Clinical evaluation of imipenem/cilastatin sodium against severe infections complicated with hematological disorders and solid tumors

Imipenem/cilastatin sodium (IMP/CS) was administered to patients with severe infections complicated by hematological disorders and solid tumors to assess its efficacy and safety. Primary diseases in this series of 76 cases included 37 cases of hematological disorders (acute leukemia in 25 cases, malignant lymphoma in 7 cases, aplastic anemia in 3 cases and 2 other diseases) and 38 cases of solid tumors (lung cancer in 7 cases, gastric cancer in 11 cases, esophageal cancer in 6 cases, pancreatic cancer in 3 cases, bile duct cancer in 4 cases, hepatocellular cancer in 3 cases, and 4 other diseases). Following results were obtained. 1. Types of infection in hematological diseases were sepsis in 5 cases, suspected sepsis in 24 cases, pneumonia in 5 cases and 3 others. The efficacy rates were 100% in sepsis, 62.5% in suspected sepsis, 80% in pneumonia and 73% in all cases. 2. Types of infection in solid tumors were sepsis in 2 cases, suspected sepsis in 13 cases, pneumonia in 10 cases, cholecystitis in 2 cases, cholangitis in 5 cases, liver abscess in 2 cases, and 4 others. The efficacy rates were 50% in sepsis, 69.2% in suspected sepsis, 80% in pneumonia, and 71.1% in all cases. 3. IPM/CS was administered in single use in 66 cases and in combination with other antibiotics in 9 cases. The efficacy rate in the single use was 72.7% and that in the combination use was 66.7%. 4. The efficacy rate in 35 cases of first use was 71.4% and that in 40 cases of second use was 72.5%.(ABSTRACT TRUNCATED AT 250 WORDS)     

Procalcitonin in sepsis and systemic inflammation: a harmful biomarker and a therapeutic target

The worldwide yearly mortality from sepsis is substantial, greater than that of cancer of the lung and breast combined. Moreover, its incidence is increasing, and its response to therapy has not appreciably improved. In this condition, the secretion of procalcitonin (ProCT), the prohormone of calcitonin, is augmented greatly, attaining levels up to thousands of fold of normal. This hypersecretion emanates from multiple tissues throughout the body that are not traditionally viewed as being endocrine. The serum values of ProCT correlate with the severity of sepsis; they recede with its improvement and worsen with exacerbation. Accordingly, as highlighted in this review, serum ProCT has become useful as a biomarker to assist in the diagnosis of sepsis, as well as related infectious or inflammatory conditions. It is also a useful monitor of the clinical course and prognosis, and sensitive and specific assays have been developed for its measurement. Moreover, it has been demonstrated that the administration of ProCT to septic animals greatly increases mortality, and several toxic effects of ProCT have been elucidated by in vitro experimental studies. Antibodies have been developed that neutralize the harmful effects of ProCT, and their use markedly decreases the symptomatology and mortality of animals that harbour a highly virulent sepsis analogous to that occurring in humans. This therapy is facilitated by the long duration of serum ProCT elevation, which allows for a broad window of therapeutic opportunity. An experimental groundwork has been established that suggests a potential applicability of such therapy in septic humans.     

Drug utilization pattern and cost for the treatment of severe sepsis and septic shock in critically ill cancer patients

Background Cancer patients are at high risk for developing sepsis. To our knowledge, there are no studies that evaluated the type of medications utilized and the associated cost in cancer patients with severe sepsis and septic shock. Objective To describe the drug utilization pattern and drug cost in the treatment of cancer patients with severe sepsis and septic shock. Setting 12-bed medical/surgical intensive care unit (ICU) of a comprehensive teaching cancer center. Methods A retrospective cohort study of cancer patients with severe sepsis or septic shock who were treated in the ICU between January and December, 2010. The ICU sepsis database was used to identify patients. The patient demographics and characteristics were recorded. In addition, the number and type of prescribed medications, total cost for each medication, type of infection, and culture results were determined. Main outcome measure The main outcomes were the type of medication classes utilized and the cost of the medications. Results During the study period, 116 cases were identified. Upon presentation, the mean Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 21.8 (SD ±7.8), 30 (25.9 %) patients had neutropenia, and 94 (81 %) had positive cultures. The total cost of the medications prescribed for this cohort of patients was 291,030 Euro. The mean number of medications prescribed per patient and the mean total cost per patient were 11.7 (SD ±4.7) and 2,509 Euro (SD ±2,844), respectively. The most commonly prescribed medication classes were acid suppressive therapy, glycopeptides, penicillins/cephalosporins and vasopressors prescribed in 113 (97 %), 104 (89.7 %), 103 (88.9 %), and 102 (88 %) patients, respectively. The highest medication costs were associated with antifungals (mean 1,288 Euro/patient) and colony stimulating factors (mean 829 Euro/patient), prescribed in 55 (47.4 %) and 37 (31.9 %) patients, respectively. Medication costs were higher in non-survivors, compared to survivors (3,664 Euro vs. 1,430 Euro, p = 0.0001), and in patients with positive cultures, compared to patients with negative cultures (3,198 Euro vs. 1,865 Euro, p = 0.0004). Conclusion In cancer patients with severe sepsis and septic shock, multiple medications are prescribed which are associated with high cost.     

降钙素原在非中性粒细胞减少肿瘤发热患者中的应用研究

目的 探讨降钙素原在非中性粒细胞减少肿瘤发热患者中的应用.方法 选取本院2010年1月～2012年1月160例非中性粒细胞减少的肿瘤发热患者,在发热1 d内和之后3 d分别测定血浆降钙素原水平,将患者分为脓毒血症组31例、局部感染组34例、无明确微生物感染组45例和肿瘤相关组50例,比较这些患者的血浆降钙素原水平.结果 局部感染组、无明确微生物感染组和脓毒血症组在3 d后降钙素原（PCT）明显有下降,而肿瘤组的PCT水平差异无可比性.同时脓毒血症组的PCT水平明显高于其他3组.结论 血浆降钙素原水平可用于判断非中性粒细胞减少肿瘤患者发热的具体原因.     

Recent advances in sepsis research: novel biomarkers and therapeutic targets

Sepsis remains a common cause of death in the intensive care units worldwide. However, in the last decade a significant development could be noticed in sepsis research regarding diagnostic markers that can help the physicians to recognize the disease in the early phase, which is the clue of the successful treatment of sepsis. This development provided the identification of new molecules and structures (i.e. cytokines, cell surface markers, receptors) that are potential biomarkers of sepsis in the clinical settings. Besides, the advance in the understanding of the pathophysiologic, immunologic and biochemical pathway of sepsis has made the way for assignment of new drug targets in the therapy of sepsis. This review aims to provide a summary about these novelties regarding our knowledge about sepsis published in the medical literature recently. We will describe the presumed pathophysiological role and diagnostic value of sepsis markers that are used even more widely in the clinical practice (i.e. procalcitonin, IL-6), summarize the data regarding the sepsis marker candidates that are investigated in some initial study (i.e. matrix metalloproteinases, microRNA fingerprints), and we will discuss substances that may be specific markers for certain organ failures related to sepsis (i.e. neutrophil gelatinase-derived lipocalin in acute renal failure). Furthermore, we will review the mediators of the immuno-inflammatory cascade in sepsis concerning their potential applicability as therapeutic targets in the treatment of this often lethal disease. In addition, we present some insights into the identification of genetic markers of sepsis.     

Acute phase reactant proteins as prognostic indicators in cancer

Raised levels of APRPs in a patients with cancer at presentation are generally an unfavourable factor for the patient's survival. The APRPs can be prognostic indicators alone but are more effective when used in combination with powerful indices such as stage and clinical performance status. The pre-treatment APRPs tend to reflect shorter term survival risks up to 18 months and are often raised during the last 6 months of life in patients with disseminated cancer, as well as acute events such as sepsis.     

植物药:免疫紊乱解决之道（英文）

Phytomedicines have been used for treating or preventing diseases throughout human history.We have been conducting in exploration of traditional or folk herbal medicines as an attempt to identify novel phytocompounds candidates for further development into botanical supplements or drugs for inflammation related diseases,including cancer,acute liver hepatitis,and sepsis.Comparative″OMICS″technology platforms in combination with various in vitro and in vivo cell-and gene-based bioassays,murine skin inflammatory and syngeneic and xenograft mammary tumor and melanoma models are employed to validate the pharmacological effects and the underlying mechanistic insights of the identified bioactive phytocompounds.The therapeutic potential of phytoagents,alone or in combination,in sensitizing the chemotherapeutic drug efficacy and/or reduction of its side effects in tumor-bearing mice are investigated.In addition,how phytoagents modulate pro-or anti-inflammatory lipid mediators,such as oxylipins,and related signaling cascades systemically or at organ levels are also addressed for understanding sepsis or cancer pathogenesis and the modes of action of bioactive phytoagents.     

Animal models of sepsis: setting the stage

Sepsis is a state of disrupted inflammatory homeostasis that is often initiated by infection. The development and progression of sepsis is multi-factorial, and affects the cardiovascular, immunological and endocrine systems of the body. The complexity of sepsis makes the clinical study of sepsis and sepsis therapeutics difficult. Animal models have been developed in an effort to create reproducible systems for studying sepsis pathogenesis and preliminary testing of potential therapeutic agents. However, demonstrated benefit from a therapeutic agent in animal models has rarely been translated into success in human clinical trials. This review summarizes the common animal sepsis models and highlights how results of recent human clinical trials might affect their use.     

The coagulation cascade in sepsis

Intravascular and extravascular fibrin formation are characteristic findings in patients with sepsis, suggesting that the activation of coagulation and the inhibiton of fibrinolysis are important in the pathogenesis of sepsis. Activation of coagulation during sepsis is primarily driven by the tissue factor (TF) pathway, while inhibition of fibrinolysis is primarily due to increases in plasminogen activator inhibitor -1(PAI-1). Downregulation of the anticoagulant Protein C pathway also plays an important role in the modulation of coagulation and inflammation in sepsis. Recent advances in the understanding of pathogenetic mechanisms of coagulation and fibrinolysis in sepsis may have therapeutic implications. Recombinant human activated protein C (rhAPC) is currently the only pharmacologic therapy that has been shown to reduce mortality in adults with severe sepsis, highlighting the importance of coagulation and fibrinolysis as a therapeutic target in sepsis. This review summarizes recent basic and clinical findings with regard to the role of the coagulation cascade in sepsis and explores potential therapeutic targets in the coagulation and fibrinolytic pathways in the management of sepsis.     

线粒体在脓毒症肝损伤发病机制及治疗中的作用

线粒体功能障碍所致的细胞能量衰竭与脓毒症期间器官功能损害密切相关。肝脏细胞中存在丰富的线粒体,肝脏是脓毒症相关器官损伤的重要靶点。本文概述了线粒体在脓毒症肝损伤发病机制中的作用,以及线粒体修复过程的动态平衡对于维持线粒体稳态和减轻肝脏损伤的重要意义,以期为脓毒症治疗提供参考。     

Endothelium as a therapeutic target in sepsis

The endothelium plays an important role in health and disease. Endothelial dysfunction contributes to sepsis pathophysiology. An important goal is to develop novel therapies that reverse endothelial dysfunction in sepsis. This review will consider the role of the endothelium in sepsis and will highlight its untapped therapeutic potential.     

Effect of plasma from cancer patients on rat skeletal muscle protein degradation and PGE2 release in vitro

Cachexia in tumour-bearing patients involves loss of skeletal muscle proteins. In order to elucidate the mechanisms underlying this phenomenon, we tested the hypothesis of the presence of a circulating proteolytic factor (possibly interleukin-1, acting through an increased PGE2 release) in the plasma of cancer patients, because such a mechanism has been demonstrated in patients with sepsis or trauma and in animals with bacteraemia or viraemia. The effect of plasma from 13 malnourished cancer patients and 14 controls on PGE2 release and protein degradation (assessed as Tyr release) in rat diaphragm in vitro was evaluated; human recombinant interleukin-1 alpha (IL-1) was used for comparison. IL-1 increased PGE2 release (+44% at 5 U/ml), but did not greatly affect proteolysis. On the contrary, human plasma (125 microliters/ml) from both control and tumour-bearing individuals did not affect PGE2 release significantly, but greatly reduced Tyr release. The decrease in Tyr release by plasma was dose-dependent. In conclusion, our data indicate that, at variance with what was demonstrated in patients with trauma or sepsis, loss of skeletal muscle proteins in cancer patients is not mediated by a circulating factor. In addition, evidence is provided of dissociation between PGE2 and Tyr release and of lack of proteolytic activity for IL-1.     

脓毒症生物标志物的最新进展

脓毒症可以导致危及生命的器官功能障碍,是危重患者死亡的主要原因之一。脓毒症的早期诊断与正确治疗是降低病死率的关键,但目前尚无诊断的金标准。理想的脓毒症生物标志物应该具有早期诊断和预测不良预后的能力,且具有较好的敏感性和特异性。脓毒症的候选生物标志物众多,本文重点综述了急性期蛋白、可溶性受体、非编码RNA和其他近期关注度较高的候选标志物的最新进展。     

血清N末端前体BNP及肌钙蛋白Ⅰ与脓毒症关系研究

目的评价N末端前体脑钠肽及肌钙蛋白I对脓毒症预后判断的作用。方法采用回顾性研究,选取住院的脓毒症患者41例,按病情严重程度分为轻度脓毒症组(22例)及严重脓毒症组(19例),严重脓毒症组根据预后情况分为生存组(11例)及死亡组(8例),同时选取同期住院的健康体检者20例为非脓毒症对照组,在入院的24h内检测NT-proBNP、CTnI等指标,应用单因素方差分析比较各组间NT-proBNP、CTnI水平,绘制受试者工作特征曲线,并计算曲线下面积,结合专业背景知识得到最优的界值和相应的灵敏度、特异度、约登指数。在校正性别、年龄、血管活性药物应用、肌酐清除率等影响因素的条件下,应用Logistics回归方法分析NT-proBNP对严重脓毒症预后判断的价值。结果严重脓毒症组BNP及CTnI与轻度脓毒症组、非脓毒症组比较均明显升高(P<0.01),严重脓毒症患者死亡组BNP及CTnI较生存组明显升高(P<0.01)。NT-proBNP及CTnI的AUC分别为0.89(95%CI为0.42～0.96)、0.67(95%CI为0.61～0.88),多元Logistics回归提示在校正性别、年龄、血管活性药物使用、肌酐清除率等影响后NT-proBNP最终进入回归模型(OR=2.914,P<0.05),提示NT-proBNP为影响严重脓毒症预后的独立预测因素,CTnI未进入回归模型。结论 NT-proBNP及CTnI对脓毒症患者危险分层及预后都有较好的价值,尤其对于严重脓毒症预后的判断,NT-proBNP优于CTnI,且NT-proBNP为严重脓毒症预后的独立预测因素。     

Matrix metalloproteinase inhibitors

The Division of Medicinal Chemistry offered a number of sub-sessions including this one on matrix metalloproteinase (MMP) inhibitors. The overexpression of matrix metalloproteinases has been associated with cancer malignancy, arthritis and several immune system-related infectious diseases such as sepsis. Encouraged by the impressive clinical trials of batimastat and marimastat (Figure 1; British Biotech plc), interest in MMP inhibitors has grown.     

MDSCs在脓毒症免疫抑制中的机制研究进展

髓源性抑制细胞（MDSCs）是一群异质性、具有免疫抑制功能的未成熟髓样细胞。常在肿瘤免疫逃避机制的研究中被提及,除此之外,MDSCs还参与慢性炎症、感染、自身免疫性疾病、创伤等疾病的免疫调节。最近研究发现,MDSCs在脓毒症的发病机制中也起着关键作用。脓毒症是由于宿主对感染的免疫反应失调而导致危及生命的器官功能衰竭。有研究表明,与脓毒症幸存者相比,非幸存者的淋巴细胞显著减少。在脓毒症发病早期,MDSCs被招募到炎症部位,起到抑制炎症的作用;然而,如果MDSCs数量增多及其组织浸润持续存在,可导致显著的病理生理学改变（如淋巴细胞减少、宿主免疫抑制和免疫瘫痪）,从而导致患者病情快速进展甚至愈后恶化。由此可见,MDSCs为脓毒症患者淋巴细胞减少提供了新的见解,现已成为脓毒症研究的一个新兴课题,并可能为脓毒症患者提供新的治疗靶点。本文综述了MDSCs的生物学特征及其在脓毒症免疫抑制中的作用机制,以期为脓毒症的基础研究和临床治疗提供新的靶点和思路。     

中性粒细胞胞外诱捕网在脓毒症病理生理及临床应用中的研究进展

脓毒症是危害性极强的临床综合征,其复杂的病理生理机制及随之而来的治疗难题一直是人们的困扰。中性粒细胞胞外诱捕网(neutrophil extracellular traps,NETs)是中性粒细胞在激发状态下产生的一种以核DNA、组蛋白为主要支架并包含多种酶及炎性因子的物质集合体。这些丰富的炎性物质与脓毒症发生发展的多种炎症反应途径有千丝万缕的联系,也成为脓毒症研究的重要突破方向。近年来,特别是新冠肺炎流行以来,NETs在脓毒症时的产生机制及临床应用的研究如雨后春笋,相关机制及途径逐渐明晰,治疗脓毒症的新方向不断涌现。该文针对NETs的形成过程及其在不同刺激下的变异,在脓毒症发生发展中可能发挥的作用及其潜在的临床应用价值,以及针对NETs及其组分的脓毒症治疗新思路进行综述。     

Lessons for the future: a review of sepsis past and present

Sepsis continues to intrigue and challenge drug developers because of the high unmet need for this illness. The large market potential for sepsis is counterbalanced by the historical failure of multiple drug candidates for this indication that have not demonstrated clinical benefit. The failure of successful drug candidates can be attributed in part to a rudimentary under-standing of complex sepsis pathophysiology, unsophisticated and poor clinical trial design, and an over-reliance on preclinical models for proof-of-concept. Recent significant scientific advancements in these areas are expected to have a positive impact on sepsis drug development. This article reviews several treatment approaches for sepsis that are in clinical development to highlight the scope of research in this field. Although a near-term clinical breakthrough for sepsis is not imminent, current research provides a substantial amount of hope for the field.     

Sepsis, apoptosis and complement

Programmed cell death (apoptosis) is a prominent feature in human and experimental sepsis, especially as it involves the lymphoid system with resulting immunoparalysis. In addition, sepsis is associated with strong activation of the complement system, resulting in generation of the powerful anaphylatoxin, C5a, as well as the upregulation of the C5a receptor (C5aR) in a variety of different organs. The consequences of C5a interactions with C5aR can be directly linked to apoptosis of thymocytes and adrenal medullary cells after cecal ligation and puncture (CLP)-induced sepsis in rodents, as well as with other accompanying complications of CLP: cardiac dysfunction, consumptive coagulopathy, organ dysfunction, and lethality. This communication reviews the evidence for the adverse roles of C5a and C5aR in the setting of experimental sepsis and linkages to the various complications of sepsis, especially apoptosis as well as the roles of the two C5a receptors (C5aR and C5L2) in experimental sepsis.