glucose, suggesting that the secretory transport of meropenem was an energy-dependent process. Cefotaxime exhibited extensively secretory-oriented permeation. On the other hand, much weaker directionalities were observed in ceftibuten and faropenem. While meropenem as well as other three β-lactam antibiotics was stable in JP 2nd fluid (pH 6.8), it declined rapidly in JP 1st fluid (pH 1.2). These results suggest that, in addition to the hydrophilic property of meropenem, its instability at gastric pH and secretory transport in the small intestine are possible factors involved in the inactivity of meropenem after oral administration.

Meropenem的抗菌活性和药代动力学

Meropenem(SM—7338)系20世纪80年代发展的一种新型广谱碳青霉烯。它与青霉素类在结构上有差别,在噻唑环C—1位上以碳原子取代硫原子,并在C—2和C—3位之间有一不饱和键(附图)。由于C—2位和C—6位上侧链的不同,形成了多种碳青霉烯类化合物。

meropenem

meropenem(SM-7338,MEPM)是注射用极广谱的碳青霉烯类抗生素.由于它与亚胺培南(IPM)碳青霉烯环的取代基结构不同,因而对人肾脱氢肽酶(DHP-1)的灭活作用极其稳定,就不必像用IPM那样必须同时用DHP-1抑制剂西司他丁(CS).

Treatment of Donor-derived Carbapenem-resistant Klebsiella pneumoniae Infection after Renal Transplantation with Tigecycline and Extended-infusion Meropenem

Objective Donor-derived carbapenem-resistant Klebsiella pneumoniae(CRKP)infection has recently emerged as a critical early complication after renal transplantation.Although CRKP is usually sensitive to tigecycline,monotherapy with this drug is often less than effective.We investigated the efficacy of a combined regimen of tigecycline with high-dose,extended-infusion meropenem in the treatment of donor-derived CRKP infection after kidney transplantation.Methods From Jan.2016 to Dec.2017,a total of 12 CRKP isolates were detected from cultures of the organ preservation solution used for soaking the donor kidneys at our institute.Probable or possible donor-derived infection(DDI)was identified in 8 transplant recipients.Clinical data were retrospectively analyzed.Results Klebsiella pneumoniae carbapenemase-2(KPC-2)-producing CRKP was reported to be positive in organ preservation solution cultures at 3.5±0.9 days after transplantation,leading to surgical site(n=3),urinary tract(n=4),and/or bloodstream(n=2)infections in 8 recipients.The drug susceptibility tests showed that CRKP was sensitive to tigecycline,but resistant to meropenem.In 7 patients who received tigecycline combined with high-dose extended-infusion meropenem,DDIs were successfully cured.The length of hospital stay was 31(18–129)days,and the serum creatinine at discharge was 105.8±16.7µmol/L.The one remaining patient who received tigecycline combined with intravenous-drip meropenem died of septic shock.A median follow-up of 43 months(33–55)showed no recurrence of new CRKP infection in the 7 surviving recipients.Conclusion It was suggested that a prompt and appropriate combination therapy using tigecycline with high-dose extended-infusion meropenem is effective in treating donor-derived KPC-2-producing CRKP infection after renal transplantation.

Effect of dobutamine combined with meropenem on serum BNP, IGF-1, IGFBP-3, TNF-a, IL-6 and hs-CRP in children with congenital heart disease and pneumonia

Objective:To study the effect of dobutamine combined with meropenem on serum BNP, IGF-1, IGFBP-3, TNF-a, IL-6 and hs-CRP in children with congenital heart disease and pneumonia.Methods:A total of 70 children with congenital heart disease and pneumonia in our hospital from June 2014 to Octomber 2016 were enrolled in this study. The subjects were divided into the control group (n=35) and the treatment group (n=35) randomly. The control group was treated with dobutamine, the treatment group were treated with dobutamine combined with meropenem. The two groups were treated for 10 days. The serum BNP, IGF-1, IGFBP-3, TNF-a, IL-6 and hs-CRP levels of the two groups before and after treatment were compared.Results: There were no significantly differences of the serum BNP, IGF-1, IGFBP-3, TNF-a, IL-6 and hs-CRP levels of the two groups before treatment. The serum BNP, TNF-a, IL-6 and hs-CRP levels of the two groups after treatment were significantly lower than before treatment, the serum IGF-1 and IGFBP-3 levels of the two groups after treatment were significantly higher than before treatment, and that of the treatment group were significantly better than the control group.Conclusion:Dobutamine combined with meropenem can significantly reduce the serum BNP, TNF-a, IL-6 and hs-CRP levels, improve serum IGF-1 and IGFBP-3 levels of children with congenital heart disease and pneumonia, and it was worthy clinical application.

Meropenem对抗生素耐药菌或不常见革兰氏阴性杆菌的抗菌活性

Meropenem(SM—7338)是一个研究中的碳青霉稀类抗生素,对某些革兰氏阴性杆菌的抗菌活性较Imipenem强,对肾脱氢肽酶比较稳定。在本研究中我们试图评价Me—ropenem、lmipenem及另外几种β—内酰胺、环丙沙星和庆大霉素,对一组抗生素耐药菌及罕见的革兰氏阴性杆菌抗菌活性。本研究以临床分离的病原菌作为实验菌株,因为它们显示对几种β—内酰胺(例如,若干肠杆菌科菌和绿脓杆菌)、氨基糖苷类和喹诺酮类的耐药性。

Meropenem的稳定性和1β-甲基取代对其在肾脱氢肽酶-1存在下稳定性的影响

最近几年,有许多新的β-内酰胺抗生素应用于临床。这些抗生素中包括一些特别有价值的碳青霉烯类。牛链霉菌产生的具有广泛抗菌谱及很强的抗革兰氏阳性菌、阴性菌活性的硫霉素(Thienamycin)的发现,开辟了β-内酰胺抗生素的新纪元。后来又发现了一些碳青霉烯,如橄榄酸、Carpetimycins、Asparenomycins 等等,并对它们中的某些物质进行了化学改造。然而,除 Imipenem(N-亚胺甲基硫霉素)外,还没有一个有效地用于临床。Imipenem 和其它相关的碳青霉烯易被肾脱氢肽酶(DHP-1)所钝化,但与一种特异的 DHP-1抑制剂(Cilastatin 联合给药后克服了 Imipenem 的这种不稳定性。这种联合给药已用于治疗各种感染。住友制药公司与 ICI

Measurement and correlation of solubility of meropenem trihydrate in binary(water＋acetone/tetrahydrofuran) solvent mixtures

The solubility of meropenem trihydrate in water+acetone mixtures and water+tetrahydrofuran mixtures were determined from T=(278.15 to 303.15) K by static method under atmospheric pressure.Effects of solvent composition and temperature on solubility of meropenem trihydrate were discussed.To extend the applicability of the solubility data,experimental solubility data in two kinds of binary solvent mixtures were correlated by the Apelblat equation and NIBS/Redlich–Kister model.It was found that the two models could satisfactorily correlate the experimental data and the Apelblat equation could give better correlation results.

The Triple Combination of Meropenem,Avibactam,and a Metallo-b-Lactamase Inhibitor Optimizes Antibacterial Coverage Against Different b-Lactamase Producers

This work explores the potential of a triple combination of meropenem(MEM),a novel metallo-blactamase(MBL)inhibitor(indole-2-carboxylate 58(InC58)),and a serine-b-lactamase(SBL)inhibitor(avibactam(AVI))for broad-spectrum activity against carbapenemase-producing bacteria.A diverse panel comprising MBL-and SBL-producing strains was used for susceptibility testing of the triple combination using the agar dilution method.The frequency of resistance(FoR)to MEM combined with InC58 was investigated.Mutants were sequenced and tested for cross resistance,fitness,and the stability of the resistance phenotype.Compared with the double combinations of MEM plus an SBL or MBL inhibitor,the triple combination extended the spectrum of activity to most of the isolates bearing SBLs(oxacillinase-48(OXA-48)and Klebsiella pneumoniae carbapenemase-2(KPC-2))and MBLs(New Delhi metallo-blactamases(NDMs)),although it was not effective against Verona integron-encoded metallo-blactamase(VIM)-carrying Pseudomonas aeruginosa(P.aeruginosa)and OXA-23-carrying Acinetobacter baumannii(A.baumannii).The FoR to MEM plus InC58 ranged from 2.22×10^(-7)to 1.13×10^(-6).The resistance correlated with mutations to ompC and comR,affecting porin C and copper permeability,respectively.The mutants manifested a fitness cost,a decreased level of resistance during passage without antibiotic pressure,and cross resistance to another carbapenem(imipenem)and a b-lactamase inhibitor(taniborbactam).In conclusion,compared with the dual combinations,the triple combination of MEM with InC58 and AVI showed a much wider spectrum of activity against different carbapenemaseproducing bacteria,revealing a new strategy to combat b-lactamase-mediated antimicrobial resistance.

产KPC肺炎克雷伯菌感染治疗的研究进展

近年来全国耐碳青霉烯类肺炎克雷伯菌(CRKP)分离率逐年上升,且由于其多重耐药、病死率高的特点,给临床治疗带来了严峻挑战。CRKP耐药最主要机制为产碳青霉烯酶,在CRKP中常见的碳青霉烯酶类型为Ambler A、B、D类,C类少见。碳青霉烯酶中最常见的是肺炎克雷伯菌碳青霉烯酶(KPC),属于A类。产KPC肺炎克雷伯菌(KPC-KP)在全球范围内广泛扩散,临床有效治疗药物非常有限。本文就KPC-KP感染治疗的研究进展进行总结,以期为临床治疗提供借鉴意义。

亚抑菌浓度美罗培南对多重耐药鲍曼不动杆菌生物膜作用的研究

目的:探讨亚抑菌浓度美罗培南对多重耐药鲍曼不动杆菌(MDR-Ab)生物膜作用的影响。方法:采用微量肉汤稀释法测定某三甲医院从临床血液标本中分离的6株碳青霉烯类耐药的多重耐药鲍曼不动杆菌(MDR-AB)对美罗培南的最低抑菌浓度(MIC),结晶紫半定量法测定菌株生物膜形成能力。A组实验用96孔聚苯乙烯板体外构建MDR-AB生物膜的模型,用亚抑菌浓度美罗培南作用于成熟生物膜;B组实验用96孔聚苯乙烯板将MDR-AB浮游菌液与亚抑菌浓度美罗培南共培养。通过结晶紫半定量染色法对生物膜进行染色,再用多功能酶标仪测生物膜在560 nm波长处的OD值。结果:A组a、b、c中所形成生物膜OD值与对照组d组比较,48 h结果有统计学意义(P<0.05),而96h无统计学意义(P>0.05);B组X、Y、Z的生物膜形成过程中,48 h和96 h后OD值与对照组W有统计学意义(P<0.05)。结论:MDR-Ab有形成生物膜的能力;亚抑菌浓度美罗培南具有破坏成熟生物膜的能力,且其破坏能力随着浓度的升高而增强;1/2 MIC、MIC浓度的美罗培南可能抑制MDR-Ab生物膜形成,而1/4 MIC浓度的美罗培南则可能诱导MDR-Ab生物膜形成。

美罗培南联合莫西沙星治疗慢性阻塞性肺疾病合并重症肺炎的疗效及对血清炎症因子水平的影响

目的探讨美罗培南联合莫西沙星治疗慢性阻塞性肺疾病(COPD)合并重症肺炎的疗效及对血清炎症因子水平的影响。方法选取2017年10月至2019年12月于武警北京市总队医院治疗的90例COPD合并重症肺炎患者作为研究对象,按照自愿原则分为A组与B组,每组45例。A组给予美罗培南联合莫西沙星治疗,B组给予莫西沙星治疗。比较两组最大呼气中段量(MMF)、最大通气量(MVV)和第1秒用力呼气容积占预计值百分比(FEV1%)、白细胞介素-8(IL-8)、肿瘤坏死因子-α(TNF-α)、转化生长因子-β_(1)(TGF-β_(1))、降钙素原(PCT)水平及临床疗效、不良反应发生情况。结果治疗后,两组MMF、MVV均大于治疗前,FEV1%均高于治疗前,且A组MMF、MVV均大于B组,FEV_(1)%高于B组,差异有统计学意义(P<0.05)。治疗后,两组血清IL-8、TNF-α、TGF-β_(1)及PCT水平均低于治疗前,且A组低于B组,差异有统计学意义(P<0.05)。A组治疗总有效率为95.56%,高于B组的82.22%,差异有统计学意义(P<0.05)。A组并发症发生率为8.89%,低于B组的24.44%,差异有统计学意义(P<0.05)。结论美罗培南联合莫西沙星治疗COPD合并重症肺炎临床疗效显著,可显著降低患者炎症因子水平,改善肺功能,降低不良反应发生率。

双歧杆菌三联活菌散联合美罗培南治疗新生儿坏死性小肠结肠炎的效果

目的:观察双歧杆菌三联活菌散联合美罗培南治疗新生儿坏死性小肠结肠炎(NEC)的效果。方法:选取2020年10月至2022年11月该院收治的116例NEC患儿进行前瞻性研究,按照随机数字表法将其分为研究组与对照组各58例。对照组采用美罗培南治疗,研究组在对照组基础上联合双歧杆菌三联活菌散治疗,比较两组临床疗效、临床症状改善时间,治疗前后炎性因子[C反应蛋白(CRP)、降钙素原(PCT)、白细胞介素-10(IL-10)]水平、肠道菌群分布指标水平,以及不良反应发生率。结果:研究组治疗总有效率为89.66%(52/58),高于对照组的75.86%(44/58),差异有统计学意义(P<0.05);研究组呕吐缓解时间、腹胀缓解时间、大便性状和次数恢复正常时间均短于对照组,差异有统计学意义(P<0.05);治疗后,两组CRP、PCT、IL-10水平均低于治疗前,且研究组低于对照组,差异有统计学意义(P<0.05);两组杆菌总数、球菌总数、球杆菌比值均高于治疗前,且研究组高于对照组,差异有统计学意义(P<0.05);两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论:双歧杆菌三联活菌散联合美罗培南治疗NEC可提高治疗总有效率,缩短临床症状改善时间,改善肠道菌群分布指标水平,降低炎性因子水平,其效果优于单纯美罗培南治疗。

美罗培南治疗新生儿脓毒症的临床实践指南(2024年版)

美罗培南是新生儿脓毒症治疗中使用最为广泛的特殊级别抗菌药物之一,但其不合理应用导致细菌多重耐药问题日益严峻。该指南遵循规范的制订方法与流程,针对9个临床问题形成了12条推荐意见,内容涵盖新生儿美罗培南的使用时机、推荐剂量、延长输注、监测与评估、抗菌药物调整方案、治疗疗程以及碳青霉烯耐药肠杆菌目细菌感染的治疗策略,以期为美罗培南在新生儿脓毒症患儿中的合理使用提供循证证据与用药建议。