Mechanism of imipenem-induced mental disorder: A meta-analysis

BACKGROUND Imipenem is a highly effective carbapenem antibiotic,which is widely used in the treatment of many serious bacterial infections.At the same time,it can also cause some adverse reactions,mental abnormalities are the most concerned central nervous system adverse reactions.Different patients respond differently to imipenem,and the effect of imipenem on psychiatric disorders is unclear.Therefore,meta-analysis summarizing the results of multiple previous studies can provide stronger evidence support for clinical guidelines to guide clinical rational use of imipenem to minimize risks.After reviewing the literature published between 2003 and 2017,seven controlled trials with a total of 550 patients were included,with 273 and 277 patients in the control and experimental groups,respectively.The sample size of the study ranged from a minimum of 30 cases to a maximum of 61 cases.Patients in the experimental group were treated with imipenem while the control group was treated with conventional drugs.Meta-analysis showed that the incidence of mental disorders in the experimental group was higher than that in the control group(odds ratio=3.66,95%confidence interval:1.11-12.11,P=0.030);however,there was no significant difference in the incidence of adverse reactions between the two groups(odds ratio=0.05,95%confidence interval:0.00 to 0.10,P=0.060).Funnel diagrams showed that the scattered points of each study were symmetrical and distributed in an inverted funnel shape;therefore,there was no publication bias.CONCLUSION Imipenem can cause mental disorders in patients.However,the low quality of the included literature may have affected the final results.Therefore,it is necessary to conduct a high-quality randomized controlled study with multiple samples to further confirm the mechanism of imipenem-induced mental disorders and provide effective guidance for clinical treatment.

Imipenem/cilastatin-induced acute eosinophilic pneumonia:A case report

Rationale:Acute eosinophilic pneumonia(AEP)is an acute pulmonary illness caused by eosinophilic infiltration of the lung parenchyma.It can happen after using drugs such as daptomycin and minocycline.AEP induced by imipenem/cilastatin is a rare condition.Patient’s Concern:A 45-year-old male patient,who previously suffered from a urinary tract infection and treated with imipenem/cilastatin antibiotic,was presented to us with acute respiratory distress,soon after the initiation of the antibiotic.Computed tomography identified pulmonary infiltrates in the upper and middle lung fields and eosinophils were found to account for 36%of differential count of the broncho-alveolar lavage fluid.He also developed peripheral eosinophilia as the disease progressed.Diagnosis:AEP,secondary to imipenem/cilastatin therapy.Interventions:Steroid therapy was administered and imipenem/cilastatin antibiotic was discontinued.Outcomes:The patient improved completely following the therapy and had clear lung fields on follow-up.Lessons:Imipenem/cilastatin is an uncommon cause of AEP and requires close monitoring during therapy.

高效超广谱抗菌新药Imipenem

Imipenem(IPM)系硫霉素第一个高效衍生物,是新型的β-内酰胺类超广谱抗生素,对临床几乎所有重要致病菌均具有强大抗菌作用,对酶高度稳定,与其它抗菌药几乎无交叉耐药性,具有持续的抗生素后效作用(PAE),且体内分布广、不良反应少。IPM在体内经近端肾小管细胞刷状缘的去氢肽酶Ⅰ代谢灭活,其分解产物对某些动物肾小管有一定毒性反应。临床上将本品与肾去氢肽酶Ⅰ抑制剂Cilastatin按1∶1制成复方制剂(Primaxin或Tienam)应用,可阻断本品在肾脏的代谢和增加泌尿道中原型浓度,并消除其单用可能生产的肾毒性。IPM/Cilastatin在临床上经验治疗各种严重的多重耐药菌感染、多种细菌(需氧菌和厌氧菌)

Imipenem与其他15种抗菌药物对厌氧菌的体外抗菌活性比较

本文报道Imipenem对93株各类厌氧菌的体外抗菌活性并与甲硝唑等15种抗菌药物的体外抗厌氧菌活性比较。结果示Imipenem对包括脆弱类杆菌在内的所有受试厌氧菌均具有强大的抗菌活性,远较其他6种受试的β-内酰胺抗生素强,对所有厌氧菌的抗菌活性等于或超过甲硝唑并优于克林霉素。测试的93株厌氧菌中无Imipenem耐药株。由于Imipenem对需氧菌亦具甚强的抗菌活性,因此在治疗严重需氧菌和厌氧菌混合感染时,Imipenem是一个很有用的抗菌药物。

Organic anion transporters also mediate the drug–drug interaction between imipenem and cilastatin

This study aimed to clarify that organic anion transporters(OATs)mediate the drug–drug interaction(DDI)between imipenem and cilastatin.After co-administration with imipenem,the plasma concentrations and the plasma concentration-time curve(AUC)of cilastatin were significantly increased,while renal clearance and cumulative urinary excretion of cilastatin were decreased.At the same time,imipenem significantly inhibited the uptake of cilastatin in rat kidney slices and in human OAT1(hOAT1)-HEK293 and human OAT3(hOAT3)-HEK293 cells.Probenecid,p-aminohippurate,and benzylpenicillin inhibited the uptake of imipenem and cilastatin in rat kidney slices and in hOAT1-and hOAT3-HEK 293 cells,respectively.The uptakes of imipenem and cilastatin in hOAT1-and hOAT3-HEK 293 cells were significantly higher than that in mock-HEK-293 cells.Moreover,the K m values of cilastatin were increased in the presence of imipenem with unchanged V max,indicating that imipenem inhibited the uptake of cilastatin in a competitive manner.When imipenem and cilastatin were co-administered,the level of imipenem was higher compared with imipenem alone both in vivo and in vitro.But,cilastatin significantly inhibited the uptake of imipenem when dehydropeptidase-1(DPEP1)was silenced by RNAi technology in hOAT1-and hOAT3-HEK 293 cells.In conclusion,imipenem and cilastatin are the substrates of OAT1 and OAT3.OAT1 and OAT3 mediate the DDI between imipenem and cilastatin.Meanwhile,cilastatin also reduces the hydrolysis of imipenem by inhibiting the uptake of imipenem mediated by OAT1 and OAT3 in the kidney as a complement.

ROLE OF OUTER MEMBRANE PROTEINS IN IMIPENEM DIFFUSION IN PSEUDOMONAS AERUGINOSA

The present study identified the properties of porins in the outer membrane in Pseudomonas aeruginosa,and showed the role of outer membrane in determining imipenem diffusion in Pseudomonas aeruginosa The molecular weight of the major outer membrane protein was analyzed by SDS PAGE The purification of the porins in Pseudomonas aeruginosa was achieved by DEAE ion exchange HPLC The purified outer membrane proteins were reconstituted with phosphatidylcholine and dicetylphosphate into membrane vesicles, and were tested by the liposomes swelling method for the diffusion of imipenem The permeability assay showed that OprC (70 kD), OprD 2 (46kD), and OprE(43 kD) were the channel forming proteins But only OprD 2 was thought to be the likely route of imipenem diffusion

耐Imipenem的绿脓杆菌

Imipenem 是第一个碳青霉烯抗生素,具有包括大部分绿脓杆菌在内的异常广谱活性。不幸之处在于本品对绿脓杆菌感染的临床应用,因分离出的耐药绿脓杆菌接近20%而复杂化。此耐药性导致约半数绿脓杆菌感染的治疗失败。此耐药性最重要的微生物学特点是对其它β-内酰胺类没有交叉耐药性。这与面对用头孢菌素类或青霉素类治疗,产生耐药性时所发现的广谱耐药性适成对照。我们研究了绿脓杆菌临床分离菌的 Imipenem 选择耐药性,并特别提到耐药分离菌特有的47kD外膜蛋白(OMP)的缺失。这些资料不只为其它研究者进一步证实。接着研究了我们所做的碳青霉烯类经由一种独有而特殊的孔蛋白,透过绿脓杆菌外膜的假说。本文描述通过通透性试验。

Evaluation of the Synergistic Effect of EDTA-Functionalized Chitosan Nanoparticles on Imipenem Delivery in Pseudomonas aeruginosa Carbapenem-Resistant Strain AG1

Metallo-β-lactamases are bacterial zinc-dependent enzymes involved in the hydrolysis of β-lactamic antibiotics representing the main cause of bacterial resistance to carbapenems, drugs of last resort for treating infections caused by multiresistant bacteria. We elaborated the hypothesis that it is possible to inhibit the enzymatic activity of metallo-β-lactamases by lowering the availability of zinc in the extracellular medium using metal chelating agents such as EDTA carried on nanoparticles. Chitosan, as linear cationic polysaccharide is frequently used in biomedical and pharmaceutical applications, has been studied as a biocompatible encapsulating agent in drug delivery systems and is an ideal transport agent for bioactive molecular complexes in antibiotic applications due to its ability to associate with negatively charged substances. We developed novel nanoparticles using chitosan as a transport matrix for β-lactamic antibiotics. Nanoparticles were synthesized according to the ion gelation method using tripolyphosphate as crosslinking agent. Nanoparticles were functionalized by the adsorption of EDTA, which acts as complexifying agent for Zn2+ ions causing inhibition of metallo-β-lactamases activity. We evaluate the antimicrobial effects of EDTA-functionalized nanoparticles with an imipenem cargo on the clinical isolate P. aeruginosa AG1, a carbapenem-resistant high-risk clone ST-111 carrying both blaIMP-18 and blaVIM-2 metallo-β-lactamases genes.

静脉注射用Primaxin亚胺硫霉素(imipenem)——脱氢肽酶抑制剂(cilastatin)钠盐

致爱好医学翻译的朋友们:想辟这个专栏,为时已久,原因是许多读者不断地向我们提出了此项建议。我们辟此新栏有两个目的:让爱好医学英译汉的朋友们有一个相互交流和彼此学习的园地;让所有的读者从译文中获得新的医药新知。请广大译者本着这两个目的,向我们提供英汉对照的稿件。谢谢! ·编者·

Detection of the Relationship between Imipenem Susceptible and Non-Susceptible Clinical Isolates of Acinetobacter Baumannii by Repetitive Element PCR-Mediated DNA Fingerprinting in an Egyptian Hospital

In this work, the authors aimed to detect the clonal relatedness of the isolated imipenem-susceptible and non-susceptible Acenitobacter baumanii. This study was conducted from September 2008 through August 2009 in Aboelreech-Elmounira paediatric-Cairo University-teaching hospital in Egypt. All the isolated acenitobacter species were identified by standard laboratory procedures. The clonal relationship of the A. baumanii （the most common detected clinical type） was studied by biotyping and AST and then confirmed using rep-PCR with primers aimed at repetitive extragenic palindromic sequences and enterobacterial repetitive intergenic consensus sequences. A total of 100 A. baumanii isolates out of 104 acenitobacter species were recovered from different clinical samples. Sixty two percent of the isolates were resistant to imipenem. The resulting rep-PCR patterns oftheA, baumanii strains revealed 8 clones, 3 clones found in the imipenem resistant group, and 5 clones in imipenem sensitive group with statistically significant clonal distribution in both groups （P-value 0.00）. Clonality was proved in imipenem resistant group with an alarming predominance of clone 1 representing 80.6% of IMP-R isolates. In accordance the prevalence of resistant acenitobacter strains seems to be correlated with inappropriate antibiotic use. These results call for strict compliance of coordinated strategy of infection control measures and judicious use of antimicrobials which is likely to effectively deal with this serious public health issue.

Characterization of Imipenem Unsusceptible Pseudomonas Aeruginosa Isolates from Inpatients without Carbapenem Treatment

Objective To identify the risk factors for imipenem resistance development and transmission of clinical Pseudomonas aeruginosa isolates.Methods Thirty-seven imipenem unsusceptible Pseudomonas aeruginosa isolates collected from patients in absence of carbapenem treatment were characterized by antimicrobial susceptibility test,pulsed field gel electrophoresis(PFGE)and carbapenem resistant mechanism analysis.Results Before the collection of imipenem unsusceptible Pseudomonas aeruginosa isolates,the average time of patients treated with more than one antimicrobial(20.0±9.5 days,n=16)was significantly longer than those treated with only one antimicrobial(12.6±4.4 days,n=21;t-test,Welch,t=-2.9004,P<0.01).And 32 isolates showed resistance to more than 3 classes of antimicrobials.Six PFGE clusters were identified and 26 isolates were grouped into one dominant cluster(C2).An ISpa1328 sequence insertion in oprD was detected in 33 isolates and the function of efflux was observed in all 37 isolates in the presence of a wide spectrum efflux inhibitor.Conclusions Our data demonstrated that exposure to non-carbapenem drug classes,especially fluoroquinolones andβ-lactams,may be important risk factors for the spread of carbapenem resistant Pseudomonas aeruginosa.

治疗VAP doripenem可能优于imipenem

发表在美国胸科医师学会2008年度会议上的一份成本-效益分析显示，凭经验使用doripenem治疗绿脓假单胞菌呼吸机相关性肺炎（VAP）可能优于用亚胺培南（imipenem）。

注射用亚胺培南西司他丁钠质量分析

目的 对国内市场中不同企业的注射用亚胺培南西司他丁钠的质量状况进行评价,发现质量风险点,为仿制药一致性评价提供质量控制关键点。方法 采用法定检验结合探索性研究的方法对样品进行检验,统计分析注射用亚胺培南西司他丁钠的整体质量水平,分析不同企业产品的差异。结果 按法定标准检验,80批次抽验样品结果均符合规定。但发现原研产品的复溶时间更快;不同企业的产品有关物质和含量结果差异较大;现行质量标准差异较大亟待提高统一。探索性研究表明,样品复溶时间与制剂中亚胺培南晶癖及粒度相关;采用LC/MS等方法对本品有关物质的来源进行了归属,对部分杂质结构进行了推断;对本品的含量测定方法进行了优化。结论 国内市场中注射用亚胺培南西司他丁钠的质量总体较好;在开展仿制药一致性评价工作中,需关注亚胺培南的晶癖以及制剂的有关物质、含量、充氮工艺和异亚丙基丙酮等质量关键点;现行标准有待统一和提高。

A randomized,controlled clinical trial on meropenem versus imipenem/cilastatin for the treatment of bacterial infections

Objective To evaluate the efficacy and safety of meropenem in Chinese patients, we conducted a study for the treatment of patients with lower respiratory tract infections, urinary tract infections and other infections Methods A total of 182 hospitalized patients were enrolled in the study 90 patients received 500 mg meropenem every 12 hours (or 1 g every 12 hours if necessary) and 92 patients received imipenem/cilastatin 500 mg/500 mg every 12 hours (or 1 g every 12 hours if necessary) by intravenous infusion The duration of treatment was 7-14 days for both groups Results Seventy of 90 cases receiving meropenem and 70 of 92 cases receiving imipenem/cilastatin were assessable for clinical efficacy The overall efficacy rates were 90% for the meropenem group and 87% for the imipenem/cilastatin group, and the bacterial eradication rates were 86% in both groups 93 (76%) of 123 strains isolated from patients produced β lactamases Adverse drug reactions were evaluated in 72 cases in the meropenem group and 70 cases in the imipenem/cilastatin group The adverse drug reaction rates were 9 7% and 8 6%, respectively The results showed that there were no statistical differences between these two groups ( P >0 05) Conclusion Meropenem is effective and safe for the treatment of bacterial infections caused mainly by beta lactamase producing strains

重症感染患者亚胺培南检测方法的建立及临床应用

目的建立适用于检测重症感染患者亚胺培南血药浓度的二维液相色谱法,并应用于临床。方法基于全自动二维液相色谱仪建立亚胺培南血药浓度检测方法,以一维色谱柱Aston SNCB(50 mm×4.6 mm,5μm)萃取分离目标物,再经二维色谱柱Aston SCB(250 mm×4.6 mm,5μm)进一步分离测定。一维流动相为亚胺培南-1D移动相[乙腈-甲醇-水(15∶10∶75,V/V/V)],流速为1.0 mL/min;二维流动相为72%OPI-1有机移动相(色谱级甲醇)-20%BPI-1碱性移动相[水(含20.0 mmol/L的磷酸铵,用三乙胺调pH至7.2)]-8%API-1酸性移动相[水(含20.0 mmol/L的磷酸铵,用磷酸调pH至3.0)],流速为1.0 mL/min;柱温为40℃,紫外检测波长为310 nm,进样量为100μL。洗脱程序:0~3.40 min,一维色谱柱(亚胺培南-1D移动相);3.40~11.00 min,二维色谱柱(72%OPI-1有机移动相-20%BPI-1碱性移动相-8%API-1酸性移动相)。结果亚胺培南检测质量浓度的线性范围为0.171~18.570μg/mL(R^(2)=0.9999),定量下限为0.171μg/mL;回收率在93.47%~106.16%(n=5),日内和日间精密度的RSD均低于15%(n=5)。51例患者的亚胺培南谷浓度为0~19.57μg/mL。结论所建立的方法前处理简单、快捷,进样量大,可用于重症感染患者亚胺培南血药浓度的检测。

基于蒙特卡罗模拟优化亚胺培南-西司他丁钠的给药方案研究

目的应用蒙特卡罗模拟亚胺培南-西司他丁钠不同输注方法针对不同致病菌的最佳给药方案。方法回顾性分析某三甲医院2021年常见革兰阴性杆菌分布情况,按照2020年美国临床实验室标准化协会标准,对肺炎克雷伯菌、大肠埃希菌、铜绿假单胞菌和鲍曼不动杆菌设定均匀分布的抑菌浓度(MIC)值,确定亚胺培南-西司他丁钠8种给药方案,运用PK/PD模型进行蒙特卡罗模拟10000例患者的目标获得概率(PTA),获得最佳给药方案。结果若MIC≤2μg·mL^(-1)时,除传统输注法0.5 g q8h与1 g q8h的给药方案PTA<90%,其余给药方案PTA均>90%;当MIC≥4μg·mL^(-1)时,采用持续输注的部分给药方式仍获得较好的抗菌效果(PTA>90%),而传统输注达不到理想的抗菌疗效(PTA<90%)。结论对亚胺培南-西司他丁钠敏感的革兰阴性杆菌,采用q6h的给药方案,传统输注与持续输注都能取得理想的治疗效果,而采用q8h的给药方案,持续输注法抗菌疗效效果佳效;对亚胺培南-西司他丁钠产生耐药的革兰阴性杆菌,需采用持续输注法才能获得理想的抗菌疗效。

亚胺培南西司他丁钠联合乌司他丁和持续血液滤过治疗重症胰腺炎并脓毒症休克的效果

目的:分析亚胺培南西司他丁钠联合乌司他丁和持续血液滤过对重症胰腺炎并脓毒症休克心肌酶谱的影响。方法:选取2017年1月1日—2022年6月30日厦门市第三医院ICU收治的重症胰腺炎并脓毒症休克96例,按照随机数字表法分为研究组(48例)和对照组(48例),对照组使用乌司他丁和持续血液滤过进行治疗,研究组则在对照组治疗基础上联用亚胺培南西司他丁钠,比较两组临床疗效。结果:研究组抢救成功率、转化生长因子-β(TGF-β)、平均动脉压(MAP)均高于对照组,且淀粉酶(AMS)、谷丙转氨酶(ALT)、肌酸激酶同工酶(CK-MB)、肌酸激酶(CK)、降钙素原(PCT)、C反应蛋白(CRP)、白细胞计数(WBC)水平均低于对照组,差异均有统计学意义(P<0.05)。结论:亚胺培南西司他丁钠联合乌司他丁和持续血液滤过治疗重症胰腺炎并脓毒症休克效果显著,能够有效提高患者抢救成功率,稳定血流动力学和心肌酶谱,同时改善其免疫功能。

肾功能亢进患者血浆中亚胺培南浓度UPLC-MS/MS测定方法的建立及药代动力学研究

目的建立了测定肾功能亢进(ARC)患者血浆中亚胺培南(IMP)浓度的超高效液相色谱-串联质谱(UPLC-MS/MS)方法,并研究IMP在ARC患者体内的药代动力学特征。方法血浆样品用乙腈沉淀蛋白处理,以阿莫西林为内标,采用UPLC-MS/MS法分析。筛选IMP的给药方案为1 g,静脉滴注,每隔8 h的ARC患者,收集不同时间点的血药浓度,计算药代动力学参数。结果IMP在0.40~200.00μg/mL范围内线性良好,精密度、准确度、基质效应、方法回收率和稳定性均符合要求。IMP在ARC患者体内的半衰期为(0.97±0.06)h,血药浓度-时间曲线下面积(AUC)为(48.49±14.93)mg/(L·h),表观分布容积为(16.15±7.90)L,肌酐清除率为(18.30±5.70)L/h,达峰浓度为(15.63±4.60)μg/mL。结论UPLC-MS/MS法准确度高、灵敏度强,可有效用于测定ARC患者血浆中IMP浓度。ARC患者体内IMP的代谢速率和清除率可能发生变化,为临床用药提供重要参考。

两种联合用药方案治疗耐碳青霉烯类鲍曼不动杆菌肺炎的效果及对炎症反应的影响

目的:探讨头孢哌酮舒巴坦分别联合莫西沙星、亚胺培南西司他丁治疗耐碳青霉烯类鲍曼不动杆菌(CRAB)肺炎的效果及对炎症反应的影响。方法:回顾性分析2022年1月至2023年6月于该院治疗的80例CRAB肺炎患者的资料,将2022年1—9月以方便抽样法抽取的40例患者设为A组,采用头孢哌酮舒巴坦联合莫西沙星治疗;将2022年10月至2023年6月以方便抽样法抽取的40例患者设为B组,采用头孢哌酮舒巴坦联合亚胺培南西司他丁治疗。比较两组患者的疗效、细菌清除效果、各项指标恢复时间、血清炎症指标及药品不良反应(ADR)发生情况。结果:B组患者的总有效率、细菌清除率分别为95.00%(38/40)、90.00%(36/40),明显高于A组的80.00%(32/40)、72.50%(29/40),差异均有统计学意义(P<0.05)。B组患者胸部CT恢复正常时间、退热时间和白细胞计数恢复正常时间短于A组,差异均有统计学意义(P<0.05)。治疗2周后,两组患者血清肿瘤坏死因子α(TNF-α)、降钙素原(PCT)及白细胞介素6(IL-6)水平低于治疗前,且B组患者TNF-α、PCT及IL-6水平低于A组,差异均有统计学意义(P<0.05)。B组患者ADR总发生率为12.50%(5/40),与A组的17.50%(7/40)比较,差异无统计学意义(P>0.05)。结论:头孢哌酮舒巴坦联合亚胺培南西司他丁治疗CRAB肺炎的效果优于头孢哌酮舒巴坦联合莫西沙星,可有效改善患者炎症状况,明显提高细菌清除效果,显著缩短体温、白细胞计数等指标恢复时间,且ADR较少。

两种抗感染药物治疗重症肺炎的效果及炎症因子水平预后比较

目的:探究哌拉西林钠他唑巴坦与亚胺培南西司他丁钠治疗重症肺炎的效果及对炎症因子水平、预后的影响。方法:选取2020年1月至2023年3月我院收治的105例重症肺炎患者,用随机数字表法分为A组(n=53)和B组(n=52),A组用亚胺培南西司他丁钠治疗,B组用哌拉西林钠他唑巴坦钠治疗。比较两组患者临床症状消失时间(咳嗽、肺阴影、肺啰音、体温恢复时间),比较治疗前和治疗7d后,两组患者严重程度[肺部感染量表(CPIS)、急性生理学及慢性健康状况(APACHEⅡ)、Murray肺损伤量表(MLIS)]、血气指标[氧饱和度(SpO_(2))、血氧分压(PaO_(2))、二氧化碳分压(PaCO_(2))]及炎症因子[白细胞总数(WBC)、C-反应蛋白(CRP)、降钙素原(PCT)]水平,统计不良反应发生情况。结果:B组咳嗽、肺阴影、肺啰音消失时间及体温恢复时间均短于A组(P均<0.05);治疗7d后,两组患者CPIS、APACHEⅡ、MLIS评分、PaCO_(2)、炎症因子(WBC、CRP、PCT)水平均显著降低,B组水平变化大于A组(P均<0.05);部分血气指标(SpO_(2)、PaO_(2))水平显著升高,B组水平变化大于A组(P均<0.05);两组患者不良反应发生率无显著性差异(P>0.05)。结论:哌拉西林钠他唑巴坦钠与亚胺培南西司他丁钠均可减轻重症肺炎患者病情及临床症状,改善血气状况,缓解炎症反应,但哌拉西林钠他唑巴坦钠效果更佳。