Rifamycins

利福霉素
  • 文章类型: Journal Article
    结核性脑膜炎(TBM)死亡率高,可能是由于治疗欠佳.开发更有效的治疗方案需要中枢神经系统(CNS)中抗结核药的药物暴露数据。利福布汀是利福霉素,在人肺结核中与利福平等效。这里,我们表明,在兔TBM模型中,人体等效剂量的利福布汀在相关CNS组织中实现了潜在的治疗性暴露,支持临床试验的进一步评估。
    Tuberculous meningitis (TBM) has a high mortality, possibly due to suboptimal therapy. Drug exposure data of antituberculosis agents in the central nervous system (CNS) are required to develop more effective regimens. Rifabutin is a rifamycin equivalently potent to rifampin in human pulmonary tuberculosis. Here, we show that human-equivalent doses of rifabutin achieved potentially therapeutic exposure in relevant CNS tissues in a rabbit model of TBM, supporting further evaluation in clinical trials.
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  • 文章类型: Letter
    暂无摘要。
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  • 文章类型: Journal Article
    背景:血管扩张和细菌脱位是失代偿期肝硬化(DLC)患者灾难性事件的主要原因。
    目的:本研究的目的是评估添加米多君和利福昔明对发病率的影响,死亡率,和DLC患者的生活质量。
    方法:这项介入临床研究包括100名连续入选的DLC患者,按1:1随机分为两组。A组接受口服米多君(5mg/8h)和利福昔明(550mg/12h)以及标准利尿剂治疗,而B组仅接受标准利尿剂治疗。临床和实验室数据,包括麦吉尔生活质量问卷,在3个月的治疗期内进行评估。
    结果:在研究组中,Child-Pugh和终末期肝病模型评分显着降低,国际标准化比率,2、6、12周平均动脉压(P<0.05)。腹水,自发性细菌性腹膜炎发病率,呕血,需要穿刺术,12周后肝性脑病较对照组改善。McGill生活质量问卷在术后6周和12周明显改善(P<0.05)。生存率显着改善(P=0.014),在单变量和多元回归分析中都有证据证实。
    结论:米多君联合利福昔明代表了对DLC患者的禀赋,在合成肝功能方面有惊人的改善,随着生活质量的提高,和生存。
    BACKGROUND: Vasodilatation and bacterial dislocation are the main contributors to the catastrophic events in patients with decompensated liver cirrhosis (DLC).
    OBJECTIVE: The aim of this study was to evaluate the impacts of adding midodrine and rifaximin on morbidity, mortality, and quality of life in patients with DLC.
    METHODS: This interventional clinical study included 100 consecutively enrolled DLC patients randomized 1 : 1 into two groups. Group A received oral midodrine (5 mg/8 h) and rifaximin (550 mg/12 h) with standard diuretic therapy, while group B received only standard diuretic therapy. Clinical and laboratory data, including the McGill Quality of Life Questionnaire, were evaluated over a 3-month treatment period.
    RESULTS: In the study group, there was a significant reduction in Child-Pugh and Model for End-Stage Liver Disease scores, international normalized ratio, and mean arterial blood pressure at 2, 6, and 12 weeks (P < 0.05). Ascites, spontaneous bacterial peritonitis incidence, hematemesis, paracentesis need, and hepatic encephalopathy showed improvement after 12 weeks compared with the control group. McGill Quality of Life Questionnaire significantly improved after 6 and 12 weeks (P < 0.05). Survival rates demonstrated a noteworthy improvement (P = 0.014), substantiated by evidence in both univariate and multivariate regression analyses.
    CONCLUSIONS: Combined midodrine with rifaximin represents an endowment to patients with DLC with spectacular improvements in synthetic liver functions, along with improved quality of life, and survival.
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  • 文章类型: Journal Article
    背景:耐多药或利福霉素的结核病(MDR/RR-TB)是重要的公共卫生问题,包括在艾滋病毒高流行的环境中。在一线TB治疗期间,TB耐药性可以直接传播或通过耐药性获得而产生。有限的证据表明,艾滋病毒感染者(PLHIV)可能会增加获得性利福霉素耐药性(ARR)的风险。
    方法:为了评估一线结核病治疗期间HIV作为ARR的危险因素,我们进行了系统评价和荟萃分析.ARR定义为治疗开始时的利福霉素敏感性,治疗期间或治疗结束时诊断为利福霉素耐药。或复发。PubMed/MEDLINE,CINAHL,科克伦图书馆,从成立到2024年5月23日,搜索了GoogleScholar数据库中的英文文章;从2004年到2021年还搜索了会议摘要。Mantel-Haenszel随机效应模型用于估计接受一线结核病治疗的个体中HIV和ARR之间任何关联的合并比值比。
    结果:确定了包含1990年至2014年收集的数据的10项研究:5项来自美国,两个来自南非,一个来自乌干达,印度和摩尔多瓦。所有研究共纳入97,564人,13,359(13.7%)感染艾滋病毒。总的来说,312(0.32%)获得利福霉素抗性,其中115人(36.9%)为PLHIV。与接受一线结核病治疗的HIV阴性个体相比,PLHIV的ARR加权几率为4.57(95%CI,2.01-10.42)倍。
    结论:现有数据,提示PLHIV在一线TB治疗期间有增加的ARR风险.需要进一步的研究来澄清具体的风险因素,包括晚期HIV疾病和结核病的严重程度。鉴于较短的引入,4个月利福霉素为基础的方案,迫切需要更多关于ARR的数据,特别是PLHIV。
    背景:PROSPEROCRD42022327337。
    BACKGROUND: Multi-drug or rifamycin-resistant tuberculosis (MDR/RR-TB) is an important public health concern, including in settings with high HIV prevalence. TB drug resistance can be directly transmitted or arise through resistance acquisition during first-line TB treatment. Limited evidence suggests that people living with HIV (PLHIV) might have an increased risk of acquired rifamycin-resistance (ARR).
    METHODS: To assess HIV as a risk factor for ARR during first-line TB treatment, a systematic review and meta-analysis was conducted. ARR was defined as rifamycin-susceptibility at treatment start with rifamycin-resistance diagnosed during or at the end of treatment, or at recurrence. PubMed/MEDLINE, CINAHL, Cochrane Library, and Google Scholar databases were searched from inception to 23 May 2024 for articles in English; conference abstracts were also searched from 2004 to 2021. The Mantel-Haenszel random-effects model was used to estimate the pooled odds ratio of any association between HIV and ARR among individuals receiving first-line TB treatment.
    RESULTS: Ten studies that included data collected between 1990 and 2014 were identified: five from the United States, two from South Africa and one each from Uganda, India and Moldova. A total of 97,564 individuals were included across all studies, with 13,359 (13.7%) PLHIV. Overall, 312 (0.32%) acquired rifamycin-resistance, among whom 115 (36.9%) were PLHIV. The weighted odds of ARR were 4.57 (95% CI, 2.01-10.42) times higher among PLHIV compared to HIV-negative individuals receiving first-line TB treatment.
    CONCLUSIONS: The available data, suggest that PLHIV have an increased ARR risk during first-line TB treatment. Further research is needed to clarify specific risk factors, including advanced HIV disease and TB disease severity. Given the introduction of shorter, 4-month rifamycin-based regimens, there is an urgent need for additional data on ARR, particularly for PLHIV.
    BACKGROUND: PROSPERO CRD42022327337.
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  • 文章类型: Journal Article
    目的:目的:探讨利福昔明和益生菌对代谢相关脂肪性肝病(MAFLD)合并2型糖尿病患者肠道通透性的影响。
    方法:材料与方法:前瞻性干预随机调查共纳入68例MAFLD合并2型糖尿病患者,他们被检查并分为2组治疗。
    结果:结果:血清白细胞介素(IL)-6,IL-10和zonulin,肝功能活动的指标,治疗组之间的肝脏衰减系数与对照组2周后,1个月,3和6个月的治疗有显著差异。2周后,治疗组血清IL-6、连蛋白水平显著降低,IL-10水平显著升高,1、3和6个月的联合治疗。当比较治疗组与治疗组之间的粪便短链脂肪酸浓度时对照组2周后,1个月,3和6个月的治疗乙酸的水平,确定了丁酸和丙酸的显着差异和水平的增加。
    结论:结论:6个月内的动力学研究结果表明,额外服用利福昔明,MAFLD和2型糖尿病患者对二甲双胍的多品种益生菌和益生元导致亚临床炎症的消除,调节肠屏障的通透性并降低增加的肠通透性,以及降低肝脏转氨酶的血清活性和降低脂肪变性的阶段。
    OBJECTIVE: Aim: To investigate the effectiveness of rifaximin and probiotics for the correction of intestinal permeability in patients with metabolic-associated fatty liver disease (MAFLD) in combination with type 2 diabetes mellitus.
    METHODS: Materials and Methods: The prospective interventional randomized investigation included 68 patients with MAFLD in combination with type 2 diabetes, who were examined and divided into the 2 groups of treatment.
    RESULTS: Results: The serum levels of interleukin (IL) - 6, IL-10 and zonulin, indicators of liver functional activity, liver attenuation coefficient between treatment group vs. control group after 2 weeks, 1 month, 3 and 6 months of therapy were significant differed. The serum levels of IL-6 and zonulin significantly decreasing and increasing of IL-10 in the treatment group after 2 weeks, 1, 3 and 6 months of combined therapy. When comparing of stool short-chain fatty acids concentration between treatment group vs. control group after 2 weeks, 1 month, 3 and 6 months of therapy the levels of acetic, butyric and propionic acids significantly differences and increase in their levels were established.
    CONCLUSIONS: Conclusions: The results of the study in dynamics during 6 months show that the additional appointment of rifaximin, multispecies probiotic and prebiotic to metformin in patients with MAFLD and type 2 diabetes led to the elimination of subclinical inflammation, modulation of the permeability of the intestinal barrier and lowering increased intestinal permeability, as well as to the lower serum activity of liver aminotransferases and decrease the stage of steatosis.
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  • 文章类型: Journal Article
    自1999年以来,多西环素和羟氯喹一直是慢性Q热的推荐治疗方法,由细菌病原体引起的威胁生命的疾病,伯内蒂柯西拉。尽管它的使用时间很长,由于治疗时间过长,治疗效果不理想,死亡率高,抗性菌株,以及禁忌使用的可能性。进行了文献检索以鉴定筛选针对C.burnetii的大量药物的研究,以鉴定具有针对C.burnetii的潜在功效的新靶标。选择了由美国食品和药物管理局批准用于人体的12种候选抗微生物剂,并确定了针对低毒力菌株9英里II期的最低抑制浓度(MIC)。利福布汀和利福昔明是表现最好的抗生素,MIC≤0.01µgmL-1。这些顶级候选药物的进一步筛选与来自同一类别的两种药物一起进行,利福平,特征良好,还有利福喷丁,以前没有针对C.Burnetii的报道。针对代表三种临床相关基因型的C.burnetii毒力菌株筛选这些菌株。利福喷丁在人单核细胞白血病细胞系中最有效,THP-1,MIC≤0.01µgmL-1。在人类肾脏上皮细胞系中,A-498利福喷丁的疗效,利福平,利福布汀在各菌株中变化,MIC在≤0.001和0.01µgmL-1之间。利福平,rifabutin,和利福喷丁对C.burnetii都是杀菌的;然而,利福布汀和利福喷丁表现出令人印象深刻的杀菌活性,低至0.1µgmL-1,鉴于其在体外的功效,应进一步探索作为替代Q发烧治疗方法。
    目的:这项工作将帮助研究人员和医生了解针对Q热病原体的潜在替代抗菌疗法,伯内蒂柯西拉。慢性Q热难以治疗,和替代抗生素是必要的。本手稿探讨了利福霉素抗生素对代表三种临床相关基因型的体外C.burnetii毒株的功效。重要的是,这项研究确定了布氏杆菌对利福喷丁的易感性,以前没有报道过。对利福霉素的杀菌活性的评估表明,利福布丁和利福喷丁在低浓度下是杀菌的,这对对抗C.Burnetii的抗生素来说是不寻常的。
    Since 1999, doxycycline and hydroxychloroquine have been the recommended treatment for chronic Q fever, a life-threatening disease caused by the bacterial pathogen, Coxiella burnetii. Despite the duration of its use, the treatment is not ideal due to the lengthy treatment time, high mortality rate, resistant strains, and the potential for contraindicated usage. A literature search was conducted to identify studies that screened large panels of drugs against C. burnetii to identify novel targets with potential efficacy against C. burnetii. Twelve candidate antimicrobials approved for use in humans by the US Food and Drug Administration were selected and minimum inhibitory concentrations (MICs) were determined against the low virulence strain Nine Mile phase II. Rifabutin and rifaximin were the best performing antibiotics tested with MICs of ≤0.01 µg mL-1. Further screening of these top candidates was conducted alongside two drugs from the same class, rifampin, well-characterized, and rifapentine, not previously reported against C. burnetii. These were screened against virulent strains of C. burnetii representing three clinically relevant genotypes. Rifapentine was the most effective in the human monocytic leukemia cell line, THP-1, with a MIC ≤0.01 µg mL-1. In the human kidney epithelial cell line, A-498, efficacy of rifapentine, rifampin, and rifabutin varied across C. burnetii strains with MICs between ≤0.001 and 0.01 µg mL-1. Rifampin, rifabutin, and rifapentine were all bactericidal against C. burnetii; however, rifabutin and rifapentine demonstrated impressive bactericidal activity as low as 0.1 µg mL-1 and should be further explored as alternative Q fever treatments given their efficacy in vitro.
    OBJECTIVE: This work will help inform investigators and physicians about potential alternative antimicrobial therapies targeting the causative agent of Q fever, Coxiella burnetii. Chronic Q fever is difficult to treat, and alternative antimicrobials are needed. This manuscript explores the efficacy of rifamycin antibiotics against virulent strains of C. burnetii representing three clinically relevant genotypes in vitro. Importantly, this study determines the susceptibility of C. burnetii to rifapentine, which has not been previously reported. Evaluation of the bactericidal activity of the rifamycins reveals that rifabutin and rifapentine are bactericidal at low concentrations, which is unusual for antibiotics against C. burnetii.
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  • 文章类型: Journal Article
    金黄色葡萄球菌被认为是细胞外病原体。然而,金黄色葡萄球菌在宿主细胞内的存活可能导致长期定植和临床失败。目前的治疗在清除细胞内细菌方面具有较差的功效。抗体-抗生素缀合物(AACs)是消除细胞内细菌的新策略。在这里,我们首次使用KRM-1657作为AAC的有效载荷,并且我们通过二肽接头(缬氨酸-丙氨酸)将其与抗金黄色葡萄球菌抗体缀合以获得新型AAC(ASAK-22)。ASAK-22具有良好的体外药代动力学特性和对细胞内MRSA的抑制活性,100μg/mL的ASAK-22能够消除细胞内MRSA至检测限。此外,体内结果表明,在菌血症模型中,单次施用ASAK-22可显着降低细菌负担,优于万古霉素治疗。
    Staphylococcus aureus is considered to be an extracellular pathogen. However, survival of S.aureus within host cells may cause long-term colonization and clinical failure. Current treatments have poor efficacy in clearing intracellular bacteria. Antibody-antibiotic conjugates (AACs) is a novel strategy for eliminating intracellular bacteria. Herein, we use KRM-1657 as payload of AAC for the first time, and we conjugate it with anti S. aureus antibody via a dipeptide linker (Valine-Alanine) to obtain a novel AAC (ASAK-22). The ASAK-22 exhibits good in vitro pharmacokinetic properties and inhibitory activity against intracellular MRSA, with 100 μg/mL of ASAK-22 capable of eliminating intracellular MRSA to the detection limit. Furthermore, the in vivo results demonstrate that a single administration of ASAK-22 significantly reduces the bacterial burden in the bacteremia model, which is superior to the vancomycin treatment.
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  • 文章类型: Journal Article
    抗菌剂被广泛使用,由于不良反应风险增加或疗效降低,药物相互作用具有挑战性。在互动中,最重要的是那些影响新陈代谢的物质,尽管那些涉及药物转运蛋白的人越来越为人所知。为了做出临床决定,知道互动的强度是关键,以及中断病原体后的持续时间和时间依赖性恢复。了解所有患者的治疗方法不仅重要,而且补充剂和天然药物也可能相互作用。虽然会带来严重的后果,大多数互动都可以通过对它们有很好的理解来得到充分的管理。特别是在患有政治药物的患者中,必须使用电子临床决策支持数据库对其进行检查。本文旨在进行叙述性综述,重点是在接受细菌感染治疗的患者中可以看到的主要临床上有意义的药代动力学药物-药物相互作用。
    Antimicrobial agents are widely used, and drug interactions are challenging due to increased risk of adverse effects or reduced efficacy. Among the interactions, the most important are those affecting metabolism, although those involving drug transporters are becoming increasingly known. To make clinical decisions, it is key to know the intensity of the interaction, as well as its duration and time-dependent recovery after discontinuation of the causative agents. It is not only important to be aware of all patient treatments, but also of supplements and natural medications that may also interact. Although they can have serious consequences, most interactions can be adequately managed with a good understanding of them. Especially in patients with polipharmacy it is compulsory to check them with an electronic clinical decision support database. This article aims to conduct a narrative review focusing on the major clinically significant pharmacokinetic drug-drug interactions that can be seen in patients receiving treatment for bacterial infections.
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  • 文章类型: Journal Article
    抗生素耐药性的出现使得细菌感染的治疗变得困难并且需要开发替代策略。靶向药物递送系统在克服传统抗生素的局限性方面引起了极大的兴趣。这里,我们旨在通过用合成的P6.2肽装饰RFX负载的聚(乳酸-共-乙醇酸)(PLGA)纳米颗粒(NP)来靶向递送利福昔明(RFX),首次用作靶向剂。我们的结果表明,将RFX封装到NP中通过改善其溶解度和提供受控释放来增加其抗菌活性,而P6.2修饰允许将NP靶向金黄色葡萄球菌细菌细胞。一种有希望的治疗细菌感染的方法,这些P6.2缀合的RFX负载的PLGANP(TR-NP)对金黄色葡萄球菌的两种菌株均表现出有效的抗菌活性。负载RFX的PLGANP(R-NP)的抗菌活性显示出显着的结果,与游离RFX相比,对金黄色葡萄球菌和MRSA分别增加了8和16倍,分别。此外,发现靶向纳米颗粒的活性增加了32或16倍,MBC值为0.0078μg/mL。发现所有纳米颗粒在它们显示抗微生物活性的剂量下是生物相容的。最后,它揭示了P6.2缀合的靶向纳米颗粒在金黄色葡萄球菌而不是大肠杆菌中极端积累。
    The emergence of antibiotic resistance makes the treatment of bacterial infections difficult and necessitates the development of alternative strategies. Targeted drug delivery systems are attracting great interest in overcoming the limitations of traditional antibiotics. Here, we aimed for targeted delivery of rifaximin (RFX) by decorating RFX-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) with synthetic P6.2 peptide, which was used as a targeting agent for the first time. Our results showed that encapsulation of RFX into NPs increased its antibacterial activity by improving its solubility and providing controlled release, while P6.2 modification allowed targeting of NPs to S. aureus bacterial cells. A promising therapeutic approach for bacterial infections, these P6.2-conjugated RFX-loaded PLGA NPs (TR-NP) demonstrated potent antibacterial activity against both strains of S. aureus. The antibacterial activity of RFX-loaded PLGA NPs (R-NP) showed significant results with an increase of 8 and 16-fold compared to free RFX against S. aureus and MRSA, respectively. Moreover, the activity of targeted nanoparticles was found to be increased 32 or 16-fold with an MBC value of 0.0078 μg/mL. All nanoparticles were found to be biocompatible at doses where they showed antimicrobial activity. Finally, it revealed that P6.2-conjugated targeted nanoparticles extremely accumulated in S. aureus rather than E. coli.
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  • 文章类型: Journal Article
    安莎霉素,以抗结核药物利福霉素为代表,是天然产品的重要家族。为了获得新的安莎霉素,含有安莎霉素生物合成基因簇的雷帕霉素链霉菌IMET43975在50L规模内发酵,随后的纯化工作导致了五个已知的和四个新的类似物的分离,其中hygrocinW(2)属于苯醌类安莎霉素,还有另外三种潮霉素,hygrocinsX-Z(6-8),是新的Seco-hygrocins.通过光谱分析(1D/2DNMR和ECD)和MS光谱数据确定安莎霉素(1-8)的结构。通过体内CRISPR碱基编辑证实了催化柄环中酯形成的Baeyer-Villiger酶。这些化合物的发现进一步丰富了安莎霉素的结构多样性。
    Ansamycins, represented by the antituberculosis drug rifamycin, are an important family of natural products. To obtain new ansamycins, Streptomyces rapamycinicus IMET 43975 harboring an ansamycin biosynthetic gene cluster was fermented in a 50 L scale, and subsequent purification work led to the isolation of five known and four new analogues, where hygrocin W (2) belongs to benzoquinonoid ansamycins, and the other three hygrocins, hygrocins X-Z (6-8), are new seco-hygrocins. The structures of ansamycins (1-8) were determined by the analysis of spectroscopic (1D/2D NMR and ECD) and MS spectrometric data. The Baeyer-Villiger enzyme which catalyzed the ester formation in the ansa-ring was confirmed through in vivo CRISPR base editing. The discovery of these compounds further enriches the structural diversity of ansamycins.
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