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1 대한내과학회지 : 제 86 권제 3 호 종설 (Review) 중심정맥관관련감염의진단과치료 경희대학교의과대학내과학교실 박기호 Diagnosis and Management of Central Venous Catheter-Related Infections Ki-Ho Park Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea Use of central venous catheters (CVCs) can lead to catheter-related bloodstream infections (CRBSIs) and such infections are associated with serious morbidity and mortality and with increased health care costs. The diagnosis of CRBSI needs to be accurate for adequate management. Semiquantitative catheter tip culture has been established as standard in most laboratories, but this method requires catheter removal. Catheter-sparing diagnostic methods, such as differential quantitative blood cultures and differential time to positivity have emerged as reliable diagnostic techniques. Management of CRBSIs involves deciding on catheter removal and the type and duration of systemic antimicrobial therapy. Such decisions depend on the identity of the organism causing the bloodstream infection and the clinical and radiographic manifestations suggesting a complicated course. (Korean J Med 2014;86: ) Keywords: Central venous catheter; Bloodstream infection; Bacteremia; Diagnosis; Treatment 중심정맥관 (central venous catheter, CVC) 은항암제, 혈액제제, 항균제, 정맥영양제등을포함한다양한약물의정맥주입및혈액검사와투석에사용되어왔다. 그러나다양한종류의중심정맥관사용은중심정맥관관련감염 (catheter-related infection) 의위험을증가시키고이로인한사망률, 이환율과의료비용의상승을초래한다 [1-4]. 다행히감염예방을위한다양한노력으로미국 [5,6] 과캐나다 [7] 등일부국가에서중심정맥관관련감염의발생률이감소하고있다. 국내병원에서시행된몇개의연구에서도다방면적포괄적중재를통하여중심정맥관관련감염을예방할수있음을보고하였다 [8-11]. 그러나전세계적으로중심정맥관관련감염의발생 률은아직도높은상황이며임상에서적절한진단과치료가여전히중요하다 [12]. 여기서는중심정맥관관련감염의예방보다는주로진단과치료에초점을두고자한다. 이전에이미출판된미국감염학회의권고지침 [13,14] 및종양환자 [15], 호중구감소증환자 [16], 투석환자 [17], 면역저하환자 [18] 에대한권고지침을참고하면서최근에새롭게발표된연구결과를함께다루고자한다. 더불어임상지침에서는자세히다루고있지않지만실제임상에서종종경험하는상황들에대하여정리하였다. Correspondence to Ki-Ho Park, M.D., Ph.D. Division of Infectious Diseases, Department of Internal Medicine, Kyung Hee University Hospital, 23 Kyungheedae-ro, Dongdaemun-gu, Seoul , Korea Tel: , Fax: , parkkiho@hotmail.com Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Ki-Ho Park. CVC-related infections - 역학미국 [5,6] 과캐나다 [7] 등의일부지역에서는감염예방을위한다양한노력으로중심정맥관연관감염 (catheter-associated infection) 의발생률이줄고있다. 미국중환자실입원환자들에서중심정맥관연관혈류감염 (catheter-associated bloodstream infection, CABSI) 은 2001년에 1,000 중심정맥관삽입일당 3.6건이발생하였으나 2009년에는 1.65 건으로감소하였다 [5,6]. 그러나개발도상국들에서는발생률이 1,000 중심정맥관삽입일당 6.8건으로여전히높다 [12]. 최근국내중환자실환자들을대상으로한조사에서는 1,000 중심정맥관삽입일당 3.0건의발생률을보였다 [19]. 병인중심정맥관관련감염은네가지경로를통하여발생할수있다. 첫번째로중심정맥관관련감염의가장흔한원발병소는환자의피부이다 [20-22]. 균에의한환자피부의집락화 (skin colonization) 가심할수록중심정맥관의집락화 (CVC colonization) 와이로인한중심정맥관관련혈류감염 (catheter-related bloodstream infection, CRBSI) 의위험이증가한다 [21,23-25]. 따라서피부의정상균무리인 Staphylococcus aureus와 coagulase-negative staphylococci가중심정맥관말단배양 (catheter tip culture) 에서가장흔하게분리되고 [26,27], 가장흔하게 CRBSI를일으킨다 [28]. 두번째는중심정맥관내강 (lumen) 을통한오염이다. 잦은혈액채취나약물주입은중심정맥관내강을오염시키고, 내강의오염은혈류감염을일으키게된다. 이러한감염경로는특히 2주이상삽입된중심정맥관이나수술을통하여삽입된중심정맥관감염의중요한원인이다 [29,30]. 세번째는다른감염병소 ( 흔히위장관 ) 에서혈행성전파 (hematogenous spread) 를통하여중심정맥관을집락화시키는것이다. 이러한감염경로는특히중증환자나장기거치중심정맥관 (long-term CVC) 을가지고있는환자에서중요하다 [23,31]. 중심정맥관을가진환자에서재발성또는지속적혈류감염이있는경우는중심정맥관이외의원발병소가존재하여서인지중심정맥관을제거하지않아서인지를감별할필요가있다. 이를구별하기위하여중심정맥관을제거하여보는것이도움이되고중심정맥관제거후감염의증상과징 후가소멸되면중심정맥관이지속적또는재발성혈류감염의원인이라고추정할수있다. 마지막으로오염된주입액 (contaminated infusate) 이중심정맥관을통하여주입되는경우도혈류감염을유발할수있다. 최근에는오염된주입액의사용에의한혈류감염은흔하지않으나이로인한의료관련감염의유행이일어날수있어주의가필요하다. 원인미생물 CRBSI 를일으키는가장흔한네가지원인균은 coagulasenegative staphylococci, S. aureus, Candida species, 그람음성막대균 (gram-negative bacilli) 이다 [28]. 감염의경로를고려할때피부의정상균무리인 coagulase-negative staphylococci와 S. aureus가가장흔한 CRBSI의원인이다. 국내중환자실환자의감염을감시한자료에서도 coagulase-negative staphylococci 와 S. aureus가가장흔한원인이었다 [19]. Candida species와그람음성막대균이차지하는비율은환자의기저질환과임상상황에따라달라진다. 진단임상양상발열, 정맥관삽입부위의염증이나화농소견, 패혈증등의증상과징후는중심정맥관관련감염의진단에도움이된다. 발열은중심정맥관관련감염의진단에가장민감한임상지표이지만특이적인지표는아니다. 반대로중심정맥관삽입주위의염증이나화농소견은특이적인지표이지만민감한지표는아니다 [32]. 다른감염병소가없으면서혈액배양에서 S. aureus, coagulase-negative staphylococci, Candida species가분리되면 CRBSI를의심하여야한다 (Table 1). 항균제치료만으로는감염의증상이나징후의호전이없던환자가중심정맥관을제거한후 24-48시간안에호전을보인다면중심정맥관관련감염을의심할수있다 [15,33]. 국소감염국소감염은출구감염 (exit site infection), 터널감염 (tunnel infection), 포켓감염 (pocket infection) 을말한다 [13]. 출구감염이나터널감염은발적, 열감, 압통등의염증소견이중심

3 - 대한내과학회지 : 제 86 권제 3 호통권제 643 호 Table 1. Diagnostic criteria for catheter-related bloodstream infections (CRBSI) Exit site infection Tenderness, erythema, and/or induration 2 cm from the catheter insertion site, with or without bloodstream infection Tunnel infection Tenderness, erythema, and/or induration > 2 cm from the catheter insertion site, with or without bloodstream infection Pocket infection Clinical signs of infection of subcutaneous pocket, with or without bloodstream infection Definite CRBSI (1) Growth of same pathogen from blood culture of peripheral vein and from culture of catheter tip (2) Differential time to positivity (DTP) 2 hr, or (3) Pathogen detected in quantitative catheter and peripheral blood cultures with a catheter CFU to peripheral CFU ratio 3:1 Probable CRBSI Pathogen detected in blood culture that is typically implicated in causing CRBSI (coagulase-negative staphylococcus, S. aureus, and Candida species) without no alternative source of bloodstream infection CFU, colony-forming unit. 정맥관출구나주변에있는것을의미한다. 출구로부터 2 cm 이내까지를출구감염으로, 2 cm 이상파급된경우를터널감염으로나누기도한다 (Table 1) [13]. 포켓감염은피부밑포켓에감염의징후가있는것을말한다. 국소감염의존재는 CRBSI를시사하는소견일수도있지만혈류감염없이도국소감염은있을수있으므로혈액배양을통하여혈류감염의동반여부를확인하여야한다 [32,34]. 혈액배양중심정맥관관련감염이의심되는환자들은말초혈관과중심정맥관에서각각한쌍이상의혈액배양을함께시행하여야한다. 여러개의내강을가지고있는중심정맥관의경우에는각내강에서혈액을채취하면혈액배양양성률이더높아진다 [35,36]. 중심정맥관말단배양검사 CRBSI의진단에가장흔하게사용되는방법은중심정맥관말단배양이다 [37]. 이방법은중심정맥관말단 5 cm를잘라서배지에굴려서배양하는방법이다. 15 colony-forming unit (CFU) 이상으로균이자랐을때의미있는균의집락화로본다. 반정량배양법 (semiquantitative culture method) 또는진단법을개발한사람의이름을따서 Maki 방법이라고부른다 [37]. 중심정맥관말단배양에서의미있게균이집락화되어있고, 말초혈액배양에서도같은균이분리된경우는확실한 CRBSI로진단할수있다 (Table 1). 정량적혈액배양중심정맥관말단배양이 CRBSI를진단할수있는가장간단하고확실한방법이지만말단배양을위해서는중심정맥관을제거하여야하는것이가장큰단점이다. 임상적으로혈소판감소증, 호중구감소증등을포함하여중심정맥관제거가여의치않은경우들이있다. 더불어 coagulase-negative staphylococci에의한 CRBSI는중심정맥관제거없이치료하여도치료성공률이높다 [38]. 따라서중심정맥관제거는이로인한득실을신중히고려하여결정하여야하는데, 그러기위해서는중심정맥관을제거하지않고 CRBSI를진단할수있는방법이필요하다. 여러가지방법이시도되었으나정량적혈액배양 (quantitative paired blood cultures) 이중심정맥관을제거하지않고 CRBSI를진단할수있는가장정확한방법으로알려져있다 [39]. CRBSI에서는중심정맥관이감염의원발병소이기때문에중심정맥관혈액배양의균량이말초혈액배양의균량보다많다고생각할수있다. 따라서중심정맥관혈액배양에서자란균량이말초혈액배양에서자란균량보다어느비율이상많으면 CRBSI로진단하게된다. 진단을위한균량의비는 1:3-1:10까지다양하게제시되고있다 [13,40]. 최근에출판된미국감염학회지침에서는 1:3의기준을권장하고있고이경우확실한 CRBSI로진단할수있다 (Table 1) [13]. 예를들면, 말초혈액배양에서균이 200 CFU 자랐고중심정맥관혈액배양에서같은균이 1,000 CFU 자랐다면정량적혈액배양을통한균량의비는 1:5로확실한 CRBSI로진단할수있다

4 - 박기호. 중심정맥관관련감염의진단과치료 - 혈액배양양성시간차 (differential time to positivity) 앞에서언급한바와같이정량적혈액배양이중심정맥관을제거하지않고 CRBSI를진단할수있는가장정확한검사법이다. 그러나이방법은검사를시행하는데시간, 노력, 비용이많이들어전세계적으로임상에서흔히사용되고있지못하다. 이러한측면에서간편하면서도중심정맥관제거없이 CRBSI를진단할수있는여러진단법들이연구되어왔다. 그중하나는말초혈액과중심정맥관에서뽑은혈액의혈액배양양성보고까지걸리는시간 (time to positivity) 의차이를이용하는방법이다 (differential time to positivity, DTP). 이방법을이용하기위해서는검사실의혈액배양장비가혈액배양에서균이자라는데걸리는시간을실시간으로감시하고보고할수있는것이라야한다. CRBSI에서는중심정맥관에서뽑은혈액의균량이말초혈관보다많기때문에중심정맥관혈액배양이말초혈액배양보다균이빨리자랄것이라는것을가정해볼수있다. 실제로 DTP를 2시간기준으로사용하였을때이방법은단기거치중심정맥관 (short-term CVC) 관련균혈증진단에 89% 의예민도와 83% 의특이도를보였다 [41]. DTP 2시간기준은중환자실환자 [42], 골수이식환자 [43], 호중구감소증을가진종양환자 [44] 에서도세균성 CRBSI의진단에유용하였다. 따라서 DTP 2시간기준은중심정맥관제거없이확실한 CRBSI 를진단할수있는유용한방법으로널리받아들여지고있다 (Table 1). 칸디다혈증의경우는혈류감염의원발병소를판단하기위한 DTP 검사가특히중요할수있다. 왜냐하면중심정맥관을가지고있는칸디다혈증의상당수는중심정맥관관련감염없이장관안으로부터내인성으로도흔히일어나기때문이다 [45]. 하지만칸디다혈증에서는 DTP의유용성과적절한진단기준이아직정립되어있지않다. 최근에시행된 24 명의칸디다혈증환자가포함된연구에서 DTP 2시간기준은중심정맥관관련칸디다혈증진단에 95% 의예민도, 40% 의특이도를보였다 [46]. 따라서세균성 CRBSI의진단에사용하는 DTP 2시간기준이칸디다혈증에서는적절하지않을수있다. 치료 CRBSI의치료에있어서우선적으로고려하여할점들은 (1) 중심정맥관의제거여부, (2) 적절한항균제의선택, (3) 항균제치료의기간등이다. 중심정맥관의제거또는유지원인균과상관없이 (1) 중증패혈증, (2) 중증감염성합병증 ( 심내막염, 감염성혈전정맥염, 골수염 ), (3) 적절항균제사용후 72시간이상혈류감염이지속될때, (4) 터널감염또는포켓감염이있는경우는중심정맥관제거가강력히권장된다 [13]. 혈류감염에의한심내막염, 감염성혈전정맥염, 골수염등의합병증이발생하였는지알수있는가장간단하고유용한지표는균혈증의기간이다 [47,48]. 균혈증이 72시간이상지속되는환자들은감염성합병증의발생률이의미있게증가한다 [47,48]. 따라서적절한항균제치료후에도 72시간이상지속되는균혈증의경우는중심정맥관제거가강력히권장된다 [13]. 더불어균혈증의기간은진단적검사의범위와치료기간을결정하는데도중요한지표가되기때문에 CRBSI로진단된환자는혈액배양이음전될때까지 2-3일에한번씩혈액배양을반복하여야한다. S. aureus [48-51] 와그람음성막대균 (Pseudomonas aeruginosa, Stenotrophomonas maltophilia, Acinetobacter species 등 ) [52] 에의한감염은중심정맥관을제거하지않는경우합병증또는재발이많아중심정맥관제거가권장된다. Candida species에의한감염은논란이많지만일반적으로중심정맥관제거가권장된다 [13,15,17]. 대조적으로 coagulase-negative staphylococci에의한 CRBSI는중심정맥관을제거하지않고호전되는경우가많아서중심정맥관을그대로두고치료해볼수있다 [38]. 항균제의선택 Coagulase-negative staphylococci와 S. aureus가 CRBSI의가장흔한균이기때문에 CRBSI가의심되는환자들에게는이균들에대한경험적항균제를사용하여야한다. 메티실린내성 staphylococci가흔한병원에서는 vancomycin이나 teicoplanin과같은 glycopeptide 계열의항균제사용이권장된다. Linezolid는 CRBSI의경험적치료제로사용되어서는안된다. CRBSI가의심되지만혈류감염이확인되지않은환자들에서 linezolid의경험적사용은 vancomycin에비하여더높은사망률을보였다 [53]. 대퇴정맥중심정맥관감염이의심되는경우는그람음성막대균과 Candida species에대한경험적항균제의사용도함께고려되어야한다 [54]. 혈액배양

5 - The Korean Journal of Medicine: Vol. 86, No. 3, Table 2. Antimicrobial therapy of catheter-related bloodstream infections depending on causative pathogen Pathogen Therapy Duration of therapy Staphylococcus aureus Methicillin-susceptible Nafcillin 2.0 gm 4hr; or cefazolin 2.0 gm q 8 hr 4-6 wk (but 2 weeks in selected cases) Methicillin-resistant Vancomycin 15 mg/kg q 12 hr 4-6 wk (but 2 weeks in selected cases) Coagulase-negative staphylococci Methicillin-susceptible Nafcillin 2.0 gm 4hr IV; or cefazolin 2.0 gm q 8 hr 5-7 days with CVC removal, days without CVC removal Methicillin-resistant Vancomycin 15 mg/kg q 12 hr 5-7 days with CVC removal, days without CVC removal Enterococcus species Ampicillin-susceptible Ampicillin 2 gm q 4-6 hr 7-14 days Ampicillin-resistant, vancomycin-susceptible Vancomycin 15 mg/kg q 12 hr 7-14 days Ampicillin-resistant, vancomycin-resistant Candida species All other pathogens including gram-negative bacteria CVC, central venous catheter. Linezolid 600 mg q 12 hr Echinocandin; or amphotericin B; or fluconazole (if organism is susceptible) According to susceptibility pattern 7-14 days 14 days after the first negative blood culture Not defined 에서원인균이확인된경우는감수성검사결과를바탕으로하여적절한항균제를선택하여치료하여야한다 (Table 2). 항균제치료기간항균제치료기간은 CRBSI의원인균, 합병증유무, 중심정맥관제거여부에따라달라진다 (Table 2). 항균제치료기간을계산할때는혈액배양이음전된날을치료첫날로계산한다. S. aureus 균혈증은감염성혈전정맥염, 심내막염, 전이성감염이흔하여일반적으로 4-6주이상의항균제치료가권장된다. 경우에따라서는최대 2주까지도치료기간을단축할수도있는데, 이에대하여는아래에서다시논의하도록하겠다. 칸디다혈증은혈액배양음전일로부터 2주이상치료하여야한다. 기타균들은일반적으로 2주정도치료하는데, coagulase-negative staphylococci에의한혈류감염은중심정맥관을제거한경우는 5-7일정도로짧게치료할수있다 (Table 2). 항균제잠금치료중심정맥관관련감염이의심되지만중심정맥관을제거 하기어려운경우는항균제잠금치료 (antibiotic lock therapy) 를고려할수있다. 항균제잠금치료는항균제를고농도로중심정맥관내강에주입후일정기간잠가두어균을죽이는방법이다. 92명의환자가포함된 2개의무작위대조군연구를함께분석하였을때항균제잠금치료의성공률은 75% 로대조군의 58% 보다높았다 [55,56]. 칸디다감염에대한항진균제잠금치료는세균감염에서보다덜효과적이다 [57-59]. 항균제잠금치료에는보통생리식염수나헤파린을항균제와함께병합한다. 그러나특정항균제들은헤파린과병합하였을때침전이생기므로주의하여야한다 [13]. 항균제잠금치료를하더라도혈류감염을효과적으로제거하기위하여정맥항균제도함께투여하여야한다 [13]. 항균제잠금치료의치료기간은정하여진바는없지만많은연구에서 2주간사용되었다. 감염성혈전정맥염적절한치료를시작하였는데도균혈증이나진균혈증이 72시간지속되는경우는감염성혈전정맥염의합병을의심하여야한다 [47,48]. 감염성혈전정맥염의진단은혈액배양

6 - Ki-Ho Park. CVC-related infections - 에서원인균이분리되고초음파나컴퓨터단층촬영과같은영상의학적검사에서혈전을확인하는것이다. 감염성정맥혈전염을일으키는가장흔한균은 S. aureus이다. 중심정맥관을가지고있는환자는감염성혈전정맥염이나심내막염과같은혈전성합병증의위험이증가한다 [60]. 중심정맥관의거치는중심정맥에서혈액의와류를일으켜서혈관내피의손상과벗겨짐 (denudation) 을유발함으로정맥혈전증의형성에기여한다. 더불어정맥혈전증은감염의위험성을증가시키고, 감염은혈전증의위험성을증가시키는악순환의고리가생긴다. 따라서감염성혈전정맥염환자들을적절히치료를하지않으면감염이호전되지않거나혈류감염이지속되는경우가종종있다. 적절한치료를위해서는우선중심정맥관을제거후같은위치에다시삽입하지않는것이좋다. 내경정맥이나쇄골하정맥으로중심정맥관을삽입하였던환자들은 ( 즉, 상대정맥에중심정맥관말단이위치하였던경우는 ) 대퇴정맥이나말초혈관을사용하는것이좋다. 대퇴정맥중심관또는말초혈관도관으로유지하기어려운환자들은 midline catheter 를사용하는것이도움이될수있다. 두번째로적절한항균제를충분한기간사용하여주는것이권장된다. 항균제치료기간은정하여진바는없지만최소 3-4주이상은사용하여야한다. 세번째로논란의여지가있지만항응고치료 (anticoagulation therapy) 를고려하는것이권장된다 [61]. 원인균에대한고려 Coagulase-negative staphylococci Coagulase-negative staphylococci는흔한피부정상균무리로혈류감염의가장흔한원인균일뿐만아니라혈액배양오염의가장흔한원인균이다. 따라서중심정맥관을가진환자의혈액배양에서 coagulase-negative staphylococci가분리되었을때는 CRBSI인지혈액배양오염인지신중히판단하여야한다. 중심정맥관혈액배양또는말초혈액배양중한쌍에서만 coagulase-negative staphylococci가분리된다면중심정맥관내강집락화 (intraluminal colonization) 또는혈액배양오염을의심해보아야한다. 원인균만고려한다면 coagulase-negative staphylococci에의한 CRBSI는중심정맥관을제거하지않고항균제만으로치료하였을때의치료성공률이가장높다. 이전연구에서 coagulase-negative staphylococci에의한 CRBSI의약 80% 가중심정맥관제거없이항균제만으로치료할수있었다 [38]. 그러나중심정맥관을제거하지않은경우에는약 20% 에서혈류감염이재발하였다 [38]. 최근에또다른연구에서도 coagulase-negative staphylococci에의한 CRBSI에서중심정맥관을유지하여도감염이호전되는경우가많지만재발은의미있게많았다 [62]. 위와같은점들을고려할때 coagulasenegative staphylococci에의한 CRBSI에서임상적으로중심정맥관제거가여의치않다면무리하게제거하지말고항균제만으로치료하여볼수있다. 그러나재발이드물지않아서중심정맥관이더이상필요하지않게되면바로제거하여주는것이좋겠고, 계속사용하여야한다면재발가능성을염두에두면서경과관찰할필요가있다. Staphylococus aureus S. aureus에의한 CRBSI는감염성혈전정맥염, 심내막염, 전이성감염등의감염성합병증의위험이높다 [47,48,60]. 몇개의연구에서 S. aureus에의한 CRBSI에서중심정맥관제거는빠른치료반응및낮은재발률과연관이있었다 [63-65]. S. aureus에의한 CRBSI의치료기간은감염성혈전정맥염, 심내막염, 전이성감염등의위험성으로인하여일반적으로 4-6주이상이필요하다 [13]. 그러나이러한감염성합병증이존재하지않거나존재할가능성이낮은경우는치료기간을최대 2주까지도단축할수있다. 치료기간을단축하기위해서는 (1) 면역저하환자가아니고, (2) 중심정맥관이제거되었고, (3) 혈관이나심장에인공삽입물이없고, (4) 영상의학적검사에서심내막염이나감염성혈전정맥염의증거가없고, (5) 항균제치료시작후 72시간이내에균혈증및발열이호전되어야하며, (6) 기타다른부위의전이성감염이없어야한다 [66]. 단기치료를고려하는환자들은심장초음파검사를시행하여심내막염을배제하여야한다. S. aureus 균혈증환자에서경식도심장초음파검사 (transesophageal echocardiography) 를시행하면 25-32% 의환자에서감염성심내막염이진단된다 [67-69]. 이전연구에서경식도심장초음파검사가경흉부심장초음파검사 (transthoracic echocardiography) 보다감염성심내막염진단에유리하였다 [70]. 그러나 S. aureus 균혈증환자들을모두경식도심장초음파로검사하여야하는지에대하여는아직도논란이많다일부전문가들은저위험환자

7 - 대한내과학회지 : 제 86 권제 3 호통권제 643 호 들에서는경흉부심장초음파를권장하기도한다. 기저질환에대한고려 Candida species 중심정맥관관련칸디다혈증환자에서일반적으로중심정맥관은제거하는것이권장된다 [13]. 이것은이러한환자들에서중심정맥관의보유가임상성적을악화시킨다는전향적연구결과에바탕을두고있다 [71-75]. 404명의칸디다혈증이포함된후향적연구에서도칸디다혈증발생후중심정맥관을 72시간이상보유하는경우는불량한임상성적과독립적인연관관계가있었다 [76]. 그러나중심정맥관을제거하여중심정맥관말단배양을하기전에는칸디다혈증의원발병소가중심정맥관인지를알기가어려운경우가많다. 임상적으로중심정맥관이칸디다혈증의원발병소임을시사하는소견은 (1) 한달이내에항암치료나스테로이드치료를받지않은경우, (2) 파종성감염이없는경우, (3) 항진균제투여에도치료반응이없는경우, (4) 완전비경구영양법 (total parenteral nutrition) 을사용하는경우등이다 [76,77]. 앞에서언급한것처럼 DTP 2시간기준은중심정맥관관련세균혈증진단에는유용한기준이지만중심정맥관관련칸디다혈증의진단에도유용할지에대하여는추가연구가필요하다. 모든칸디다혈증환자들에게서는안내염의합병여부를확인하기위하여동공확대안저검사 (dilated funduscopic examination) 를치료시작 1주이내에시행하여야한다 [78]. Gram-negative bacilli 그람음성막대균에의한혈류감염은일반적으로요로감염, 복강내감염, 폐렴등다양한감염에의하여발생한다. 그람음성막대균에의한 CRBSI의발생빈도는앞의 3가지균에비하여상대적으로낮지만다양한그람음성균에의한 CRBSI가보고되어왔다 [52,79]. Stenotrophomonas maltophilia 와 non-aeruginosa Pseudomonas species에의한혈류감염연구에서많은경우의균혈증은중심정맥관과관련이있었다 [52]. 이환자들에서중심정맥관을제거하지않았을때높은치료실패율및재발과연관이있었다 [52]. 다른연구에서그람음성막대균에의한 CRBSI에서중심정맥관유지는높은재발률과연관이있었으나중심정맥관을제거한경우에는단지 1% 의환자에서만재발이있었다 [79]. 혈액투석환자혈액투석용중심정맥관이감염되었을경우는중심정맥관을제거후혈액투석을위한중심정맥관을언제다시삽입할지가문제가된다. 중심정맥관을제거한후최소 2-3일이상발열이없고혈액배양이음전된것을포함하여감염의모든증상과징후가소실된후에혈액투석용중심정맥관을다시삽입하는것이좋다 [17]. 만약감염의증상과징후의소실이느려질때는다른부위에중심정맥관을삽입할수있다. 감염의증상과징후의호전이없으면서다른부위의혈액투석용중심정맥관삽입도용이하지않는경우들도있다. 이러한상황이예상될때는 (1) guide-wire을이용한중심정맥관교체나 (2) 항균제잠금치료를이용한중심정맥관유지시도를고려할수있다 [13,17]. 항균제잠금치료를하는경우는 1주일후에혈액배양을시행하여혈류감염이소실되었는지확인하여야한다 [13,17]. 둘중어떠한치료를시도하든지임상적악화가없는지주의깊은관찰이필요하고치료후에도 2-3일이상발열이나혈류감염이지속되면중심정맥관을제거하여야한다 [17]. 종양환자고형종양또는혈액종양을가진환자들에서는장관에서기인한그람음성막대균이혈류감염의중요한원인균이다 [80]. 그러나이환자들에게도 CRBSI의가장흔한원인균은 coagulase-negative staphylococci와 S. aureus이다 [44,81]. 이환자들에서그람음성막대균과 Candida species는 CRBSI의 20-25% 와 5-13% 를차지한다 [44,81-83]. 종양환자에서중심정맥관관련감염의진단과치료는종양이없는환자들과크게다르지않다 [15]. 호중구감소증환자호중구감소증환자에서중심정맥관관련감염의치료에대한자료는매우제한적이다 [16]. 터널중심정맥관 (tunneled CVC) 을가지고있는환자들에대한이전연구들에서중심정맥관감염위험성은호중구감소증기간에증가함에따라상승하였다 [84-86]. 그러나호중구감소증이있는환자의중심정맥관관련감염의발생률이호중구감소증이없는환자보다높다는확실한증거는없다

8 - 박기호. 중심정맥관관련감염의진단과치료 - 면역저하환자고형장기이식환자의혈류감염은장기이식후초기에가장많다. 신장이식환자를제외한고형장기이식환자의혈류감염의가장흔한원발병소는중심정맥관이다 [87]. 신장이식환자의경우는요로감염이가장흔한혈류감염의원발병소이다. 면역저하환자에서발생한중심정맥관감염에대하여중심정맥관유지치료는위험하므로가능하면중심정맥관을제거하는것이권장된다 [18]. 항균제치료를얼마나하여야하는지알수는없지만, 면역기능이정상인환자에서보다더긴치료가필요할수있다 [18]. 임상에서부딪히는문제들적절한치료에도지속되는혈류감염적절한항균제가투여되고중심정맥관이제거되었는데, 혈류감염이 72시간지속되는경우는감염성합병증의발생을의심하여야한다 [47]. 가장흔한감염성합병증은감염성혈전정맥염이고, 종양환자와 S. aureus 혈류감염환자에서는더욱흔하다 [47,60]. 따라서적절한치료에도혈류감염이 72시간지속되면이전에중심정맥관이삽입되었던정맥혈관들에대하여혈전이없는지확인하기위하여초음파또는컴퓨터단층촬영과같은영상의학적검사가필요하다. 다음으로심내막염에대한고려가필요한데, 특히 S. aureus 에의한균혈증에서는더욱중요하다. 상당수의 S. aureus 균혈증환자들은임상적으로심내막염이의심되지않아심내막염이진단되지않는다 [88]. 따라서적절한항균제투여와중심정맥관제거에도 72시간이상지속되는 S. aureus에의한 CRBSI를가진환자들은심장초음파검사를받아야한다. 그러나앞에서언급한것처럼이환자들을모두경식도심장초음파로검사하여야하는지에대하여는논란이있다. 마지막으로전이성감염에의한고려가필요하다. S. aureus 에의한혈류감염은골수염이있는경우혈류감염이오래지속되는경향이뚜렷하다 [47,89,90]. 가장흔한골수염의위치는척추이므로 S. aureus에의한지속적혈류감염환자가허리통증을호소할때는혈행성척추골수염 (hematogenous vertebral osteomyelitis) 확인을위한영상의학적검사를하는것이좋다 [51]. 혈관내도관 (intravascular catheter) 은원발병소가확인된 S. aureus 혈행성척수골수염원발병소의 34-69% 를차지하고있다 [91,92]. 혈류감염없이중심정맥관말단배양에서균이분리되는경우중심정맥관을제거하더라도임상적으로중심정맥관관련감염이의심되지않는경우는중심정맥관말단배양을시행하지않는것이권장된다 [93]. 그러나중심정맥관관련감염이의심되어시행한중심정맥관말단배양에서균이분리되었으나혈액배양은음성인경우들이종종있다. 이환자들의 % 에서만향후혈류감염이발생하기때문에이환자들을모두항균제치료하는것은옳지않다 [26,94]. 그러나 S. aureus나 Candida species와같이 CRBSI를잘일으키는균에대하여는치료가필요하다는주장이있어왔다 [14,95]. 특히면역저하환자나판막질환이있는환자들에게는더욱그렇다 [14,95]. 이러한경우에대하여항균제치료가필요한지에관하여최근여러연구들이있었다 [26,96-99]. 우선 S. aureus 에관하여는최근세개의연구에서이러한환자들에게적절한경험적항균제가투여되었을때 S. aureus 혈류감염의발생을줄일수있었다 [96,97,99]. 그러나다른두개의연구에서는경험적항균제치료와환자의임상성적과는관련이없었다 [26,98]. 이와같은점들을고려할때아직논란의여지가있지만, 혈류감염없이중심정맥관말단배양에서 S. aureus가분리된경우는 5-7일정도의항균제치료를하고감염의증상및징후가지속되는지주의깊게관찰하는것이권장된다 [13]. 혈류감염없이 Candida species 에의하여중심정맥관말단이집락화된경우에대하여한개의연구가있었고, 항진균제치료는환자의임상성적과관련이없었다 [100]. 그러나이환자들의 7-12% 에서향후칸디다혈증이발생하는것을고려할때 [26,101], 고위험환자에서는항진균제치료를고려하는것이좋겠다. 중심정맥관혈액배양에서만양성인경우중심정맥관에서뽑은혈액에서만균이분리되고말초혈관에서뽑은혈액에서는균이분리되지않는경우는세가지상황을고려할수있다. 첫번째는중심정맥관내강에균이집락화되어있지만혈류감염이아직발생하지않은경우 (intraluminal colonization) 이다. 두번째는중심정맥관을통해서혈액배양을시행하는과정에서혈액이오염된경우 (contamination) 이다. 마지막은말초혈관에서혈액을뽑는것이중심정맥관에서혈액을뽑는것보다더어렵기때문에, 말초혈관에서더적은혈액을뽑은경우이다 (false negative peri

9 - The Korean Journal of Medicine: Vol. 86, No. 3, pheral blood culture results) [102]. 임상적으로세가지중어디에해당할지구분하기어려운경우가대부분인데, coagulasenegative staphylococci 의경우는첫번째나두번째경우가많아서혈액배양을반복하면서치료하지않고경과를보는것이권장된다 [13]. 그러나 S. aureus, Candida species, 그람음성막대균의경우는중심정맥관에서뽑은혈액에서만균이분리되었더라도 CRBSI와똑같이취급하는것이안전하다 [102]. 중심정맥관재삽입시기 CRBSI로진단되어중심정맥관제거와항균제치료를시작한경우에언제다시중심정맥관을삽입하는것이좋은지에대한연구는거의없다. 가능하면감염증치료가종료될때까지삽입하지않는것이이상적이겠지만어려울때가많다. 따라서최소 2-3일이상발열이없고혈액배양이음전된것을포함하여감염의모든증상과징후가소실된후에중심정맥관을다시삽입하는것이좋다 [17]. 이조차어려운상황에는이전삽입된혈관과다른혈관을이용하여삽입하거나, 이전혈관에다시삽입할수밖에없는경우는정맥혈전증이없는지영상의학적검사를통하여확인후삽입하면좋다. 중심정맥관을이전혈관에다시삽입할수밖에없는데삽입부위에정맥혈전증도있는경우는도관말단이중심정맥까지이르지않는 midline catheter 삽입을고려하여볼수있다. 결론중심정맥관은중증환자에서발생한혈류감염의가장흔한원발병소이다. 중심정맥관관련감염의진단, 예방, 치료가발전되어왔음에도불구하고이질환은여전히임상에서흔하며, 종종임상의를어려움에처하게만든다. CRBSI의성공적인치료를위해서는중심정맥관제거여부, 효과적인항균제와치료기간을적절히결정하는것이중요하겠다. 이러한결정을위해서는원인균, 감염성합병증의존재, 임상경과, 영상의학적소견, 환자의기저질환등을종합적으로고려하여야하겠다. 중심단어 : 중심정맥관 ; 혈류감염 ; 균혈증 ; 진단 ; 치료 REFERENCES 1. O'Grady NP, Alexander M, Dellinger EP, et al. Guidelines for the prevention of intravascular catheter-related infections: Centers for Disease Control and Prevention. MMWR Recomm Rep 2002;51: Mermel LA. Prevention of intravascular catheter-related infections. Ann Intern Med 2000;132: Rello J, Ochagavia A, Sabanes E, et al. Evaluation of outcome of intravenous catheter-related infections in critically ill patients. Am J Respir Crit Care Med 2000;162: Dimick JB, Pelz RK, Consunji R, Swoboda SM, Hendrix CW, Lipsett PA. Increased resource use associated with catheter-related bloodstream infection in the surgical intensive care unit. Arch Surg 2001;136: Fagan RP, Edwards JR, Park BJ, Fridkin SK, Magill SS. Incidence trends in pathogen-specific central line-associated bloodstream infections in US intensive care units, Infect Control Hosp Epidemiol 2013;34: Centers for Disease Control Prevention (CDC). Vital signs: central line-associated blood stream infections: United States, 2001, 2008, and MMWR Morb Mortal Wkly Rep 2011;60: Fontela PS, Platt RW, Rocher I, et al. Epidemiology of central line-associated bloodstream infections in Quebec intensive care units: a 6-year review. Am J Infect Control 2012;40: Kim OS, Kim SM. Prevention of central venous catheter-related infections. Korean J Nosocomial Infect Control 1999; 4: Yoo S, Ha M, Choi D, Pai H. Effectiveness of surveillance of central catheter-related bloodstream infection in an ICU in Korea. Infect Control Hosp Epidemiol 2001;22: Yoo S, Jung SI, Kim GS, et al. Interventions to prevent catheter-associated blood-stream infections: a multicenter study in Korea. Infect Chemother 2010;42: Jeong IS, Park SM, Lee JM, Song JY, Lee SJ. Effect of central line bundle on central line-associated bloodstream infections in intensive care units. Am J Infect Control 2013;41: Rosenthal VD, Bijie H, Maki DG, et al. International Nosocomial Infection Control Consortium (INICC) report, data summary of 36 countries, for Am J Infect Control 2012;40: Mermel LA, Allon M, Bouza E, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 update by the Infectious Diseases Society of America. Clin Infect Dis 2009;49: Mermel LA, Farr BM, Sherertz RJ, et al. Guidelines for the management of intravascular catheter-related infections. Clin Infect Dis 2001;32:

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