万古霉素耐药肠球菌对院内肠球菌肺部感染预后的影响

目的 探讨万古霉素耐药肠球菌对医院内肺部感染预后的影响。方法 应用回顾性调查的方法对1993年1月～2001年12月96例医院内肺部肠球菌感染病人进行分析。结果 96例院内肺部肠球菌感染以粪肠球菌为多(73％)，屎肠球菌次之(22％)。肠球菌对临床常用抗生素的耐药率高，对万古霉素的耐药率为12．5％，屎肠球菌的耐药率明显高于粪肠球菌。96例肺部肠球菌感染患者，病死率40％(38/96)。感染的肠球菌对万古霉素耐药的病人病死率最高，达92％，明显高于万古霉素敏感肠球菌肺感染的病死率(26％)(P＜0．05)。结论 万古霉素耐药肠球菌肺感染发病率呈上升趋势，病死率高，需引起临床的高度重视。     

对比达托霉素和利奈唑胺治疗耐万古霉素肠球菌血流感染临床疗效和安全性的Meta分析

目的： 系统评价达托霉素和利奈唑胺治疗耐万古霉素肠球菌血流感染的临床疗效及安全性。方法： 计算机检索PubMed、The Cochrane Library、Embase、CNKI、维普、万方等数据库,检索时限为从建库至2019年10月。由两名评价者按照纳入标准与排除标准独立筛选文献、提取资料并使用NOS表评价纳入研究质量后,采用RevMan 5.3进行Meta分析。结果： 共纳入队列研究18篇,包括4 830例患者,其中达托霉素组2 254例,利奈唑胺组2 576例。Meta分析结果显示：（1）疗效方面：达托霉素和利奈唑胺的全因死亡率、30 d死亡率、临床治愈率、细菌清除率及复发率方面差异无统计学意义（P>0.05）。（2）安全性方面：达托霉素的血小板减少症发生率明显低于利奈唑胺[OR=0.58,95%CI（0.37,0.91）,P=0.02],两者的肌酸激酶升高发生率差异无统计学意义（P>0.05）。结论： 临床上达托霉素与利奈唑胺治疗耐万古霉素肠球菌血流感染的疗效相当,安全性上达托霉素优于利奈唑胺。     

Glycopeptide carboxamides active against vancomycin-resistant enterococci

Glycopeptide antibiotics were synthesized via the PyBOP mediated condensation of aliphatic, heterocyclic and aromatic amines with the C-terminus of vancomycin, LY264826 (A82846B) and semi-synthetic derivatives of these natural products. Amides of LY264826 and vancomycin demonstrated excellent activity against staphylococci and streptococci as compared to the parent natural product. However, the amides of N-alkylated LY264826 and N-alkylated vancomycin were active against vancomycin-resistant enterococci as well as other gram-positive pathogens such as Staphylococcus aureus, S. haemolyticus, S. epidermidis and Streptococcus pneumoniae.     

治疗耐万霉素肠球菌的药物及其机制研究

耐万古霉素肠球菌(VRE)引起的全球公共卫生问题愈发严重,VRE耐药性不断增加,这意味着可有效治疗肠球菌感染的药物选择余地越来越小,本文总结了常用及最新的治疗VRE药物,并介绍其对VRE的作用机制.     

Repurposing niclosamide for intestinal decolonization of vancomycin-resistant enterococci

Enterococci are commensal micro-organisms present in the gastrointestinal tract of humans. Although normally innocuous to the host, strains of enterococcus exhibiting resistance to vancomycin (VRE) have been associated with high rates of infection and mortality in immunocompromised patients. Decolonization of VRE represents a key strategy to curb infection in highly-susceptible patients. However, there is a dearth of decolonizing agents available clinically that are effective against VRE. The present study found that niclosamide, an anthelmintic drug, has potent antibacterial activity against clinical isolates of vancomycin-resistant Enterococcus faecium (minimum inhibitory concentration 1–8?µg/mL). E. faecium mutants exhibiting resistance to niclosamide could not be isolated even after multiple (10) serial passages. Based upon these promising in-vitro results and the limited permeability of niclosamide across the gastrointestinal tract (when administered orally), niclosamide was evaluated in a VRE colonization-reduction murine model. Remarkably, niclosamide outperformed linezolid, an antibiotic used clinically to treat VRE infections. Niclosamide was as effective as ramoplanin in reducing the burden of vancomycin-resistant E. faecium in the faeces, caecal content and ileal content of infected mice after only 8 days of treatment. Linezolid, in contrast, was unable to decrease the burden of VRE in the gastrointestinal tract of mice. The results obtained indicate that niclosamide warrants further evaluation as a novel decolonizing agent to suppress VRE infections.     

Therapeutic options for infections due to vancomycin-resistant enterococci

Background: Vancomycin-resistant enterococci (VRE) are an important cause of nosocomial infection occurring in critical care or immunocompromised patients. Objectives: To provide updated information about therapeutic options for VRE infection. Methods: MEDLINE, EMBASE, and the Cochrane Library were searched to identify in vitro susceptibility data of VRE isolates, randomized and non-randomized controlled trials, case series, and cohort studies of VRE therapy published before 31 July 2008. Results/conclusion: The updated in vitro susceptibility data for VRE show high resistance to ampicillin and aminoglycosides. Quinupristin-dalfopristin is limited by its lack of activity against vancomycin-resistant Enterococcus faealis and its musculoskeletal side effects. Emerging linezolid resistance has been reported to cause hospital spread and may be related to prolonged linezolid use. Quinupristin-dalfopristin resistance is usually linked to agricultural use of streptogramin. Nitrofurantoin and fosfomycin are alternatives in uncomplicated VRE urinary tract infection. Daptomycin and tigecycline have shown excellent potential for treating VRE infection.     

Peritoneal dialysis fluid concentrations of linezolid in the treatment of vancomycin-resistant Enterococcus faecium peritonitis

OBJECTIVE: To determine linezolid concentrations in peritoneal dialysis fluid after multiple oral doses of the drug in a 46-year-old man with vancomycin-resistant Enterococcus faecium peritonitis who was undergoing peritoneal dialysis. METHODS: After administration of oral linezolid 600 mg twice/day was started, peritoneal dialysis fluid was collected at the end of several 4- and 8-hour dwell times and submitted for analysis of linezolid concentration. Before linezolid therapy was begun, and immediately after several peritoneal dialysis exchanges, 30 ml of expended peritoneal dialysis fluid was collected in a sterile container and immediately frozen at -70 degrees C until analysis by high-performance liquid chromatography. RESULTS: Peritoneal dialysis concentrations of linezolid greater than 4 microg/ml were achieved after the first dose of linezolid and maintained after repeated doses. During the course of therapy, mean linezolid concentrations in peritoneal dialysis fluid tended to increase (mean 7.60 pg/ml, range 3.54-16.2 microg/ml). All assayed peritoneal dialysis samples demonstrated linezolid concentrations greater than 4 microg/ml at the end of 4- or 8-hour dwell times, except for one level after a missed dose on linezolid treatment day 3. Duration of dwell times did not appear to correlate with linezolid concentrations. CONCLUSION: In this patient, linezolid 600 mg twice/day penetrated into peritoneal dialysis fluid at or above the concentrations necessary to treat common gram-positive bacteria. Linezolid therapy is likely to have a role in peritoneal dialysis-associated peritonitis based on its antimicrobial activity, pharmacokinetic properties, ease of administration, and tolerability.     

Multivalent antibiotics via metal complexes: potent divalent vancomycins against vancomycin-resistant enterococci

Dimers of vancomycin (Van), linked by a rigid metal complex, [Pt(en)(H(2)O)(2)](2+), exhibit potent activities (MIC approximately 0.8 mug/mL, approximately 720 times more potent than that of Van itself) against vancomycin-resistant enterococci (VRE). The result suggests that combining metal complexation and receptor/ligand interaction offers a useful method to construct multivalent inhibitors.     

Prevalence and characterization of vancomycin-resistant enterococci in chicken intestines and humans of korea

The prevalence, genotype for antibiotic resistance and antibiotic susceptibility of vancomycin resistant enterococci (VRE) were determined. And molecular typings of the Enterococcus faecium isolates were analyzed. Prevalence of VRE in chickens, healthy children and intensive care unit (ICU) patients was 41.6%, 7.9%, and 20.4%, respectively. Forty out of 54 isolates from chicken intestines, and 9 out of 11 from ICU patients were identified as Enterococcus faecium. Eleven out of 13 isolates from non-hospitalized young children were E. gallinarium. Twelve strains of E. faecalis were isolated from chicken intestines. The gene for the antibiotic resistance in E. faecium, and E. faecalis was vanA, while that in E. gallinarium was vanC1. E. faecium isolates were resistant to most of antibiotics except ampicillin and gentamicin. Molecular typing of the E. faecium strains obtained by pulse field gel electrophoresis and repetitive sequence-based PCR suggest that VRE transmit horizontally from poultry to humans, especially young children, via the food chains in Korea.     

Genetic diversity of Tn1546-like elements in clinical isolates of vancomycin-resistant enterococci

We have investigated the genetic diversity of Tn1546 among 17 vancomycin-resistant enterococci (VRE) isolates of Enterococcus faecium. Most of these multidrug-resistant strains harboured plasmids of 2 kb to >300 kb in size. The vancomycin resistance marker vanA was located on both the plasmid and the chromosomal DNA. VRE isolates 18 and 22 failed to amplify the orf1-IR(R) and orf2-IR(R) but contained the orf1 and orf2. VRE3 failed to amplify the orf1, orf2, vanR and vanS, but still yielded a larger than expected (4.4 kb vs. 2.3 kb) vanSH amplicon. VRE9, 10, 21 and 22 also yielded larger (5.5 kb) vanSH amplicons; all others yielded 4.0 kb vanSH amplicons. Sequence analysis of the vanSH amplicons from VRE9, 10, 21 and 22 revealed the presence of IS1251 between the vanS and vanH genes in these isolates. The observed vanSH amplicon from VRE3 contained orf31, orf30 and orf29 of the plasmid pRUM followed by the vanHAXYZ region of Tn1546. Translocation of Tn1546 to a pRUM-like plasmid in VRE3 resulted in the loss of its orf1, orf2, vanR and vanS elements and a loss of the orf32 of pRUM, leading to a unique structural arrangement of vanA elements that is hitherto unknown.     

Impact of a piperacillin-tazobactam shortage on antimicrobial prescribing and the rate of vancomycin-resistant enterococci and Clostridium difficile infections

States in 2002 on antimicrobial prescribing and associated rates of vancomycin-resistant enterococci (VRE) and Clostridium difficile infections.Design. Retrospective chart review.Setting. University-affiliated medical center.Measurements and Main Results. Microbiologic reports, patient demographics, and antimicrobial utilization were evaluated for patients admitted 6 months before the shortage (March 1-August 31, 2001) and for 6 months during the shortage (March 1-August 31, 2002). Significant increases in usage of alternative mu-lactamase inhibitor combinations, cefepime, levofloxacin, vancomycin, clindamycin, and metronidazole were observed during the shortage; in contrast, a significant decrease in the use of ceftriaxone took place. No change in the rate of VRE infection was observed from before to during the piperacillin-tazobactam shortage. However, a paradoxical 47% decrease in the rate of C. difficile colitis was documented during the shortage. Subsequent multivariate analyses suggested the reduced use of ceftriaxone and increased use of levofloxacin, but not the reduced use of piperacillin-tazobactam, correlated with the decreased rate of C. difficile infections.Conclusion: The piperacillin-tazobactam shortage was associated with significant changes in antimicrobial prescribing, which resulted in a significant reduction in the rate of C. difficile but not VRE infections.     

Characteristics of clinical and environmental vanM-carrying vancomycin-resistant enterococci isolates from an infected patient

vanM, an uncommon glycopeptide resistance gene, was first identified in an Enterococcus faecium isolate (Efm-HS0661) from Shanghai, China, in 2006 and has been predominant in this city since 2011. A vanM-carrying E. faecium was isolated from the bloodstream of a patient in an intensive care unit (ICU) in Hangzhou, China, in 2014. Further surveillance screening of a rectal swab and environmental surfaces of the patient yielded a large number of vanM-positive E. faecium. These isolates (including 1 from the bloodstream, 1 from the rectal swab and 43 representative isolates from environmental samples) were classified into four pulsed-field gel electrophoresis (PFGE) patterns and two sequence types (ST78 and ST564). PCR amplification and sequence analysis indicated that the genetic structure surrounding the vanM gene of these isolates was similar to that of the original vanM-carrying isolate Efm-HS0661. This study highlights the emergence of infections and environmental contamination caused by vanM-carrying E. faecium in an ICU of another Chinese city outside of Shanghai.     

Fosfomycin resistance among vancomycin-resistant enterococci owing to transfer of a plasmid harbouring the fosB gene

The presence and characterisation of plasmid-mediated fosfomycin resistance determinants were investigated among 45 clinical vancomycin-resistant enterococci (VRE) isolated in Zhejiang Province, China. In total, 19 VRE were resistant to fosfomycin, of which 18 isolates had conjugative fosfomycin resistance and were positive for fosB. No reported fos genes were detected in the remaining isolate. Among the 18 fosB-carrying isolates, the fosB gene was always flanked by tnpA, suggesting the same novel fosB transposon. In 10 of the 18 fosB-carrying isolates, the fosB and tnpA genes were found reversely inserted in the vanA transposon Tn1546. In the remaining eight isolates the fosB and vanA genes were located on different plasmids. These findings indicate that acquisition of the conjugative plasmid harbouring the novel fosB transposon (ISL3-like transposon) and the Tn1546-like transposon (containing vanA and fosB) may explain, at least in part, the recent increase in fosfomycin-resistant Enterococcus faecium in China.     

Antivirulence activity of auranofin against vancomycin-resistant enterococci: in vitro and in vivo studies

Introduction: Vancomycin-resistant enterococci (VRE) are a leading cause of nosocomial infections because of the limited number of effective therapeutic options. In an effort to repurpose FDA-approved drugs against antibiotic-resistant bacteria, auranofin has been identified as a potent drug against VRE.Methods and ResultsThe present study determined that auranofin's antibacterial activity was not affected when evaluated against a higher inoculum size of VRE (~10⁷ CFU/mL), and auranofin successfully reduced the burden of stationary phase VRE cells via a time-kill assay. In addition, auranofin reduced VRE production of key virulence factors, including proteases, lipase and haemagglutinin. The promising features of auranofin prompted evaluation of its in vivo efficacy in a lethal mouse model of VRE septicaemia. All mice receiving auranofin at 0.125 mg/kg orally, 0.125 mg/kg subcutaneously (SC) or 0.0625 mg/kg (SC) survived the lethal VRE challenge. Additionally, auranofin was superior to linezolid, the current drug of choice, in reducing VRE burden in the liver, kidneys and spleen of mice. Remarkably, auranofin successfully reduced VRE below the limit of detection in murine internal organs after 4 days of oral or subcutaneous treatment.ConclusionThese results indicate that auranofin warrants further investigation as a new treatment for systemic VRE infections.     

Monthly Update Anti-infectives: LY333328, a new glycopeptide active against vancomycin-resistant enterococci

LY333328 is a novel glycopeptide from Lilly Research Laboratories which is claimed to have activity both in vitro and in vivo against vancomycin-resistant enterococci. Information on this compound has been published at three recent meetings, the 7th European Congress of Clinical Microbiology and Infectious Diseases (March 26 - 30, Vienna, Austria); On the Frontier of Antibacterial Drug Discovery (April 27 - 28, Princeton, USA); and the 19th International Chemotherapy Congress (July 16 - 21, Montreal, Canada). This update draws together the published data and attempts to assess the potential therapeutic use of this interesting new compound.     

Antimicrobial activity of oleanolic acid from Salvia officinalis and related compounds on vancomycin-resistant enterococci (VRE)

An extract from Salvia officinalis (Sage) leaves showed antimicrobial activity against vancomycin-resistant enterococci (VRE). We isolated the effective compound and identified it as oleanolic acid, a triterpenoid. We also tested antimicrobial activity of similar triterpenoids, ursolic acid, uvaol, betulinic acid and betulin. We found that ursolic acid also showed antimicrobial activity against VRE. The minimum inhibitory concentrations (MICs) of oleanolic acid and ursolic acid were 8 and 4 microg/ml, respectively. These two compounds also showed antimicrobial activity against Streptococcus pneumoniae and methicillin-resistant Staphylococcus aureus (MRSA). These compounds showed bactericidal activity against VRE at least for 48 h when added at concentrations that were two-times higher than their MICs.