Korean J Clin Microbiol Vol. 11, No. 2, October, 2008 Resistance Mechanism and Epidemiology of Vancomycin-resistant Enterococci Wee Gyo Lee Department of Laboratory Medicine, Ajou University School of Medicine, Suwon, Korea Since vancomycin-resistant enterococci (VRE) were first isolated in Europe, rates of VRE colonization and infection have risen steadily. Today VRE have emerged as important nosocomial pathogens worldwide; hence, it is crucial to understand the underlying mechanism in the spreading of VRE. This article reviews the mechanism of resistance to vancomycin and global epidemiology of VRE, as well as the current molecular techniques that are being applied to the epidemiological studies of VRE. (Korean J Clin Microbiol 2008;11:71-77) Key Words: Enterococci, Vancomycin, Epidemiology, Molecular techniques 서 Vancomycin 내성장알균 (vancomycin-resistant enterococci, VRE) 은 1986년유럽에서처음보고된이래현재에이르기까지 20여년간전세계적으로분리빈도가증가하여중요한병원감염균으로자리잡고있다 [1]. National Nosocomial Infections Surveillance (NNIS) 보고에의하면 2003년중환자실환자에서분리된장알균중 VRE 빈도를 28.5% 로보고하였고, European Antimicrobial Resistance Surveillance System (EARSS) 의 2006년보고에의하면 vancomycin-resistant Enterococcus faecium의분리율이유럽국가마다차이가있으나 42% 까지증가하였다 [2,3]. 국내에서는 1992년최초로 vana Enterococcus durans가발견된이래로 1997년까지드물게분리되다가 1998 년부터경구용 vancomycin 사용의증가와더불어현저하게증가하고있다 [4,5]. VRE의대부분은기존의타약제에내성을보이는다제내성균으로최근에는 quinupristin-dalfopristin이나 linezolid 내성장알균의빈도도증가하고있어치료약제선택에한계가있고, 항균제내성을다른세균에용이하게전달할수있는특성이있어병원감염관리가시급한시점이다 [6-9]. 또한 2002년에는 vana 유전자를가진 vancomycin 내성황색포도알균 (Vancomycin-resistant S. aureus, VRSA) 까지출현하여현재까지약 7주의 VRSA가보고되었다 [10-13]. Received 21 July, 2008, Accepted 30 August, 2008 Correspondence: Wee Gyo Lee, Department of Laboratory Medicine, Ajou University School of Medicine, San 5, Woncheon-dong, Yeongtong-gu, Suwon 442-749, Korea. (Tel) 82-31-219-5785, (Fax) 82-31-219-5778, (E-mail) weegyo@ajou.ac.kr 론 VRE는현재광범위 cephalosporin과항혐기성제제의무분별한사용과병원감염관리의부족으로인하여대부분의병원에서토착화된상태이며시간이갈수록빈도가증가하고있다. 이에 VRE의내성기전과역학을이해하고병원감염관리에신중을기해야하겠다. 내성기전 1. 생화학적기전 Vancomycin은그람양성균의세포벽합성단계중최종전구물질의말단인 D-alanine-D-alanine과결합하여더이상의세포벽합성을방해함으로써항균작용을나타낸다. VRE는다음과같은 2 가지경로를통하여세포벽합성을계속함으로써내성을나타낸다 (Fig. 1) [1,14-16]. 1 peptidoglycan 합성과정중 D-alanine-D-alanine 대신 vancomycin에친화성이떨어지는 D-alanine-D-lactate나 D-alanine-D-serine을만들어 vancomycin 의결합을막는다. 2 장알균염색체에원래부터있던 ddl 유전자에의해정상적으로합성된 D-alanine-D-alanine을분해한다. 2. 유전적기전 VRE는내성유전자군중 resistance ligases의염기서열에따라 vana, vanb, vanc, vand, vane, vang의 6가지내성형으로나뉜다 (vanf는 Paenibacillus popilliae에서발견되어명명되었다 )[17,18]. 이중 vanc를제외한 5가지내성형은획득성내성이고, vana와 vanb만이내성전달이증명된바있다. 각내성형의특징은 Table 1과같다 [16]. 각내성형에대하여표현형을나타낼때는대문자 Van으로표기하고, 유전자형을나타낼때는소문자이탤릭체 van으로표기한다. 71
72 Korean J Clin Microbiol 2008;11(2):71-77 Fig. 1. Peptidoglycan biosynthesis and mechanism of action of vancomycin. Binding of the antibiotic to the C-terminal D-Ala-D-Ala of late peptidoglycan precursors prevents reactions catalyzed by transglycosylases, transpeptidases, and D,D-carboxypeptidases. Ddl, D-Ala: D-Ala ligase; MurF, a synthetase protein; UDP, uracil diphosphate. Adapted from reference 16. Table 1. Level and type of resistance to vancomycin in enterococci. Adapted from reference 16 Acquired resistance level, type Intrinsic resistance, Strain Low low level, characteristic High Variable, Moderate, type VanC1/C2/C3 VanA VanB VanD VanG VanE MIC, mg/l Vancomycin 64 100 4 1,000 64 128 16 8 32 2 32 Teicoplanin 16 512 0.5 1 4 64 0.5 0.5 0.5~1 Conjugation Positive Positive Negative Positive Negative Negative Mobile element Tn1546 Tn1547 or Tn1549............ Expression Inducible Inducible Constitutive Inducible Inducible Constitutive inducible Location Plasmid chromosome Plasmid chromosome Chromosome Chromosome Chromosome Chromosome Modified target D-Ala- D-Lac D-Ala- D-Lac D-Ala- D-Lac D-Ala- D-Ser D-Ala- D-Ser D-Ala- D-Ser Note. D-Ala- D-Lac, D-alanine- D-lactate; D-Ala- D-Ser, D-alanine- D-serine. 1) VanA 형 : vana형내성은획득성유도성내성으로 vancomycin과 teicoplanin에내성을나타낸다. vana gene cluster 는주로 transposon Tn1546에포함되어있으며, prototype Tn1546은 10,581 bp의크기로 transposase (ORF1), resolvase (ORF2) 및 vana gene cluster로구성되어있다 [19,20]. VanA VRE는 prototype Tn1546에다양한 Insertional Sequences (IS1216V, IS1251, IS1476, IS1542 등 ) 가삽입된형태가대부분이며이는내성유전자의전파를용이하게하기위한유전자진화과정의결과로추정된다 [21-24]. vana형은 VRE 중가장흔한형이며대부분 E. faecium이다. VRSA에서발견된내성형도아직까지는 vana 뿐이다 [12]. VanB-phenotype vana genotype VRE; vana VRE 중 teicoplanin에감수성이거나 intermediate 감수성을나타내는경우로일본, 대만및한국에서보고되었고, 국내검사실에서는드 물지않게분리되고있다 [25-27]. 기전은 vans의점돌연변이, vany나 vanz 유전자의부분결실이나완전결실등으로밝혀져있다 [28]. vans의점돌연변이는 Hashimoto 등이처음으로보고하였으나이후보고된대부분의 VanB-phenotype vana genotype VRE는 vans의점돌연변이보다는 vany나 vanz 유전자재조합에의한것으로보고되었다 [25,27]. 항균제감수성검사에서 VanB로보이나내성유전자 PCR시 vana이므로결과판독에유의하여야하고, 이러한균주감염시 teicoplanin 치료효용성에관하여는아직논란이있으나송등은 in vivo 연구를통해치료실패의가능성이있음을보고하였다 [29]. 2) VanB 형 : vanb형내성은획득성유도성내성으로 vancomycin에다양한정도의내성을보이고, teicoplanin 에는감수성을보인다. vanb gene cluster는 vana gene cluster와비교하여 vanz 유전자가없고, vanw 유전자가있으며, Tn1547과
Wee Gyo Lee : Resistance Mechanism and Epidemiology of Vancomycin-resistant Enterococci 73 Tn5382에포함되어있다 [30,31]. vanb 유전자내의유전자변이에따라 vanb1, vanb2, vanb3의 3가지형으로나뉜다 [32]. 이중 vanb2형이흔하며아형과 vancomycin 내성정도와는연관성이없다 [33]. vanb형 VRE는유럽보다는미국에서흔한데이는미국에서 teicoplanin이사용되고있지않기때문이다 (vancomycin은사용시 vana/vanb VRE를모두선택하나 teicoplanin는 vana VRE만을선택하기때문이다 ). 3) VanC 형 : 선천성구성적내성으로 vancomycin 에저도내성을나타내며 teicoplanin에는감수성이다. 내성유전자는염색체내에위치하며, vanc1은 E. gallinarum, vanc2는 E. casseliflavus, vanc3은 E. flavescens에서보인다 [34]. VanC형은자연내성이므로감염관리대상은아니나감별동정이필요하다. 왜냐하면 VanC형은내성이전파되지않으므로분리시감염관리를할필요가없기때문에불필요하게감염관리를하게되는경우를방지하고, 만약 VanB형이 VanC형으로동정된경우는감염관리가필요한경우임에도불구하고방치하게되는것을막기위함이다 [35]. VanC with vana/vanb VRE; 최근 vana나 vanb 유전자가 VanC VRE로전달되어함께보유하는경우가많으며이런경우에는표현형은 VanA와동일하게 vancomycin과 teicoplanin 에내성을나타내면서균종동정시에는 VanC 균종으로동정되므로검사실에혼동을초래할수있다 [36,37]. 이는 VanC 균주가 vana나 vanb 유전자를수평전달받은것으로이러한균주는다른장구균에 vancomycin 고도내성을전달할수있으므로임상적으로는 VanA나 VanB VRE 감염과같으며감염관리도동일하게하여야한다. 4) VanD 형 : 구성적내성으로염색체내에위치하며다른장알균으로전달이보고된바없다 [38]. 아형은 vand1-vand5까지있다 [39,40]. 5) VanE 형 : vane형은유도성내성으로 vancomycin에저도내성을나타내며, E. faecalis에서보고되었다 [41]. 생화학적으로 vanc형과같이 peptidoglycan 전구체말단이 D-alanine- D-serine으로구성되어있고, 약 55% 유사성을보인다. 6) VanG 형 : E. faecalis에서보고되었고, vancomycin MIC 12 16 mg/l, teicoplanin MIC 0.5 mg/l 이하를보인다 [42]. vang operon은 vanc나 vane와유사하게 D-alanine-D-serine을생성한다. 유전자전달은아직증명된바없다. 7) Vancomycin-dependent enterococci: 성장시 vancomycin을필요로하는장알균으로대개 VanA/VanB VRE에서나타났다. Vancomycin 치료를장기간시행한환자에서분리된 VRE에서파생된것으로, 기전은염색체에있는 ddl ligase의기능이소실되어 D-alanline-D-alanine 생성이되지않는경우이다 [43,44]. 일반배양에서음성으로나오며 vancomycin을포함한배지에서 vancomycin에의하여 vancomycin 내성유전자가유도되어성장이가능하므로검사실에서검출이안되는수가많다. 대개 혈액배양병에서처음배양시배양이되다가계대배양시음성으로나오는경우가흔하다. Vancomycin 치료중단시 VRE 로다시 reversion되므로치료에유의하여야한다. 역학 1. 대륙별역학 VRE가최초로발생하기시작한유럽에서는 VRE의병원내분리율이낮고, 다양한균주에의한산발적발생양상을보이며, 가축이나환경에서분리되고있어사람에서의 VRE 발생이먹이사슬에의한연쇄반응의산물로추측하고있다 [45]. 유럽은 1970년대중반이후로 vancomycin과교차내성이생기는항생제 avoparcin을가축의성장촉진제로사용하다가 VRE 감염이문제가되어 1997년부터금지하였다. 유럽보다 2년늦게 VRE가나타나기시작한미국은유럽과는두가지면에서차이가있다. 첫째는 avoparcin이축산사료로허용되지않았고, 둘째는병원에서 vancomycin 사용이많다는점이다. 이로인하여가축이나일반환경및건강인에서는분리되는경우는극히드물다 [46,47]. 미국에서의 VRE 감염은병원감염의양상으로발생하고병원내, 병원간및도시간에단일균주에의한전파로시작하여현재는 polyclonal endemicity를보이고있다 [48,49]. 국내에서의 VRE 발생은병원감염으로전파되는미국의경우와유사하여처음대형병원을중심으로발생하기시작하여최근에는중소병원까지토착화의양상을보이고있다 [33]. 국내에서도유럽과같이 avoparcin을가축의배합사료제조시사용하여왔고가축에서 VRE 분리도보고되고있지만 vana Tn1546 구조분석이나 pulsed-field gel electrophoresis (PFGE) 분석상가축균주가사람으로전파된증거는아직없으며건강인에서분리된예도없다 [50,51]. 2. VRE 집락화와감염 VRE에의한감염을위해서는장내집락화가선행되어야한다. VRE 장내집락화는사람간전파와 selective antibiotic pressure 에의해발생한다. VRE 장내집락화가선행된후숙주의상태에따라감염으로진행되기도하고, 감염진행없이다른환자로 VRE를전파하는보균자의역할만을하기도한다 [52]. VRE 전파를방지하기위하여 Centers for Disease Control 의 Hospital Infection Control Practices Advisory Committee (HICPAC) 기준에따라 VRE 집락이형성된환자는격리하고적어도 1주 1회변배양을시행하여연속적으로 3회음성인경우격리를해지하도록하고있다 [53]. 국내에서도대부분의대학병원의경우이기준에따른격리조치를취하고있다. 하지만장내집락은소멸되었다가도재집락되는경우가흔하다. 이는집락이완전히없어졌다기보다는장내집락수가줄어서배양민감도가떨어진것으로추정된다. 장내집락수가줄어서
74 Korean J Clin Microbiol 2008;11(2):71-77 연속적인 surveillance 배양 3회음성시격리가해제될수있으나이경우에도장내에는적은수의 VRE가존재하다가다시항균제치료등에의하여재집락을야기하고감염을일으킬수있다. 병원감염관리대상이되는 VRE는내성전달이증명된 VanA형과 VanB형이며, VanC형중 vana나 vanb 유전자가전달되어서같이존재하는 VRE도대상에포함된다. 3. 분자유전학적역학 VRE 감염은전세계적으로 VanA E. faecium이대부분이다. 그래서분자유전학적역학분석도대개 VanA E. faecium 을대상으로하고있다. VRE 전파양상을분석하기위하여전통적으로는 pulsed-field gel electrophoresis (PFGE) 법을많이이용하나이는단기간의균주간유전적상관관계만을반영하고, 장기간유전적상관관계나유전자진화등을알아낼수없는단점이있다. 이를위하여 PFGE 이외의분자유전학적역학분석법이도입되었다. 1) Tn1546 typing: VRE의전파양상을알아내기위한분자생물학적연구결과들에의하면 VRE가분리되기시작한초기에는균주들이유사한 PFGE 결과를보여단일균주에의한 VRE의유행이전파의주요기전이라고여겨졌다. 그러나, VRE 가분리되기시작한지수년이지난후에는많은연구에서유전적관련성이없는균주들이동일한내성유전자의구조를가지는결과가보고되어내성유전자의수평이동에의한 VRE의전파가주요기전으로밝혀졌다. 역학분석을위하여내성유전자의구조분석인 Tn1546 typing이이용된다 [20-24]. vana gene cluster는 vans, vanr, vanh, vana, vanx와 vany의 6개유전자들로구성되어있으며, mobile DNA element인 Tn1546 내에포함되어있다 [23]. Tn1546은최초로보고된균주인 E. faecium BM4147에서는유전자재조합이전혀일어나지않았고이를 prototype으로하여 Tn1546 typing을시행한다. 대부분의임상분리주들은 prototype에서 point mutations, insertion sequence (IS) elements와 deletions 등의다양한유전자재배열을보인다. 이러한유전자재배열을하는이유는내성유전자를좀더용이하게전파하기위한것으로추정된다. 현재까지알려진삽입IS는 IS1216V, IS1251, IS1542, IS1476, IS19 등이있으며이들은대륙별차이를보이는데, IS1216V는전세계적으로널리분포하고, IS1542의경우는대부분유렵분리주에서, IS1251은미국에서보고되었다. 국내에서분리된 VRE의대부분은지역이나병원의차이가없이 IS1542와 IS1216V가삽입되어있어유럽분리주와유사하다 [20-24,54]. 2) Multilocus sequence typing (MLST): PFGE법은유전자의단기적변화만을반영하고또한검사방법의표준화가수립되어있지않아검사실간비교가힘들어서전세계적인 VRE 역학을규명하기어려운단점이있다. MLST법은균주내 multiple housekeeping genes의유전적다양성을분석하는방법으로 7개의 house-keeping genes (450 500 bp) 의염기서열을분석하여유형 (ST) 을결정한다. 이는유전자의장기적역학변동을반영하고검사실간변이가없어전세계적역학을추정할수있다. E. faecium 의경우 adk (adenylate kinase), atpa (ATP synthase, alpha subunit), ddl (D-alanine:D-alanine ligase), gyd (glyceraldehyde-3-phosphate dehydrogenase), gdh (glucose-6-phophate dehydrogenase), purk (phosphoribosylaminoimidazol carboxylase ATPase subunit), psts (phosphate ATP-binding cassette transporter) 유전자의염기서열분석후 ST를결정한다 [55]. Fig. 2. eburst diagram of the analysis of the sequence types (STs) of the entire public E. faecium MLST database. The circle indicates the CC17. Adapted from MLST web sites. http://www.mlst.net (last visited on 26 June 2008).
Wee Gyo Lee : Resistance Mechanism and Epidemiology of Vancomycin-resistant Enterococci 75 Type 결정은 MLST website (http://www.mlst.net) 를이용한다. 미국과유럽에서분리된 VRE에대한 MLST 분포는균주들은숙주에따른특이성을보였고, 병원내집단발생의원인이된균주는 house-keeping gene 중 purk 유전자와병독성유전자인 esp 유전자에서독자적인유전적특성을보였다 [56]. 국내에서분리된 VRE에대한연구에의하면국내분리주는총 11 개의 ST를나타냈다 [57, 58]. 가장흔한 ST는 ST 78이었고이는 Italy의유행균주형이다 [59]. 두번째로흔한형은 ST 203형으로이는독일등에서보고되었다 [60]. 국내에서분리된 VRE MLST는유럽형과유사함을알수있었다. 3) Multiple-locus variable number tandem repeats analysis (MLVA): MLST법이 housekeeping genes의유전자서열변이를알아보는것인데비하여 MLVA는세균유전자내의 small repetitive elements의반복수 (variable number of tandem repeats, VNTRs) 를비교하는방법이다 [61]. MLST법이염기서열분석을해야하는반면 MLVA는특정 primer를이용하여 PCR만을시행함으로써분석할수있다는편리한점이있다. 반복수분석후 MLVA website (http://www.mlva.umcutrecht.nl) 에서유형 (MT) 을결정한다. 4. Clonal Complex 17 Clonal Complex 17 (CC17) 은 MLST 상 ST 17형을포함하여이로부터파생된 ST에속하는군으로전세계의병원에서유행하는 VRE 의대부분을차지하며다음과같은특징을가진다 (Fig. 2). (1) ampicillin 및 quinolone에내성을보이고, (2) variant esp gene이포함된 E. faecium pathogenicity island (PAI) 를보유하고있다 [62, 63]. CC17 은병원환경에오랜기간노출되어적응된군으로전세계적으로발견되고있고, 병원감염이흔하지않았던유럽에서도 CC17에의한집단발생이보고되고있어전세계적으로토착화하는양상을보이고있다. 이러한유전군의병원토착화를 Genetic capitalism 이라하며이는병원에유입된세균중유전적으로병원환경에서생존이유리한군이살아남는것을말한다. CC17 군은초기에 ampicillin 내성을보유한균주들이병원환경에서선택되고, 이중병독성인자인 PAI 양성군이전파력이우세하게되고이러한군이병원환경에적응되어있다가 vancomycin 내성도획득한것으로추정된다. 국내실정도다르지않아병원에서분리되는대부분의균주가 CC17에속한다 [57,58]. 결론장알균은병독성이높은균은아니나중요한병원감염균이며최근 VRE가병원환경에토착화되는양상을보임에따라의료계에서도 VRE에관한역학과최신정보를활용하여적극적인 VRE 관리를시행하여야한다. 궁극적으로 CC17 군의토 착화방지를위하여항균제사용을관리함으로써감수성균주로의재구성에노력하여야한다. 현재상황에서는 CC17 군의조기발견을통하여관리함으로써토착화를방지하여야하겠다. 그러므로향후국내 VRE 전파확산방지를위하여국내분리주의유형분석을통한국가적 database를마련하고환자의이송이나전원시정보교환을통하여병원간 VRE, 특히 CC17 군의확산을방지하여야하겠다. 참고문헌 1. Leclercq R, Derlot E, Duval J, Courvalin P. Plasmid-mediated resistance to vancomycin and teicoplanin in Enterococcus faecium. N Engl J Med 1988;319:157-61. 2. NNIS (2004) National Nosocomial Infections Surveillance (NNIS) System Report, Data Summary from January 1992 through June 2004, issued October 2004. Am J Infect Control 2004;32:470-85. 3. EARSS. EARSS web sites. EARSS Annual Report 2006. http://www.rivm.nl/earss/[online] (last visited on 26 June 2008). 4. Kim JM and Song YG. Vancomycin-resistant enterococcal infections in Korea. Yonsei Med J 1998;39:562-8. 5. Shin JW, Yong D, Kim MS, Chang KH, Lee K, Kim JM, et al. Sudden increase of vancomycin-resistant enterococcal infections in a Korean tertiary care hospital: possible consequences of increased use of oral vancomycin. J Infect Chemother 2003;9:62-7. 6. Werner G, Klare I, Heier H, Hinz KH, Bohme G, Wendt M, et al. Quinupristin/dalfopristin-resistant enterococci of the sata (vatd) and satg (vate) genotypes from different ecological origins in Germany. Microb Drug Resist 2000;6:37-47. 7. Baysallar M, Kilic A, Aydogan H, Cilli F, Doganci L. Linezolid and quinupristin/dalfopristin resistance in vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus prior to clinical use in Turkey. Int J Antimicrob Agents 2004;23:510-2. 8. Herrero IA, Issa NC, Patel R. Nosocomial spread of linezolidresistant, vancomycin-resistant Enterococcus faecium. New Engl J Med 2002;346:867-9. 9. Bae HG, Sung H, Kim MN, Lee EJ, Koo LS. First report of a linezolid-and vancomycin-resistant Enterococcus faecium strain in Korea. Scand J Infect Dis 2006;38:383-6. 10. Centers for Disease Control and Prevention. Staphylococcus aureus resistant to vancomycin-united States, 2002. Morb Mortal Wky Rep 2002;51:565-7. 11. Centers for Disease Control and Prevention. Vancomycin-resistant Staphylococcus aureus-new York, 2004. Morb Mortal Wky Rep 2004:53:322-3. 12. Clark NC, Weigel LM, Patel JB, Tenover FC. Comparison of Tn1546-like elements in vancomycin-resistant Staphylococcus aureus isolates from Michigan and Pennsylvania. Antimicrob Agents Chemother 2005;49:470-2. 13. Zhu W, Clark NC, McDougal LK, Hageman J, McDonald LC, Patel JB. vancomycin-resistant Staphylococcus aureus isolates associated with Inc18-like vana plasmids in Michigan. Antimicrob Agents Chemother 2008;52:452-7. 14. Arthur M, Reynolds P, Couvalin P. Glycopeptide resistance in enterococci. Trends Microbiol 1996;4:401-7. 15. Uttley AH, Collins CH, Naidoo J, George RC. Vancomycinresistant enterococci. Lancet 1988;1:57-8. 16. Courvalin P. Vancomycin resistance in Gram-positive cocci. Clin
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