Filoviruses: Recent Advances and Future Challenges

The appearance and dissemination of vancomycin resistance among clinically important Gram-positive bacteria was an important watershed in antimicrobial resistance trends that drastically narrows therapeutic options, particularly among the enterococci. Clinical resistance despite apparent susceptibility has also become an increasingly recognized issue with vancomycin treatment of methicillin-resistant Staphylococcus aureus pneumonia and endocarditis, which may be, in part, due to vancomycin-heteroresistant strains. The newly developed glycopeptides telavancin, dalbavancin and oritavancin have superior in vitro activity, enhanced bactericidality and unique pharmacokinetic properties compared with vancomycin and teicoplanin. Current clinical trial data show noninferiority to vancomycin or standard-of-care antistaphylococcal therapy for complicated skin–skin structure infections, and acceptable safety profiles. Although promising, whether or not these new compounds are clinically efficacious for the true therapeutic deficits created by in vitro and clinical vancomycin resistance is yet to be determined.     

Management of healthcare-associated methicillin-resistant Staphylococcus aureus

Healthcare-associated methicillin-resistant Staphylococcus aureus is a major cause of nosocomial infections worldwide, with significant attributable morbidity and mortality in addition to pronounced healthcare costs. Treatment results with vancomycin – the current recommended antibiotic for serious methicillin-resistant S. aureus infections – have not been impressive. The recent availability of effective antimicrobial agents other than glycopeptides, such as linezolid and daptomycin, as well as the anticipated approval of newer agents with diverse mechanisms of action, has somewhat ameliorated the threat posed by this organism. However, these drugs are expensive, and there is still no overall satisfactory strategy for reducing the incidence of healthcare-associated methicillin-resistant S. aureus in endemic regions. Although early results with the Society for Healthcare Epidemiology of America guidelines give cause for cautious optimism, long-term experience is lacking, and it is likely that these guidelines will have to be adapted according to local conditions and resources before implementation. Trends to keep in mind when considering the problem of healthcare-associated methicillin-resistant S. aureus include the advent of community-associated methicillin-resistant S. aureus, and the propensity of S. aureus to evolve and acquire resistance determinants over time. This was last vividly demonstrated by the handful of vancomycin-resistant S. aureus isolated recently, which had acquired the vancomycin resistance gene from vancomycin-resistant enterococci.     

O-glycosylated versus non-glycosylated MUC1-derived peptides as potential targets for cytotoxic immunotherapy of carcinoma

Due to the fact that many cellular proteins are extensively glycosylated, processing and presentation mechanisms are expected to produce a pool of major histocompatibility complex (MHC) class I-bound protein-derived peptides, part of which retain sugar moieties. The immunogenic properties of the presented glycosylated peptides in comparison to their non-glycosylated counterparts have not been determined clearly. We assessed the cellular immunogenicity of MUC1 (mucin)-derived peptides O-glycosylated with a Tn epitope (GalNAc) using HLA-A*0201 single chain (HHD)-transfected cell lines and transgenic mice. For part of the compounds Tn moiety did not interfere with the HLA-A*0201 binding. Moreover, part of the glycopeptides elicited effective cytotoxic responses, indicating recognition of the glycopeptide-HLA-A*0201 complex by the T cell receptor (TCR) and subsequent cytotoxic T lymphocyte (CTL) activation. The CTLs exhibited a substantial degree of cross-reactivity against target cells loaded with glycosylated and non-glycosylated forms of the same peptide. The studied (glyco)peptides showed cellular immunogenicity in both MUC1-HHD and HHD mice and induced effective lysis of (glyco)peptide-loaded target cells in CTL assays. However, the elicited CTLs did not induce selective lysis of human MUC1-expressing murine cell lines. Moreover, immunization with (glyco)peptide-loaded dendritic cells (DCs) did not induce significant immunotherapeutic effects. We conclude that Tn glycosylated MUC1-derived peptides can be presented by MHC class I molecules, and may be recognized by specific TCR molecules resulting in cytotoxic immune responses. However, the studied glycopeptides did not offer significant benefit as targets for cytotoxic immune response due apparently to (a) cross-reactivity of the elicited CTLs against the glycosylated and non-glycosylated forms of the same peptide and (b) low abundance of glycopeptides on tumour target cells.     

药用植物活性肽类研究进展

本文综述了药用植物活性肽的研究进展,着重介绍植物中寡肽类、环肽类、大环寡肽、糖肽类化合物的生物活性、结构特点、提取分离和鉴定方法。     

A review of the current place of glycopeptides in turkish medical practice

Background: Glycopeptide antibiotics are considered by many investigators to be the last resort in the treatment of gram-positive bacterial infections.Objective: The aim of this review was to assess the place of glycopeptides in the treatment of common gram-positive bacteria in accordance with the current epidemiologic data in Turkey.Methods: A search of both the English- and Turkish-language literature indexed on MEDLINE, Ulakbim (Turkey), and Pleksus (Turkey) was performed using the terms: vancomycin, teicoplanin, and glycopeptides, or their Turkish-language counterparts. The complete texts of the articles found in these databases were obtained from the electronic library of Gulhane Medical Academy, Ankara, Turkey. Articles from regional journals, without the support of an electronic format, were obtained by direct communication. Articles of interest were those based on studies occurring in Turkish populations, with special consideration given to publications in press after 2002.Results: Staphylococci were the most frequent gram-positive pathogens encountered in Turkish hospitals. Studies have found that ∼74% of strains were Staphylococcus aureus and the remaining strains were coagulase-negative staphylococci (CoNS). Overall methicillin resistance in staphylococci was reported as ∼60%. In Turkey, S aureus was one of the most common infectious agents found inside hospitals and is deemed a growing threat in the community. While the rate of methicillin resistance in community-acquired isolates is ∼4%, the data from hospitals suggest that reduced resistance comprises most of the isolates. In the studies reviewed, older quinolones like ciprofloxacin and ofloxacin seem to be ineffective in nearly half of the S aureus isolates. Alternatives like rifampicin, gentamicin, tetracycline, trimethoprim/sulfamethoxazole (TMP/SMX), clindamycin, and erythromycin have had substantial resistance profiles in >50% of the strains. In recent Turkish studies, in vitro profiles of linezolid, quinupristin/dalfopristin (QD), and daptomycin have had positive results. As in the S aureus isolates, resistance trends have been observed in the CoNS group of pathogens. The possible use of β-lactams seems restricted, and alternative approaches have become necessary. Quinolones, gentamicin, tetracycline, TMP/SMX, clindamycin, and erythromycin have resistance profiles of >50%. Although glycopeptide resistance was not detected, the frequency of heterogenous vancomycin-intermediate S aureus, a precursor to future resistance, was 13% in 1 study. Current studies in Turkey have found that Enterococcus faecalis comprises three quarters of enterococci while the rest are comprised of Enterococcus faecium. Initial studies performed with linezolid, QD, and daptomycin suggest that these drugs might be effective alternatives for future enterococcal infections that may have high glycopeptide resistance. Approximately 8% of the Streptococcus pneumoniae strains had high-level resistance in Turkey. However, 10 million units of crystallized penicillin or 3 g of oral amoxicillin maintains the optimum treatment of pneumococcal infections outside the central nervous system (CNS). Resistance profiles in third-generation cephalosporins in Turkey range between 2% and 2.5%.Conclusions: In Turkey, a review of the existing literature found that the current use of glycopeptides in pneumococcal infections is restricted to CNS infections facing therapeutic failure in due course. However, the belief that these drugs are the last resort, either in staphylococcal or enterococcal infections, is no longer valid. If a patient has a critical status due to probable gram-positive microorganisms, clinicians should consider the empiric use of glycopeptides. However, new molecules such as linezolid, QD, and daptomycin, offered for use in the treatment of gram-positive bacterial diseases, should be reserved for the future, when glycopeptides eventually become obsolete.     

Highly drug-resistant bacteria: Is intra- and inter-hospital communication optimal?

ObjectivesCommunication represents a key component of the control of highly drug-resistant bacteria (HDRB) in healthcare settings. This survey assessed communication strategies developed and adopted in a large hospital network.MethodsAn online survey was sent to 83 infection control specialists working in hospitals of the Pays de la Loire region, France, in June 2016. Internal and external systems of identification and communication of HDRB status (colonized and contact patients) were assessed at the following steps of the hospital pathway: patient admission, during the stay, at discharge, and at readmission.ResultsSixty-one hospitals (73%) participated in the survey: 31 (51%) had recently managed colonized patients and 51 (93%) had recently managed contact patients. At patient admission, 28 (46%) hospitals had an identification system for repatriated patients. During hospital stay, the colonized or contact status was informed in computerized patient records for 47/57 (82%) and 43 (75%) hospitals, respectively. At patient discharge, 56/61 (92%) hospitals declared transmitting the HDRB status to the downstream ward. Twenty-six and 25/60 (43% and 42%) hospitals had an automated alert system at readmission of colonized or contact patients, respectively. This strategy met the expectations of 15/61 (26%) infection control specialists.ConclusionEfforts are still required in terms of communication for HDRB control. Sharing experiences and tools developed by hospitals may be beneficial for the entire hospital network.     

薄芝糖肽抑制大鼠实验性癫痫发作及其机制研究

目的研究薄芝糖肽对大鼠癫痫发作的抑制作用及对免疫指标的影响。方法 30只SD大鼠分为空白组、模型组、薄芝糖肽组,以腹腔注射青霉素的方法制作大鼠癫痫模型,注射前60 min模型组经尾静脉给予生理盐水2 mL,薄芝糖肽组经尾静脉给予薄芝糖肽2 mL(含5 mg多糖,1 mg多肽)。观察各组大鼠行为,描记脑电图,测定T淋巴细胞亚群和血清免疫球蛋白浓度。结果薄芝糖肽组痫性发作程度较模型组明显减轻(p<0.05)。薄芝糖肽组出现痫样波形的潜伏时间延长,频率降慢、幅度降低。模型组致痫后免疫系统出现抑制现象,薄芝糖肽组大鼠的免疫指标较模型组有明显的提升(p<0.05)。结论薄芝糖肽可抑制大鼠癫痫发作,其机制可能与薄芝糖肽可以明显恢复大鼠免疫指标有关。     

基于肿瘤相关糖抗原的抗肿瘤疫苗研究进展

由于肿瘤细胞可以逃避免疫系统监视,使得人体免疫系统将肿瘤细胞误认为正常细胞而不予杀死。同时,肿瘤细胞与正常体细胞的相似性,又使已有的药物无法高选择性地杀死肿瘤细胞而不伤及正常细胞。因而,寻找无或低副作用肿瘤治疗药物,一直是药物研究的重要方向。现在,人们对肿瘤的发生、发展及其与机体相互作用机制有了十分深入的     

Safety profiles of old and new antimicrobials for the treatment of MRSA infections

ABSTRACT

Introduction: Methicillin-resistant Staphylococcus aureus (MRSA) is a frequent cause of severe nosocomial and community-acquired infections. Various adverse effects have been associated with compounds that are commonly used in the treatment of MRSA.

Areas covered: Prolonged use of high-dose vancomycin has been linked with nephrotoxicity. Linezolid use has been associated with lactic acidosis in regimens longer than 14 days and occurrence of thrombocytopenia in patients with renal impairment. Daptomycin use correlates with reversible and often asymptomatic myopathy. Among new compounds, telavancin has shown increased toxicity compared to vancomycin, especially in patients with severe renal impairment, while a low rate of adverse effects was reported others glycolipopeptides such as dalbavancin and oritavancin and for new cephalosporins. Recently studied oxazolidinones (tedizolid and radezolid) also showed mild adverse effects in Phase 2 and 3 clinical trials.

Expert opinion: Due to the constant increase in antimicrobial resistance, the use of higher doses and prolonged regimens of antibiotics employed in the treatment of Gram-positive infections has become more common and linked to increased toxicity. Furthermore, new compounds with MRSA activity have been recently approved and will be regularly employed in clinical practice. The knowledge of the adverse effects and risk factors for the development of toxicity associated with anti-MRSA antimicrobials is paramount for the correct use of old and new compounds, especially in the treatment of severe infections.