Emergence and management of drug-resistant enterococcal infections

The treatment of multidrug-resistant enterococcal infections continues to be a challenge for clinicians. Glycopeptide and beta-lactam resistance is now a common feature of the majority of Enterococcus faecium hospital isolates, and resistance to aminoglycosides, quinupristin-dalfopristin, linezolid and daptomycin further complicates the problem. New antibiotics, such as tigecycline, lipoglycopeptides (dalbavancin, oritavancin and telavancin) and cephalosporins with activity against Enterococcus faecalis (ceftobiprole and ceftaroline), may have potential activity against certain resistant enterococcal strains in specific clinical settings, as may some older antibiotics, such as ampicillin, chloramphenicol, doxycycline, minocycline and nitrofurantoin. However, the treatment of endovascular infections (particularly endocarditis, where bactericidal therapy is important for optimal cure rates) caused by resistant enterococci continues to be an immense challenge even with the availability of new agents. The optimal therapy for these infections is not well established and clinical data are usually limited to case reports with conflicting results. Therefore, treatment decisions may have to be based on animal models and sporadic experiences and the best approach is for the physician to consider carefully each patient on a case by case manner and gather all the clinical and microbiological information possible regarding species identification and susceptibilities in order to choose a therapeutic regimen that would appear to be active.     

肠球菌属感染临床特点及耐药性研究

目的研究肠球菌属感染的临床特点及其耐药性,指导临床合理使用抗菌药物。方法采用回顾性调查方法对临床分离的924例肠球菌属相关资料进行统计分析。结果临床标本中肠球菌属在尿液中的分布最高,占71.32%;屎肠球菌与粪肠球菌对抗菌药物的耐药率不尽相同,万古霉素耐药菌株逐年增多。肠球菌属引起的院内感染病例占63.42%;60岁以上老年人占64.41%,所有患者均有较严重的基础病。结论肠球菌已是医院感染的重要致病菌,老年及免疫功能低下患者易感,以尿路感染最常见;肠球菌属对多种抗生素耐药,耐万古霉素肠球菌株明显增加。     

A review of linezolid: the first oxazolidinone antibiotic

Resistance of Gram-positive bacterial pathogens, such as Staphylococcus aureus and Enterococcus faecium, to existing antibiotics continues to increase, and new antibiotics with activity against these pathogens are in demand. Linezolid (Zyvox^®, Pharmacia and Upjohn) is the first agent of a new class of antibiotics called the oxazolidinones. Linezolid possesses excellent microbial activity against a wide variety of Gram-positive pathogens including those resistant to methicillin and vancomycin (Vancocin^®, Eli Lilly). Linezolid is available for intravenous and oral administration and possesses excellent bioavailability. It exhibits good penetration into pulmonary, as well as skin and related structure tissues, and does not require dosage adjustment in hepatic or renal dysfunction. Linezolid is generally well-tolerated, with the predominant adverse effect manifesting as a duration dependent, reversible thrombocytopenia. Linezolid possesses monoamine oxidase inhibitor activity and caution is warranted with coadministration of adrenergic or seritonergic medications. Clinical trials conducted with linezolid in skin and structure infections, lower respiratory tract infections and vancomycin-resistant enterococcal infections demonstrate that linezolid is an effective therapy. Recent data suggest that linezolid may be superior to vancomycin for the treatment of infections caused by methicillin-resistant S. aureus. Linezolid is an excellent and promising new antibiotic for the treatment of resistant Gram-positive pathogens.     

A review of linezolid: the first oxazolidinone antibiotic

Resistance of Gram-positive bacterial pathogens, such as Staphylococcus aureus and Enterococcus faecium, to existing antibiotics continues to increase, and new antibiotics with activity against these pathogens are in demand. Linezolid (Zyvox, Pharmacia and Upjohn) is the first agent of a new class of antibiotics called the oxazolidinones. Linezolid possesses excellent microbial activity against a wide variety of Gram-positive pathogens including those resistant to methicillin and vancomycin (Vancocin, Eli Lilly). Linezolid is available for intravenous and oral administration and possesses excellent bioavailability. It exhibits good penetration into pulmonary, as well as skin and related structure tissues, and does not require dosage adjustment in hepatic or renal dysfunction. Linezolid is generally well-tolerated, with the predominant adverse effect manifesting as a duration dependent, reversible thrombocytopenia. Linezolid possesses monoamine oxidase inhibitor activity and caution is warranted with coadministration of adrenergic or seritonergic medications. Clinical trials conducted with linezolid in skin and structure infections, lower respiratory tract infections and vancomycin-resistant enterococcal infections demonstrate that linezolid is an effective therapy. Recent data suggest that linezolid may be superior to vancomycin for the treatment of infections caused by methicillin-resistant S. aureus. Linezolid is an excellent and promising new antibiotic for the treatment of resistant Gram-positive pathogens.     

肠球菌的耐药性及脉冲场凝胶电泳分型研究

目的研究临床分离的肠球菌对常用抗生素的耐药性及肠球菌与感染性疾病的关系。方法应用纸片扩散法检测从临床标本中分离的３１１株肠球菌的耐药性；脉冲场凝胶电泳（ＰＦＧＥ）对细菌分型；病例回顾性分析。结果肠球菌对临床常用的１５种抗生素的耐药率以万古霉素最低；其次为氨苄西林／舒巴坦耐药率为１７．４％；亚胺硫霉素耐药率为１８．３％。粪肠球菌与屎肠球菌对抗生素的耐药率有明显差异。应用ＰＦＧＥ法将粪肠球菌分为Ａ型及亚型、Ｂ型、Ｃ型及亚型、Ｄ型，屎肠球菌分为Ａ、Ｂ、Ｃ型。结论肠球菌对临床常用的１５种抗生素的敏感性以万古霉素最敏感。肠球菌引起的不同系统感染，以泌尿系统最常见。ＰＦＧＥ对肠球菌感染流行监测是一个有力的工具。     

424株临床分离肠球菌属细菌的耐药性变异

目的探讨肠球菌属临床分离情况与耐药变迁,为指导临床合理用药,控制感染提供依据。方法对广东省东莞中山大学附属东华医院2007--2009年临床送检标本进行常规微生物培养、鉴定和药敏试验,并用WHONET5．4软件统计分析这3年间肠球菌临床分离株在各标本、科室中的分布与耐药性的变迁情况。结果2007--2009年临床分离出肠球菌属细菌424株,其中粪肠球菌338株,占79．7％,屎肠球菌75株,占17．7%,鸟肠球菌11株,占2．6％;肠球菌属在各标本中的分布以尿液为主,占50．2％,其次为伤口分泌物（14．4％）、血液（12．5％）。3年来肠球菌属的菌种和耐药均发生了较大变化,粪肠球菌所占比率每年保持在80％左右,屎肠球菌呈逐年上升趋势,从2007年的13．9%上升至2009年的20．9％,而鸟肠球菌则逐年下降,从4．7％降至0．6％。粪肠球菌对红霉素和四环素的耐药率最高,分别为79．4％～85．7％和84．1％～87．4%,屎肠球菌对氨苄西林、青霉素以及呋喃妥因的耐药率明显高于粪肠球菌,对红霉素、左氧氟沙星、青霉素的耐药率高达80％以上,对呋喃妥因、高浓度的庆大霉素、环丙沙星、四环素、氨苄西林等抗菌药物的耐药率也接近或超过50％。2007年发现1株屎肠球菌对万古霉素耐药。结论肠球菌属耐药性较为严重,不同菌种耐药性有所差异。临床抗感染治疗应以分离菌株的体外抗菌药物敏感性为依据,合理选用抗菌药物,以提高疗效。     

271株肠球菌属细菌的分布和耐药性分析

目的了解内蒙古鄂尔多斯市中心医院临床分离的肠球菌属细菌的分布情况及对各类抗菌药物的耐药性。方法使用VITEK 2 compact全自动细菌检测分析系统对2010年1月至2013年6月从临床标本中分离的271株肠球菌属细菌进行菌种鉴定和药敏试验,并用WHONET5．6软件对结果进行统计分析。结果271株肠球菌属细菌中,屎肠球菌137株（50．6％）,粪肠球菌80株（29．5％）,其他肠球菌54株（19．9％）。肠球菌属细菌主要分离自尿液69株（25．5％）、脓液40株（14．8o,4）、伤口等分泌物34株（12．5％）。粪肠球菌对万古霉素和利奈唑胺的耐药率分别为1．3％和1．5％;未检出呋喃妥因耐药株;对青霉素和氨苄西林的耐药率较低,分别为11．8％和2．6％;对高浓度庆大霉素和高浓度链霉素的耐药率分别为31．0％和22．9％。屎肠球菌的耐药率明显高于粪肠球菌,对万古霉素的耐药率为4．4％,未检出利奈唑胺耐药株,对呋喃妥因的耐药率为19．1％;对高浓度庆大霉素和高浓度链霉素的耐药率分别为44．8％和26．4％;但对四环素和奎奴普丁一达福普汀的耐药率低于粪肠球菌,分别为58．3％和0。结论屎肠球菌对抗菌药物的耐药率较粪肠球菌高;并已出现对万古霉素耐药株;其耐药性存在地区和菌种间差异,临床治疗应根据细菌药敏结果合理选用抗菌药物。     

泌尿系统分离肠球菌耐药性分析

目的了解该院患者泌尿系统分离的肠球菌耐药现状,为临床合理用药提供依据。方法对该院2011年1月至2012年12月期间所有泌尿系统分离的肠球菌药敏结果进行回顾性分析。结果泌尿系统共分离肠球菌109株,屎肠球菌分离率（53.2%）,略高于粪肠球菌（44.0%）。肠球菌对万古霉素、替考拉宁的敏感性最高,均高于90%。发现耐万古霉素的屎肠球菌（VRE）4株,其中3株同时耐高浓度的氨基糖苷类抗菌药物（HLAR）;对红霉素、克林霉素、复方磺胺、阿米卡星、庆大霉素、妥布霉素、苯唑西林、头孢西丁耐药率最高,均高于90%。屎肠球菌对青霉素类、氨苄西林、呋喃妥因、环丙沙星耐药率均高于粪肠球菌;对四环素、奎努普丁/达福普汀耐药率低于粪肠球菌。结论肠球菌是引起泌尿系统感染的重要病原菌之一,且呈多重耐药性,屎肠球菌和粪肠球菌耐药水平差异较大,临床应根据不同种类的肠球菌及药敏结果合理选择抗菌药物。     

尿路感染肠球菌的耐药性分析及临床分布特点

目的 了解引起尿路感染的肠球菌对常用抗菌药物的耐药情况,及其临床分布特点,为临床治疗肠球菌性尿路感染提供参考依据。 方法 对我院2008年1月至2012年12月间临床尿培养检出的肠球菌进行鉴定,采用K-B纸片扩散法进行药敏试验,用WHONET 5.6软件对药敏结果进行统计分析,用Excel表对患者的临床分布特点进行分析。 结果 从临床尿路感染患者中分离出的111株肠球菌中,屎肠球菌61株(55.0%),粪肠球菌47株(42.3%),其他种类肠球菌3株(2.7%)。药敏结果显示引起尿路感染的肠球菌对临床常用抗菌药物耐药严重,耐药率最低的是万古霉素。屎肠球菌对大多数抗菌药物的耐药率要明显高于粪肠球菌,但是氯霉素和四环素例外。肠球菌引起的尿路感染以50岁以上的患者为主,占86.5%;感染最多见于泌尿外科病房和重症医学科,分别占26.1%和22.5%。 结论 肠球菌已成为尿路感染的重要病原菌,屎肠球菌的比率已超过粪肠球菌,不同种类的肠球菌耐药性差别大,应加强对重点人群的监测和管理,并根据药敏结果、感染的严重程度合理选择适当的抗菌药物。     

Absence of synergistic activity between ampicillin and vancomycin against highly vancomycin-resistant enterococci.

The emergence of clinical enterococcal isolates resistant to both ampicillin and vancomycin is a cause of great concern, as there are few therapeutic alternatives for treatment of infections caused by such organisms. We evaluated the effects of the combination of ampicillin with vancomycin against vancomycin-resistant clinical enterococcal isolates. Using both the checkerboard technique and time-kill curves, we examined 28 strains of enterococci (17 Enterococcus faecalis and 11 Enterococcus faecium strains) with different levels of resistance to vancomycin. Of these, 15 strains were also highly gentamicin resistant, and 9 demonstrated resistance to ampicillin. Only seven strains of E. faecalis were inhibited synergistically by the combination of vancomycin with ampicillin, and even then, the concentrations of vancomycin at which synergism was demonstrated were above levels achievable in serum. None of the ampicillin-resistant isolates (all E. faecium) were inhibited synergistically at any concentration of the drugs. In no instance was bactericidal synergism observed, and in most cases the combination resulted in less killing than with ampicillin alone. Antagonism was not observed at clinically relevant concentrations. The results of this study suggest that the combination of vancomycin with ampicillin has little to offer against these emerging pathogens.     

肠球菌感染的临床调查

目的：了解肠球菌所致感染的概况及其对抗菌药的敏感性。方法：调查与分析复旦大学附属华山医院1998年6月～1999年3月临床分离获肠球菌住院患的临床资料,用KB法测定细菌药敏。结果：116例患中,属医院感染、院外感染分别为37和13例,带菌66例,感染部位多为尿路(64％)、次为腹腔(18％),粪肠球菌(64％)多于屎肠球菌(36％)。患严重基础疾病、接受介入诊疗操作、应用广谱抗菌药可能是肠球菌医院感染的危险因素。药敏结果显示：氨苄西林、万古毒素对肠球菌抗菌活性相对较高,抑菌率分别为75．8％和96．9％,屎肠球菌耐药率高于粪肠球菌。结论：肠球菌已成为医院感染患主要病原菌之一,及时、合理诊治是治愈该类感染的关键。     

Treatment and prevention of enterococcal infections – alternative and experimental approaches

Enterococci are one of the leading types of organisms isolated from infections of hospitalised patients and the third most common cause of nosocomial bloodstream infections. They contribute significantly to patient mortality and morbidity, as well as healthcare costs. The emergence of resistance against virtually all clinically available antibiotics and the ability to transfer these resistance determinants to other pathogens demonstrates the urgency for an improved understanding of enterococcal virulence mechanisms, and the development of alternative treatment and prevention options. This article reviews new antimicrobials, vaccine targets, bacteriophage therapy, as well as treatments targeting virulence factors and biofilm, for their potential to treat and/or prevent enterococcal infections. Although clinical isolates often cause serious infections, so-called ‘non-pathogenic’ strains are used as therapeutics in the form of probiotics. Understanding the differences between true pathogens and beneficial commensals may help to evaluate future treatment and prophylactic options.     

Treatment and prevention of enterococcal infections--alternative and experimental approaches

Enterococci are one of the leading types of organisms isolated from infections of hospitalised patients and the third most common cause of nosocomial bloodstream infections. They contribute significantly to patient mortality and morbidity, as well as healthcare costs. The emergence of resistance against virtually all clinically available antibiotics and the ability to transfer these resistance determinants to other pathogens demonstrates the urgency for an improved understanding of enterococcal virulence mechanisms, and the development of alternative treatment and prevention options. This article reviews new antimicrobials, vaccine targets, bacteriophage therapy, as well as treatments targeting virulence factors and biofilm, for their potential to treat and/or prevent enterococcal infections. Although clinical isolates often cause serious infections, so-called 'non-pathogenic' strains are used as therapeutics in the form of probiotics. Understanding the differences between true pathogens and beneficial commensals may help to evaluate future treatment and prophylactic options.     

儿童患者中肠球菌属临床分离株耐药特征分析

目的了解儿童患者临床分离肠球菌属的耐药特征，指导临床合理用药。方法测定11种抗菌药物对158株肠球菌的MIC，Nithocefin纸片法检测B内酰胺酶，数据用WHONET5．3软件分析处理。结果158株儿童临床分离肠球菌中，粪肠球菌、屎肠球菌、坚韧肠球菌、鸟肠球菌和海氏肠球菌分别占56．3％、39．9％、1．3％、1．3％和1．3％；屎肠球菌对氨苄西林、阿莫西林-克拉维酸和环丙沙星的耐药率分别为96．8％，95，2％和84．1％，粪肠球菌对上述3种抗菌药的耐药率分别为23．6％，18％和49，4％，屎肠球菌的耐药率明显高于粪肠球菌（P〈20，001）；粪肠球菌出现2株万古霉素MIC为8mg／L的耐药菌，粪肠球菌和屎肠球菌对替考拉宁全部敏感。儿童患者中多重耐药肠球菌属菌株占88．6％。结论儿童患者肠球菌属的耐药状况十分严重，尤其屎肠球菌对B内酰胺类、氨基糖苷类和氟喹诺酮类抗菌药耐药率很高。     

Novel antibiotic regimens against Enterococcus faecium resistant to ampicillin, vancomycin, and gentamicin.

Enterococci have emerged as significant nosocomial pathogens. Enterococci with resistance to commonly used antibiotics are appearing more frequently. We encountered at our institution several infections caused by Enterococcus faecium with high-level resistance to ampicillin, vancomycin, and gentamicin. The optimal antibiotic therapy for serious infections with unusually resistant enterococci has not been established. Using time-kill studies, we tested the effectiveness of various antibiotic combinations against 15 isolates of multidrug-resistant enterococci. No antibiotic was consistently effective when used alone. The combination of ampicillin plus ciprofloxacin was bactericidal for the 12 isolates for which the ciprofloxacin MIC was < or = 8 micrograms/ml. The combination of ciprofloxacin plus novobiocin also demonstrated activity against these isolates. No combination was found to be bactericidal for the remaining three isolates, which were highly ciprofloxacin resistant. These antibiotic combinations may be important for the future treatment of serious infections caused by these resistant pathogens.     

Update on vancomycin resistance

Enterococci can be responsible for severe infections such as endocarditis, meningitis and septicaemia and are one of the most important causes of nosocomial infections. Resistance in enterococci concerns many classes of antibiotics including, since 1986, glycopeptides. These antibiotics act by blocking cell wall formation, and resistance is due to synthesis of modified peptidoglycan precursors. Resistance can be acquired or intrinsic and strains may be resistant to vancomycin and teicoplanin, or to vancomycin only. Five types of glycopeptide resistance and their biochemical mechanisms have been described. Furthermore, strains that are dependent on vancomycin for growth have been isolated from clinical samples. Data suggest that resistance could originate in glycopeptide-producing organisms or in enterococcal species intrinsically resistant to these antibiotics.     

Comparison of daptomycin, vancomycin, and ampicillin-gentamicin for treatment of experimental endocarditis caused by penicillin-resistant enterococci.

Infections with enterococci that are resistant to multiple antibiotics are an emerging clinical problem. We evaluated the antibiotic treatment of experimental enterococcal endocarditis caused by two strains with different mechanisms of penicillin resistance. Enterococcus faecalis HH-22 is resistant to aminoglycosides and penicillin on the basis of plasmid-mediated modifying enzymes; Enterococcus raffinosus SF-195 is susceptible to aminoglycosides but is resistant to penicillin on the basis of low-affinity penicillin-binding proteins. Animals infected with strain HH-22 received 5 days of treatment with the following: no treatment; daptomycin (20 mg/kg of body weight twice daily [b.i.d.], intramuscularly [i.m.]), vancomycin (20 mg/kg b.i.d., intravenously), or ampicillin (100 mg/kg three times daily, i.m.) plus gentamicin (2.5 mg/kg b.i.d. i.m.). Although vancomycin was superior to ampicillin-gentamicin (P less than 0.01), daptomycin was significantly better than all other treatment regimens (P less than 0.01) in reducing intravegetation enterococcal densities, although no vegetations were rendered culture negative by this agent. Animals infected with strain SF-195 received 5 days of no therapy, ampicillin, ampicillin-gentamicin, vancomycin, or daptomycin (all at the dosage regimens described above). Daptomycin, vancomycin, and ampicillin-gentamicin each lowered intravegetation enterococcal densities significantly better than did ampicillin monotherapy or no treatment (P less than 0.01); moreover, these three treatment regimens rendered significantly more vegetations culture negative than did ampicillin monotherapy or no treatment (P less than 0.05). Serum daptomycin levels remained above the MICs and MBCs for both enterococcal strains throughout the 12-h dosing interval used in the study. Daptomycin and vancomycin were both active in vivo in these models of experimental enterococcal endocarditis caused by penicillin-resistant strains, irrespective of the mechanism of resistance. This activity correlated with the unique cell wall sites of action of these agents (binding to lipoteichoic acid and pentapeptide precursor, respectively) compared with the sites of action of beta-lactams (penicillin-binding proteins). Beta-Lactamase production by strain HH-22 precluded in vivo efficacy with ampicillin-gentamicin combinations. In contrast, this combination was active in vivo against strain SF-195, which exhibited intermediate-level penicillin resistance (MIC, 32 micrograms/ml), likely reflecting the ability of high-dose ampicillin to achieve enough binding to low-affinity penicillin-binding proteins to cause augmented aminoglycoside uptake.     

Ceftaroline fosamil: a new cephalosporin active against resistant Gram-positive organisms including MRSA

The growing prevalence of resistant Gram-positive pathogens such as methicillin-resistant Staphylococcus aureus continues to pose a dilemma to clinicians. With strains developing reduced susceptibility to vancomycin, effective and well-tolerated antibiotics to combat these resistant pathogens are needed. Ceftaroline is a new parenteral cephalosporin that has been available in the USA for almost 2 years. Similar to other cephalosporins, it is well tolerated with mostly mild adverse events; however, compared with existing parenteral cephalosporins, ceftaroline has the unique attribute of being bactericidal against resistant Gram-positive aerobes including both hospital- and community-acquired methicillin-resistant S. aureus, S. aureus strains with reduced susceptibility or complete resistance to vancomycin, and resistant Streptococcus pneumoniae including multidrug-resistant strains. Current indications in the USA and Europe include treatment of adults with complicated skin, skin-structure infections and community-acquired pneumonia. This paper will review the properties of ceftaroline, its spectrum of activity, clinical use, safety profile and future role.     

Phage Therapy in the Resistance Era: Where Do We Stand and Where Are We Going?

PurposeWidespread antibiotic-resistant bacteria are threatening the arsenal of existing antibiotics. Not only are antibiotics less likely to be effective today, but their extensive use continues to drive the emergence of multidrug-resistant pathogens. A new-old antibacterial strategy with bacteriophages (phages) is under development, namely, phage therapy. Phages are targeted bacterial viruses with multiple antibacterial effector functions, which can reduce multidrug-resistant infections within the human body. This review summarizes recent phage therapy clinical trials and patient cases and outlines the fundamentals behind phage treatment strategies under development, mainly through bench-to-bedside approaches. We discuss the challenges that remain in phage therapy and the role of phages when combined with antibiotic therapy.MethodsThis narrative review presents the current knowledge and latest findings regarding phage therapy. Relevant case reports and research articles available through the Scopus and PubMed databases are discussed.FindingsAlthough recent clinical data suggest the tolerability and, in some cases, efficacy of phage therapy, the clinical functionality still requires careful definition. The lack of well-controlled clinical trial data and complex regulatory frameworks have driven the most recent human data generation on a single-patient compassionate use basis. These cases often include the concomitant use of antibiotics, which makes it difficult to draw conclusions regarding the effectiveness of phages alone. However, human data support using antibiotics as phage potentiators and resistance breakers; thus, phage adjuvants are a promising avenue for near-term clinical development. Current knowledge gaps exist on the appropriate routes of administration, phage selection, frequency of administration, dosage, phage resistance, and pharmacokinetic and pharmacodynamic properties of the phages. In addition, we highlight that some phage therapies have mild adverse effects in patients.ImplicationsAlthough more translational research is needed before the clinical implementation is feasible, phage therapy may well be pivotal in safeguarding humans against antibiotic-resistant infections.     

高水平氨基糖苷耐药肠球菌的监测

目的了解高水平氨基糖苷耐药(HLAR)肠球菌的分离率,探讨青霉素类或糖肽类与氨基糖苷类药物合用对院内感染肠球菌的协同杀菌作用,为临床治疗肠球菌感染提供参考与指导。方法采用VITEK-AMS仪器对分离自临床标本的101株肠球菌进行氨苄西林、青霉素、万古霉素耐药性和高水平庆大霉素耐药(HLGR)及高水平链霉素耐药(HLSR)测定。结果101株肠球菌中,粪肠球菌、屎肠球菌、鸟肠球菌、母鸡肠球菌和耐久肠球菌菌株分别为71、13、8、7和2株。药敏测试结果显示肠球菌对氨苄西林、青霉素、万古霉素耐药分别为21、34和0株;HLGR和HLSR分别为79株和46株。结论院内感染肠球菌对抗菌药物存在严重耐药性,合理的抗菌药物治疗对高水平氨基糖苷耐药肠球菌感染患者的康复尤为重要。