2012 년제 63 차대한내과학회추계학술대회 근거창출임상연구국가사업단임상진료지침 국내지역사회획득중증패혈증및패혈쇼크의항생제치료지침 ( 안 ) 고려대학교의과대학내과학교실 손장욱 서론 1. 배경및목적중증패혈증은감염에의한이차적으로발생하는급성장기부전을의미하며패혈쇼크는수액요법에반응하지않는저혈압을지닌중증패혈증을의미한다 [1]. 이들중증패혈증과패혈쇼크는전세계적으로매년수백만명이이환되며사망률이각각약 30% 와 50% 에이르는주요질환군으로발생률이증가추세에있다 [2-4]. 지역사회획득중증패혈증에대한연구는많지는않으나의료관련감염을포함하는경우와달리항생제내성양상이심하지않은양상을보인다. 지역과시대에따라원인균의분포가다르고내성양상이다르므로국내실정을감안한치료지침은반드시필요하다. 항생제는현대의학에있어서매우중요한위치를차지한다. 비록다른의학기술이지난수세기동안인간의생명을연장시켰을지라도항생제는감염질환을지닌무수히많은생명을살렸다. 이런항생제의성공은결국남용을유발하여항생제내성의증가를초래하였고이는점차좁은항균력을지닌항생제의효과를감소시켰으며치료하기힘든감염질환의증가를초래하였다. 가장적절한항생제의선택은현재임상의에게중요한도전이되고있다. 항생제내성시대에있어적절한항생제치료는환자의예후와내성균출현의억제에중요한요소로중증패혈증및패혈쇼크에있어서적절한초기경험적항생제는환자의예후에중요하다. 일부연구에있어서는항생제보다환자의기저질환이나환자의중증도가중증패혈증과패혈쇼크에있어서사망에미치는주요위험인자로보고되고있으나적절한항생제역시사망에영향을미치는중요요소이다. 패혈증은중증세균감염의결과로발생하는것으로경험 적항생제는추정된또는감염된장기에흔한원인균을겨냥하여사용하게되므로중증패혈증및패혈쇼크의원인균분포에관한역학적자료는매우중요하다. 본치료지침에서는국내에서수행된지역사회획득중증패혈증및패혈쇼크에관한연구결과를서술하였다. 이는치료지침의근간이되는중요자료이며이들질환의특성을이해하고환자를돌보는데매우유용한자료로사료된다. 현시점에서국내치료지침개발에있어중요한근거자료가될국내연구성과가미흡하나근거중심의치료지침제정작업을통하여적적한항생제치료를위한국내임상연구를활성화시킴으로써수년후개정될치료지침에서는전향적인연구결과를바탕으로하는보다완성된치료지침이제정될것으로기대된다. 본치료지침은성인에있어서중증패혈증및패혈쇼크의항생제치료를가이드하기위하여만들어진것으로환자의특수상황을고려한임상의의판단을본이대치할수는없다. 일부의료기관에서는자원의부족으로임상의들이본을따르는데제한이있을수있다. 2. 범위본치료지침은중증패혈증및패혈쇼크의일반적치료지침이아니라초기경험적항생제치료에관한것으로의료기관관련감염에의한중증패혈증및패혈쇼크는제외하고지역사회획득중증패혈증및패혈쇼크만을대상으로하였다. 국내지역사회획득중증패혈증의역학자료에근거하여약 90% 의빈도를보였던호흡기계감염, 요로감염, 복강내감염, 피부및연조직감염을위주로초기경험적항생제치료에관하여다루었다. 소아에대한부분은본치료지침에서는다루지않았다. - 209 -
- 2012 년제 63 차대한내과학회추계학술대회 - 방법 1. 검색전략체계적인문헌검색을위하여 2001년 1월부터 2011년12월까지최근 10년동안출판된지침과관련문헌을 Pubmed (www. pubmed.gov) 검색엔진을사용하여검색하였다. 검색시영문으로쓰여진문헌과 19세이상의성인, 사람을대상으로한연구에국한하였다. 국내문헌검색을위하여같은기간내에 KoreMed(www.koreamed.org), 한국학술정보 (http;//kiss.kstudy. com) 를통하여자료를검색하였다. 사용된검색어는아래와같다 ("residence characteristics" [MeSH Terms] OR ("residence" [All Fields] AND "characteristics" [All Fields]) OR "residence characteristics" [All Fields] OR "community" [All Fields]) AND acquired [All Fields] AND ("sepsis" [MeSH Terms] OR "sepsis" [All Fields] OR ("severe" [All Fields] AND "sepsis" [All Fields]) OR "severe sepsis" [All Fields]) AND ("anti-infective agents" [MeSH Terms] OR ("anti-infective" [All Fields] AND "agents" [All Fields]) OR "anti-infective agents"[all Fields] OR "antimicrobial" [All Fields] OR "anti-infective agents" [Pharmacological Action]) AND ("therapy" [Subheading] OR "therapy"[all Fields] OR "therapeutics" [MeSH Terms] OR "therapeutics" [All Fields]) AND ("humans" [MeSH Terms] AND English [lang] AND "adult" [MeSH Terms]). 검색어선정은각데이터베이스에적절하게보완하였고각데이터베이스에서수집된문헌은 Endnote를통해중복문헌을배제하였다. 2. 근거평가방법 1) 문헌의질평가개별연구는연구설계에따라무작위임상실험의경우 Cochrane 에서제시한비뚫림의위험 (Risk of bias) 을평가하였으며무작위임상실험을제외한비무작위연구는뉴캐슬오타와척도 (Newcastle-Ottawa Scale) 를이용하여평가하였다. 2) 근거의수준평가근거수준평가는 Grade Group에서제시한근거수준의방법론에적용하여평가하였으며, 각각의핵심질문에포함된개별연구의연구설계를기반으로연구결과간의일관성및연구대상및중재적용의직접성, 출판편견의가능성, 연구결 과의정확성, 포함된문헌의질평가에따른비뚫림의가능성을평가하여 4개의근거수준으로구분함. Level A: High-quality evidence Level B: Moderate-quality evidence Level C: Low-quality evidence Level D: Very low-quality evidence or expert opinion ( 권위있는전문가의임상경험에기초한의견이나, 전문가로구성된위원회에서발표된연구결과나보고자료에서얻은근거 ) 3. 등급결정및합의안도출과정권고의등급결정은 Grade Group 에서제시한도출의방법론을적용하였다. 각핵심질문의근거의수준을기반으로해당중재의적용대상, 위해, 편익, 사회적개인적비용, 환자의기호를고려하여권고의등급을결정하였으며권고의수준은강력한권고 (grade 1), 약한권고 (grade 2) 로구분하였다. 권고등급의결정은자문위원회협의를통해최종확정할예정이다. 강력한권고의표현은본문에서는 권고한다 또는 권고하지않는다 로표현하였고, 약한권고는 고려한다 또는 고려하지않는다 로표현하였다. 핵심질문요약 1. 초기경험적항생제선택이환자의예후에영향을미치는가? 2. 경험적항생제투여시기는? 3. 어떤경험적항생제를사용할것인가? 3-1. 추정되는일차감염부위에따른경험적항생제 3-1-1. 폐렴을포함한호흡기계감염이의심되는경우? 3-1-2. 요로감염이의심되는경우? 3-1-3. 복강내감염이의심되는경우? 3-1-4. 피부및연조직감염이의심되는경우? 3-2. 일차감염부위를모르는경우경험적항생제를어떻게사용할것인가? 4. 항생제투여후추적검사는어떻게할것인가? - 210 -
- 손장욱. 국내지역사회획득중증패혈증및패혈쇼크의항생제치료지침 ( 안 ) - 국내지역사회획득중증패혈증및패혈쇼크의역학국내성인지역사회획득중증패혈증및패혈쇼크에관한자료로는한국패혈증등록시스템의자료로 2005년 4월부터 2009년 2월까지 12개대학병원에서 23개의중환자실을대상으로전향적관찰연구의결과가있다. 연구결과총 1192명이지역사회획득중증패혈증으로연구에포함되었으며이중 62.1% 가패혈쇼크이었다. 평균나이는 65 ± 14.2세로 50세이상이전체의 84.8%, 60세이상이전체의 68.3% 로주로노인연령층에서호발하였으며, 남자가 55% 로성비에서는차이가없었다. 평균 APACHE II 점수는 18.8 ± 7.3이었으며, 28 일사망률과, 병원내사망률은각각 23%, 28% 이었다. 중증패혈증의경우 28일사망률과병원내사망률은각각 17.9%, 23.5% 이었으며, 패혈쇼크의경우각각 26.1%, 30.8% 이었다. 기저질환으로는심혈관계질환이 37.6% 로가장많았고, 다음이당뇨등대사성질환으로 28.1%, 암 14.7%, 중추신경계질환 14.3% 순이었으며, 기저질환이없는경우도 28.9% 에달하였다. 중증패혈증및패혈쇼크의일차적인감염부위는호흡기계감염이전체의 30.2% 로가장많았고다음이요로계감염 26.4%, 복강내감염 24.2%, 피부및연조직감염 8.1% 순서이었다 (Table 1). 전체 1192예중약 70% 에서원인균이규명되었으며, 그람음성균이 43%, 그람양성균이 20.4% 로그람음성균의비율이높았다. 가장흔한원인균은 Escherichia coli로 22.1% 이었고 Klebsiella species 12.6% Staphylococcus aureus 8.4%, Table 1. Primary infection site (n=1192) Primary site of infection No. (%) Respiratory system 360 (30.2%) Urinary tract 315 (26.4%) Abdomen 288 (24.2%) Skin and soft tissue 97 (8.1%) Primary bloodstream 52 (4.4%) Systemic infection 21 (1.9%) Cardiovascular system 18 (1.5%) Central nervous system 18 (1.5%) Bone and joint 11 (0.9%) Head and neck 6 (0.5%) Reproductive tract 4 (0.3%) Unknown 2 (0.2%) Streptococcus pneumonia 4.5% 순이었다 (Table 2). 각일차감염부위에따른원인균분포는호흡기계감염에 Table 2. Causative microorganism detected from 1192 patients with community-acquired severe sepsis and septic shock Causative organisms No. (%) Gram positive 243 (20.4) Staphylococcus aureus 100 (8.4) Coagulase negative staphylococci 8 (0.7) Streptococcus pneumoniae 54 (4.5) Streptococcus species 54 (4.5) Enterococcus species 26 (2.2) Other gram positive 1 (0.1) Gram negative 513 (43.0) Escherichia coli 263 (22.1) Klebsiella species 150 (12.6) Pseudomonas species 34 (2.9) Enterobacter species 17 (1.4) Vibrio vulnificus 6 (0.5) Other Enterobacteriaceae 24 (2.0) Other gram negative 19 (1.6) Mixed 43 (3.6) Unproven 361 (30.3) Table 3. Causative microorganisms associated with respiratory infection (n=360) Causative organisms No. (%) Gram positive 96 (26.7) Streptococcus pneumoniae 50 (13.9) Staphylococcus aureus 39 (10.8) Streptococcus species 5 (1.4) Coagulase negative staphylococci 2 (0.6) Gram negative 75 (20.8) Klebsiella species 39 (10.8) Pseudomonas species 17 (4.7) Hemophillus influenzae 6 (1.7) Enterobacter species 4 (1.1) Escherichia coli 4 (1.1) Other gram negatives 6 (1.7) M. tuberculosis 4 (1.1) Other organisms 2 (0.6) Mixed 8 (2.2) Unproven 175 (48.6) - 211 -
- 2012 년제 63 차대한내과학회추계학술대회 - Table 4. Causative microorganisms associated with urinary tract infection (n=315) Causative organisms No. (%) Gram positive 23 (7.3) Enterococcus species 13 (4.1) Streptococcus species 5 (1.6) Staphylococcus aureus 5 (1.6) Gram negative 225 (71.4) Escherichia coli 179 (56.8) Klebsiella species 24 (7.6) Proteus species 7 (2.2) Pseudomonas species 6 (1.9) Enterobacter species 4 (1.3) Other gram negatives 6 (2.2) Other organisms 2 (0.6) Mixed 8 (2.5)-8.1% Unproven 56 (17.8) Table 6. Causative microorganisms associated with skin and soft tissue infections (n=97). Causative organisms No. (%) n=97 Gram positive 55 (56.7) Staphylococcus aureus 26 (26.8) Streptococcus species 22 (22.7) Coagulase negative staphylococci 4 (4.1) Enterococcus species 3 (3.1) Gram negative 15 (15.5) Escherichia coli 4 (1.1) Moganella morganii 3 (3.1) Pseudomonas species 2 (2.1) Klebsiella species 2 (2.1) Other gram negatives 4 (4.1) Other organisms 2 (2.1) Mixed 4 (4.1) Unproven 21 (21.6) Table 5. Causative organisms associated with Intraabdominal infection (n=288) Causative organisms No. (%) Gram positive 21 (7.3) Streptococcus species 10 (3.5) Enterococcus species 9 (3.1) Other gram positives 2 (0.7) Gram negative 152 (52.8) Klebsiella species 72 (25) Escherichia coli 64 (22.2) Enterobacter species 6 (2.1) Pseudomonas species 4 (1.4) Other gram negatives 6 (2.1) Anaerobes 6 (2.1) Mixed 22 (7.6) Unproven 87 (29.2) 있어서는원인균이규명된경우가 42.4% 이었다. 규명된원인균중 S. pneumoniae가 27% 로가장많았고, S. aureus, Klebsiella species 각각 21.1%, 다음이 Pseudomonas species 9.2% 순이었다 (Table 3). 요로계감염의원인균은 82.2% 에서규명되었으며, 규명된원인균중 E. coli 가 69.1% 로가장많았고, 다음이 Klebsiella species (9.3%), Enterococcus species (5.0%) 순이었다 (Table 4). 복강내감염의원인균은 70.8% 에서규명되었으며, 규명된 원인균중가장흔한원인균은 Klebsiella species(35.8%) 이었고다음이 E. coli(31.8%) 이었다 (Table 5). 피부및연조직감염은 78.4% 에서원인균이규명되었고, 규명된원인균중 S. aureus 가 34.2% 로가장많았고다음이 Streptococcus species (28.9%) 순이었다. 그람음성균은 20.8% 이었다 (Table 6). 일차혈류감염은 4.4% (52/1192) 이었으며가장흔한원인균은 S. aureus (21.2%) 이었고, Klebsiella species (17.3%), E.coli (11.5%) 순이었다. 중증패혈증및패혈쇼크의항생제치료 1. 초기경험적항생제선택이환자의예후에영향을미치는가? 1. 중증패혈증또는패혈쇼크에있어서는초기경험적항생제의선택은환자의사망률에영향을미치므로초기에적정항생제를선택할것을권고한다 (grade 1B). 근거요약적정항생제의사용은모든가능한임상적, 약리학적, 미생물학적근거에바탕을둔적합한항생제의사용으로정의할수있다. 항생제감수성검사결과가있는경우에있어서좁은항균력을지닌항생제의사용을포함하며적절한용량 - 212 -
- 손장욱. 국내지역사회획득중증패혈증및패혈쇼크의항생제치료지침 ( 안 ) - 과투여간격감염부위의투과력등을고려하여사용하는것을의미한다 [5]. 부적절한항생제치료는일반적으로사용하는항생제가원인균의항생제감수성결과와맞지않는경우로정의될수있으며이는환자의예후에영향을미칠수있다 [6]. 중증패혈증및패혈쇼크를대상으로한연구에있어서부적절한항생제사용의비율은 17% 에서 29% 에이르며이들부적절한항생제치료는적정항생제치료에비해통계적으로유의한사망의위험인자이었다 [7-11]. 2. 경험적항생제투여시기는? 1. 중증패혈증및패혈쇼크를인지한후가급적빠른시간내에초기경험적항생제를정주로투여할것을권고한다 (grade 1B). 적절한배양검사는항생제투여전에시행하여야하나배양검사를위해서항생제투여시기를늦추어서는안된다 (grade 1D). 근거요약중증패혈증및패혈쇼크의치료에있어서혈관확보와수액치료는가장우선되나즉각적인항생제치료도매우중요하다 [12,13]. 패혈증가이드라인에서는패혈쇼크를인지한후 1시간이내에항생제투여를권고하고있다 (14). 패혈쇼크에있어서적절한항생제투여가매시간늦어질때마다사망률이증가하며 [13], 중증패혈증에있어서도 1시간이내투여와 6시간이내적절한항생제를투여하지못한경우에있어서사망률에유의한차이가있다 [12]. 그러나무분별한항생제투여는최근문제가심각한항생제내성을유발하고의료비용을증가시킬수있다. 다양한경우에있어서이들상황과유사한임상양상이나타날수있으므로세균감염에의한것과아닌상황에대한감별이무엇보다도중요하다. 3. 어떤경험적항생제를사용할것인가? 추정되는일차감염부위가있는경우와없는경우로나누어서을서술하였다. 추정되는일차감염부위가있는경우에있어서폐렴인경우, 요로감염인경우, 복강내감염인경우, 피부및연조직감염인경우로나누어서기술하였다. 3-1. 중증패혈증및패혈쇼크의추정되는일차감염부위에따른경험적항생제 3-1-1. 폐렴이의심되는경우초기경험적항생제는? 3-1-1-1. P. aeruginosa 감염이의심되지않는경우 1. 베타락탐 (cefotaxime, ceftriaxone, 또는 ampicillin/sulbactam) + azithromycin (grade 1C) 또는플르오르퀴놀론 (levofloxacin, moxifloxacin) 의 (grade 1B) 병합요법을권고한다. 근거요약국내지역사회획득폐렴의원인균에대한자료는제한적으로있지만중증패혈증또는패혈쇼크를유발하는지역사회획득중증폐렴에대한자료는앞에서언급한한국패혈증등록시스템의자료외에는없다. 이자료에따르면가장흔한원인균은 S. pneumoniae가 27% 로가장많았고, S. aureus, Klebsiella species가각각 21.1%, 다음이 Pseudomonas species 9.2% 순이었다 (Table 3). 이는국내에서수행된지역사회획득폐렴의원인균과유사한분포양상을보인다 [15-20]. 국내지역사회획득폐렴에있어서비정형폐렴의유병률과원인미생물에관한연구는제한적이나보고된비정형폐렴원인균의분포를보면 Mycoplasma 폐렴은 6.3-9.2% 를차지하고있으며, Chalmydia pneumoniae는 7.3-13.2%, 외국의경우중증폐렴을유발한다고알려져있는 Legionella는 0-5.3% 로보고되었다 [16,21-24]. Legionella는중환자실입원이필요한중등도이상의폐렴에서다른비정형폐렴균에비해더흔한원인균이었다 [16,25]. 최근지역사회획득폐렴에있어서도메치실린내성포도알균이나 Extended spectrum beta-lactamase(esbl) 생성균이보고되고있으나이들연구가모두후향적연구 (18-20) 이었고빈도가낮아본치료지침에서는이들의치료에대하여서는언급하지않았다. 그러나이들내성균이증가하는경우이들에대한추기경험적치료도고려하여야할것이다. 중증패혈증이나패혈쇼크의경우통상적으로항생제임상시험에서제외되므로폐렴에의한중증패혈증또는패혈쇼크의경우무작위대조연구결과는없는실정이다. 그러므로은증례연구나후향적코호트연구또는전향적관찰연구를기반으로하여추론되었다. 병합요법이좋은지단독요법이좋은지논란이되고있지 - 213 -
- 2012 년제 63 차대한내과학회추계학술대회 - 만 2007년 IDSA/ATS 가이드라인이나국내지역사회획득폐렴치료지침에서는중증폐렴에대하여병합요법을권고하고있다 [26,27]. 근거로는플루오르퀴놀론단독요법이중증폐렴에서확립되어있지않다는점 [28] 과균혈증을동반한폐렴알균에의한감염에있어서병합요법이치료성적이좋았고 [29-31], 가장흔한원인균인 S. pneumoniae와 Legionella 종을겨냥하기위하여병합치료를권고하고있다. 최근전향적연구의이차적인분석에서지역사회획득폐렴에의한패혈쇼크의경우에있어서병합요법이단독요법보다효과적이라는연구결과가있고 [32] 폐렴중증지표인 PSI (pneumonia severity index) V이상인환자를대상으로한전향적연구에있어서도병합요법이단독요법보다효과가좋았다 [33]. 병합요법의기전은비정형폐렴균에대한항균력, 면역조절효과등이제시되고있으나아직확실히규명되어있지않다 [34]. 이상을근거로지역사회획득폐렴에의한중증패혈증및패혈쇼크에서는베타락탐에 Azithromycin 또는플르오르퀴놀론의병합요법을권고하였다. 베타락탐과마크로라이드의병합요법과베타락탐에플르오르퀴놀론병합요법중어느것이좋은지에대하여서는아직무작위대조군연구는없다. 그러나기관지삽관을요구하는중증지역사회획득폐렴에대한전향적관찰연구에서는마크로라이드의병합요법이치료성적이좋았으며 [35], 폐렴에의한중증패혈증을대상으로한후향적코호트연구에서도마크로라이드병합요법이치료성적이좋았다 [36]. 그러나 S. pneumoniae에대한마크로라이드내성이 40% 정도인국가에서시행된연구로마크로라이드내성이 80% 이상인국내현실을감안시이를그대로적용하기는힘들것으로사료되며이에대한국내다기관무작위대조연구가필요하리라생각된다. 3-1-1-2. P. aeruginosa 감염이의심되는경우초기경험적항생제는? 1. 아래와같은 3종류중하나의병합요법을고려한다 (grade 2D). antipneumococcal, antipseudomonal B-lactam (cefepime, piperacillin/tazobactam) + Ciprofloxacin or levofloxacin 또는 antipneumococcal, antipseudomonal B-lactam + aminoglycoside + azithromycin 또는 antipneumococcal, antipseudomonal B-lactam + aminoglycoside + Antipneumococcal fluorquinolone (Moxifloxacine or levofloxacine) 근거요약 Pseudomonas 감염에의한경우초기경험적항생제가부적절할수있어환자의예후에부정적영향을미칠수있기때문에이를방지하기위하여병합요법을추천하며, 감수성결과가확인되는경우감수성이있는단일항생제와병합요법간에환자의예후에영향이없으므로감수성결과가확인되는경우단일항생제로변경할것을권고한다 [37]. Pseudomonas 감염이의심되는경우에있어서도폐렴알균에대한항균력이있으면서동시에 Pseudomonas에항균력을지닌항생제를선택해야하는데어느항생제가적정한지에대한임상연구는충분하지않은실정으로본치료지침은 2007년 IDSA/ATS 과 2009년지역사회획득폐렴의치료지침을토대로논의를거쳐을확정하였다. 최근 carbapenem 내성균이증가하는추세로 carbapenem 항생제의사용을줄이기위하여본에서는 carbapenem 을제외하였으나지역적특성환자의특수한상황을고려시임상의는이의선택도고려할수있다. Pseumonas 감염에대한위험인자로는음주, 기관지확장증등폐의구조적질환, 반복되는만성폐쇄호흡기질환악화로인한항생제와스테로이드를자주투여해온병력, 최근 3개월이내항생제투여력등이있다 [26,27]. 3-1-2. 요로감염이의심되는경우초기경험적항생제는? 1. 광범위세팔로스포린 (cefotaxime, ceftriaxone, ceftazidime, cefepime) 또는 Aminopenicillin/ bata-lactamase inhibitor (piperacillin/tazobactam) 를권고한다 (gade 1C) 2. 항생제내성균이의심되어 aminoglycoside가필요한경우이의추가를고려한다 (grade 2D). 3. 중증패혈증이나패혈쇼크를동반한경우에있어서 ampi- - 214 -
- 손장욱. 국내지역사회획득중증패혈증및패혈쇼크의항생제치료지침 ( 안 ) - cillin, 플르오르퀴놀론 (ciprofloxacin, levofloxacin) 또는 trimethoprim/sulfamethoxazole 단독요법을사용하는것은권고하지않는다 (grade 1D). 4. 아미노글라이코사이드단독요법은요로감염에서는효과적이나중증패혈증또는패혈쇼크가동반된경우에서는임상자료가부족하여권고하지않는다 (grade 1C). 근거요약지역사회획득요로감염의원인균의분포및항생제내성에관한전국적인자료는 KARMS (Korean Antimicrobial Resistance Monitoring System) 의자료가있다 [38]. 가장흔한원인균으로는 E. coli (72.7%), Enterococcus faecalis (10.7%), K. pneumonia (3.5%), S. agalactiae (3.0%), P. aeruginosa (1.9%), E. faecium (1.9%) 순으로, 국내일차감염부위가요로감염인중증패혈증및패혈쇼크의원인균분포와유사하다 (Table 4). 이들원인균의항생제내성은감염증별로차이가있으며, 하부요로감염에비해상부요로감염인경우, 단순요로감염에비해복잡성요로감염인경우항생제내성률이높은경향을보였으며지역별차이를보였다. E. coli 경우 ampicillin 내성율은 60.1-74.1%, ciprofloxacin 내성율은 24.8-40.7%, lelevofloxa 내성율은 21.3-35.8%, trimethoprim/sulfamethoxazole (TMP/SMX) 내성율은 25.7-35.3%, cefuroxime 내성율은 9.9-22.2%, ceftriaxone 내성율은 5.3-11.8%, amikacin 내성율은 0.3-1.8%, tobramycin 내성율은 5.4-11.8% 로 3세대세팔로스포린과아미노글라이코사이드항생제내성율이가장낮았다. E. faecalis의경우 ampicillin 내성은 5.0-28.6%, ciprofloxacin 내성율은 42.1-57.1%, TMP/SMX 내성율은 36.7-57.9% 이었고 gentamicin 내성율도 45-57.1% 로높았다. K. pneumonia 경우 ampicillin 내성율이 88.5-100%, ceftriaxone 내성율이 13.5-22.2%, amikacin 내성율은 5.8-11.1% 이었다 [38]. 원인균의빈도및항생제내성양상을고려시초기경험적항생제는광범위세팔로스포린계항생제 (cefotaxime, ceftriaxone, ceftazidime, cefepime) 또는 Aminopenicillin/bata-lactamase inhibitor (piperacillin/tazobactam) 가적절할수있다 [39-42]. 항생제내성균의가능성이높은경우부적절한항생제치료를예방하기위하여아미노글라이코사이드의병합요법을고려할수있다. ESBL 생성 E. coli 는지역사회에증가하는양상으로환자의특성이나병원별, 지역별항생제감수성결과를바탕으로이러한균이의심되는경우에있어서는 carbapenem (ertapenem, imipenem, meropenem) 계항생제사용을고려할수있으나최근 carbapenem계항생제에내성인균의증가추세로항생제의선택적압력을고려하여임상의는이들항생제사용에신중을기울여야할것이다. 아미노글라이코사이드의요로감염원인균에대한감수성결과는매우높은편이다. 요로감염에대한아미노글라이코사이드의메타분석결과를보면일차적인치료성적은효과적이나미생물학적실패률은높은것으로나타나고있으며중증감염에대하여서는임상자료가부족하다 [43]. 중증감염에대하여임상자료가부족하고중증감염에있어서단독요법의효능이의심스럽다는관찰연구결과를토대로요로감염에의한중증패혈증또는패혈쇼크에있어서아미노글라이코사이드단독요법은권고하지않는다 [44,45]. 3-1-3. 복강내감염이의심되는경우초기경험적항생제는? 1. 광범위세팔로스포린 (cefepime, ceftazidime) + metronidazole 또는 Aminopenicillin/bata-lactamase inhibitor (piperacillin/tazobactam) 를권고한다 (grade 1B). 2. Fluorquinolone 은항생제감수성결과를확인후사용할수있으며주요원인균에대한국내내성양상을감안시초기경험적항생제로권고하지않는다 (grade 1B) 3. Aminoglycoside의통상적인병합요법은고려되지않는다. 단, 항생제내성균이의심되어이들항생제가필요한경우이의병합을고려한다 (grade 1B). 4. Enterococci에대한경험적항생제사용을고려할수있다 (grade 2D). 5. MRSA 또는진균감염에대한항생제는이들균에의한감염의증거가없는한사용을고려하지않는다 (grade 2C). 근거요약복강내감염의원인균분포는 E. coli 가가장많고혐기성균에있어서는 Bacteroides fragilis 그람양성균중에서는 streptococcus가가장많다 [46-48]. 지역사회획득복강내감염의원인균분포에관한자료는극히제한적이나이들을종 - 215 -
- 2012 년제 63 차대한내과학회추계학술대회 - 합하면 E. coli 가가장많고 Bacteroides, Klebsiella, Pseudomonas, Enterococcus 순으로외국과유사한양상을보인다 [49-51]. Enterococcus 중지역사회획득감염은대부분 E. faecalis이고 E. faecium 경우대부분은의료관련감염과관련이높다 [52]. 한국패혈증등록시스템의자료를보면원인균이규명된경우에있어서그람음성균이 75.6%, 그람양성균이 10.4%, 혼합감염이 10.9%, 혐기성균감염이 3% 로중증감염에있어서는혐기성균감염의빈도가적은것으로보여진다. 가장흔한균은 Klebsiella species로 35.8%, E. coli 가 31.8% 로두균이약 70% 를차지하며, Streptococcus species 가 5%, Enterococcus species가 4.5% 를차지한다 (Table 5). 원인균의항생제내성양상은균혈증을동반한복강내감염의원인균중그람음성균중에서광범위세팔로스포린항생제에대한내성률은 6.8% (25/365) 이었고 [52], 지역사회획득 E. coli 균혈증에있어서 ESBL 생성균은 3.2% (10/314) 이었고 ciprofloxacin 내성은 23.3% 이었다 [53]. 혐기성균중복강내감염의주된원인균인 B. fragilis군에대한항생제내성양상은 piperacillin 내성율은 33-49%, cefoxitin 내성률은 4-11%, cefotetan 내성률은 14-60%, clindamycin 내성 51-76%, piperacillin/ tazobactam 내성 1-6%, imipenem 내성 1-4%, metronidazole 내성 0% 이었다 [54]. E. faecalis 페니실린내성율은국내에서약 6% 로보고되고있다 [55]. 주요원인균인 E. coli 의퀴놀론내성율이 20% 이상이며 ampicillin/sulbactam 내성율이 30% 로국내에서보고되고있어서 [55], 초기경험적항생제로퀴놀론및 ampicillin/ sulbactam의사용은권고되지않는다. 중증패혈증및패혈쇼크의경우그람음성균과혐기성균에대한항균력을지닌광범위한항생제의사용이권장된다. cepefime 또는 ceftazidime 에 metronidazole 병합이나 piperacillin/ tazobactam 등이권장된다. Carbapenem (imipenem-cilastin, meropenem, doripenem) 의경우이들항생제내성균의증가로심각한위협이초래되고있으므로항생제의선택적압력을고려시 ESBL 생성균의위험성이있는환자또는병원별, 지역별특성을고려하여신중히사용하여야한다 [56]. 아미노글라이코사이드항생제의경우상대적으로좁은항균력을지니며, 신독성과이독성이타항생제에비해높은것으로알려져있다. 이들항생제의병합요법에대한메타분석결과다른항생제요법에비해복강내감염에서효과가적은것으로알려져있으며 [57], 패혈증환자를대상으로한 메타분석결과에서도베타락탐단독요법에비해 aminoglycoside 병합요법의효과가우월하지않았고신독성의위험만증가시키는것으로보고되고있어통상적인병합요법은권고되지않는다 [58]. MRSA 와진균에의한국내지역사회획득복강내감염에대한자료는거의없으며, 빈도는낮을것으로사료되어이들감염의증거가없는한통상적으로이들균을겨냥한항생제사용은고려되지않는다. 3-1-4. 피부및연조직감염이의심되는경우초기경험적항생제는? 1. Piperacillin/tazobactam + clindamycin 또는 ampicillin/sulbactam + clindamycin + ciprofloxacin 병합을권고한다 (grade 1B) 2. 비브리오감염이의심되는경우에있어서는 cefotaxime 또는 ceftazidime + doxycycline or tetracycline의병용요법을권고한다 (grade 1C). 근거요약중증패혈증및패혈쇼크를유발하는피부및연조직감염의주요원인균은 S. aureus와 Streptococcus species로각각 34.2% 와 28.9% 이었고그람음성균이 15.5% 이었다 (Table 6). 외국의경우흔한원인균으로 Streptococcus species, S. aureus, 혼합균감염등을들수있다 [59]. 피부및연조직감염에서중증패혈증을유발할수있는질환으로는괴사성근막염을들수있으며, 이의원인균으로는 S. pyogenes, S. aureus, Vibro vulnificus, Aeromonas hydrophila, anaerobic streptococci (Peptostreptococcus species 등 ), 혐기성균과그람음성간균의혼합감염등이흔하다 [60]. 또한중증질환으로 Clostridial가스괴저를들수있으며이의가장흔한원인균은 C. perfringens이다 [60]. 이들질환에대한무작위대조군연구는수행되지않았고일부가이드라인에서는 Piperacillin/tazobactam + clindamycin 또는 ampicillin/sulbactam + clindamycin + ciprofloxacin 이들의병합요법을추천하고있다 [60]. Vibrio vulnificus 감염일경우 cefotaxime 또는 ceftazidime 에 doxycycline 또는 tetracycline의병합요법이추천된다 [61]. 세팔로스포린을사용할수없는경우퀴놀론이대안이될수 - 216 -
- 손장욱. 국내지역사회획득중증패혈증및패혈쇼크의항생제치료지침 ( 안 ) - 있다 [62]. 지역사회에서 MRSA 의증가가문제가되고있다. 국내지역사회관련 MRSA 의빈도는 6% 로보고되고있고 [63], 응급실로내원한환자의피부및연조직감염에의한 S. aureus 균혈증에서 MRSA 의빈도는 23.7% 이었다. 이연구는한대학병원에서시행되었고의료관련감염을배제하지않아 MRSA 의빈도가높았을가능성과피부및연조직감염에의한경우는 38예로증례가적다는단점이있다 [64]. 아직국내상황에서피부및연조직감염에서 MRSA 를경험적으로치료해야한다는증거는미약하나 MRSA 감염이의심되는상황에서 Vancomycin 투여도고려하여야할것이다. 3-2. 일차감염부위가확실하지않은경우? 1. Pseudomonas 감염이의심되는경우와그렇지않은경우로나누어서권고한다 (grade 2D). 2. Pseudomonas 감염이의심되지않는경우? 3. Piperacillin/tazobactam 또는광범위세팔로스포린 (ceftriaxone, cefotaxime, cefepime) +/- vancomycin 4. Pseudomonas 감염이의심되는경우? cefepime 또는 Piperacillin/tazobactam +/- fluorquinolone (ciprofloxacin, levofloxacin, moxifloxacin) 또는 aminoglycoside 근거요약한국패혈증등록시스템의연구결과 S. aureus, Klebsiella species, E. coli가일차혈류감염이약 50% 를차지한다. 그러므로원인이확실하지않은경우이들균주에대한항균력이있는항생제를선택하여야하며지역별, 병원별내성양상과환자의특성을고려하여항생제를선택하여야한다. 이에대한연구는외국에도거의없는상황이며일부가이드라인이나교과서역시대부분이전문가의의견을수렴한형태이다. 본치료지침안에서도전문가의자문과회의를통하여을결정하였다 (grade 2D). 4. 항생제투여후추적조사는어떻게할것인가? 1. 사용하고있는항생제요법은항균력을최적화하고내 성을억제하고독성을줄이고비용을감소시키기위하여매일재평가할것을권고한다 (grade 1D). 2. 중증패혈증에서항생제를경험적으로투여하는경우에있어서감수성결과를확인후가능한빨리가장적절한단일항생제로변경할것을권고한다 (grade 1D). 3. 감염성원인이아닌경우내성발생과약제이상반응을예방하기위하여즉각적으로항생제투여를중단할것을권고한다 (grade 1D). 본치료지침의제한점 중증패혈증및패혈쇼크는일반적인임상시험에서통상적으로제외기준에해당하기에무작위대조군연구가거의없어근거가주로관찰연구또는환자대조군연구에국한되어근거가약하다는단점이있다. 또한국내에서이들질환에대한연구도미미한상태로국내실정을정확히반영하기는힘든점도있으나가급적국내자료에의거하여본치료지침을작성하였다. 국내지역사회획득중증패혈증또는패혈쇼크를대상으로한치료지침으로의료관련감염은배제하였다는점을임상의는고려하여야할것이다. 본지침을이용시의료관련감염과지역사회감염의감별은중요하다. 가장문제가되는점은국내지역사회에서내성양상이변하고있는점으로치료지침을임상에서이용시이를고려하여야할것이다. 본치료지침은항생제사용의증가로인한다제내성균이증가하는상황에서현실에서문제가되고있는주요항생제의선택적압력을줄일수있는방향으로을작성하였다. REFERENCES 1. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest. 1992; 101(6):1644-55. Epub 1992/06/01. 2. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. The New England journal of medicine. 2003;348(16):1546-54. Epub 2003/ 04/18. 3. Linde-Zwirble WT, Angus DC. Severe sepsis epidemiology: sampling, selection, and society. Crit Care. 2004;8(4):222-6. Epub - 217 -
- 2012 년제 63 차대한내과학회추계학술대회 - 2004/08/18. 4. Dombrovskiy VY, Martin AA, Sunderram J, Paz HL. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Critical care medicine. 2007;35(5):1244-50. Epub 2007/04/07. 5. Gyssens IC. Quality measures of antimicrobial drug use. International journal of antimicrobial agents. 2001;17(1):9-19. Epub 2001/01/04. 6. Harbarth S, Nobre V, Pittet D. Does antibiotic selection impact patient outcome? Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2007;44(1): 87-93. Epub 2006/12/05. 7. Kumar A, Ellis P, Arabi Y, Roberts D, Light B, Parrillo JE, et al. Initiation of inappropriate antimicrobial therapy results in a fivefold reduction of survival in human septic shock. Chest. 2009;136(5):1237-48. Epub 2009/08/22. 8. Garnacho-Montero J, Garcia-Garmendia JL, Barrero-Almodovar A, Jimenez-Jimenez FJ, Perez-Paredes C, Ortiz-Leyba C. Impact of adequate empirical antibiotic therapy on the outcome of patients admitted to the intensive care unit with sepsis. Critical care medicine. 2003;31(12):2742-51. Epub 2003/12/12. 9. Micek ST, Isakow W, Shannon W, Kollef MH. Predictors of hospital mortality for patients with severe sepsis treated with Drotrecogin alfa (activated). Pharmacotherapy. 2005;25(1):26-34. Epub 2005/03/16. 10. Harbarth S, Garbino J, Pugin J, Romand JA, Lew D, Pittet D. Inappropriate initial antimicrobial therapy and its effect on survival in a clinical trial of immunomodulating therapy for severe sepsis. The American journal of medicine. 2003;115(7):529-35. Epub 2003/11/06. 11. Paul M, Shani V, Muchtar E, Kariv G, Robenshtok E, Leibovici L. Systematic review and meta-analysis of the efficacy of appropriate empiric antibiotic therapy for sepsis. Antimicrobial agents and chemotherapy. 2010;54(11):4851-63. Epub 2010/ 08/25. 12. Ferrer R, Artigas A, Suarez D, Palencia E, Levy MM, Arenzana A, et al. Effectiveness of treatments for severe sepsis: a prospective, multicenter, observational study. American journal of respiratory and critical care medicine. 2009;180(9):861-6. Epub 2009/08/22. 13. Kumar A, Roberts D, Wood KE, Light B, Parrillo JE, Sharma S, et al. Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Critical care medicine. 2006;34(6):1589-96. Epub 2006/04/21. 14. Dellinger RP, Levy MM, Carlet JM, Bion J, Parker MM, Jaeschke R, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Critical care medicine. 2008;36(1):296-327. Epub 2007/12/26. 15. Woo JH KJ, Kim YS, Shin WS, Ryu JH, Choi JH, Kim YR, Cheong HJ, Uh ST, Park CS, Chung MH, Chung KS, Lee CJ, Ryu J. A Prospective Multicenter Study of Community-acquired Pneumonia in Adults with Emphasis on Bacterial Etiology. Korean J Infect Dis. 2001;33(1):1-7. 16. Sohn JW, Park SC, Choi YH, Woo HJ, Cho YK, Lee JS, et al. Atypical pathogens as etiologic agents in hospitalized patients with community-acquired pneumonia in Korea: a prospective multi-center study. Journal of Korean medical science. 2006; 21(4):602-7. Epub 2006/08/08. 17. Song JH, Oh WS, Kang CI, Chung DR, Peck KR, Ko KS, et al. Epidemiology and clinical outcomes of community-acquired pneumonia in adult patients in Asian countries: a prospective study by the Asian network for surveillance of resistant pathogens. International journal of antimicrobial agents. 2008; 31(2):107-14. Epub 2007/12/29. 18. Park HK, Song JU, Um SW, Koh WJ, Suh GY, Chung MP, et al. Clinical characteristics of health care-associated pneumonia in a Korean teaching hospital. Respiratory medicine. 2010;104(11): 1729-35. Epub 2010/07/08. 19. Jeon EJ, Cho SG, Shin JW, Kim JY, Park IW, Choi BW, et al. The difference in clinical presentations between healthcare-associated and community-acquired pneumonia in university-affiliated hospital in Korea. Yonsei medical journal. 2011;52(2):282-7. Epub 2011/02/15. 20. Jung JY, Park MS, Kim YS, Park BH, Kim SK, Chang J, et al. Healthcare-associated pneumonia among hospitalized patients in a Korean tertiary hospital. BMC infectious diseases. 2011;11:61. Epub 2011/03/15. 21. Lee DD SE, Lee SM, Lee EY, Kim YS, Lee MK, Kim JM, Lee HK, Chang CL. Frequency of Legionella Infection in Patients with Community-Acquired Pneumonia. Korean J Lab Med. 2005;25(6):416-20. 22. Kim MJ CH, Sohn JW, Shim HS, Park DW, Park SC, Woo JH, Kang JM, Kim, YK, Shin WS, Kim YR, Lee HJ, Kim JH. A Prospective Multicenter Study of the Etiological Analysis in Adults with Community-Acquired Pneumonia: Legionella, Leptospira, Hantaan virus and Orientia tsutsugamushi. Korean J Infect Dis. 2001;33(1):24-31. 23. Joo CH YH, Nam JH, Moon MS, Cho YK, Woo JH, Kang JM, Shin WS, Kim YR, Kim MJ, Chung HJ, Lee HJ, Kim YK. A Prospective Multicenter Study on the Etiological Analysis of Community-Acquired Pneumonia in Adult Patients in Korea: Detection of Mycoplasma pneumoniae and Chlamydia pneumoniae Infections Korean J Infect Dis. 2001;33(1):15-24. 24. Lee SJ, Lee MG, Jeon MJ, Jung KS, Lee HK, Kishimoto T. Atypical pathogens in adult patients admitted with communityacquired pneumonia in Korea. Japanese journal of infectious diseases. 2002;55(5):157-9. Epub 2002/12/27. 25. Lee JS CJ, Koh Y, Lim CM, Jung YJ, Oh YM, Shim TS, Lee SD, Kim WS, Kim DS, Kim WD, Hong SB. The Etiologies and Initial Antimicrobial Therapy Outcomes in One Tertiary Hospital - 218 -
- 손장욱. 국내지역사회획득중증패혈증및패혈쇼크의항생제치료지침 ( 안 ) - ICU-admitted Patient with Severe Community-acquired Pneumonia. Tuberc Respir Dis. 2005;59(5):522-9. 26. Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, et al. Infectious Diseases Society of America/ American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2007;44 Suppl 2:S27-72. Epub 2007/02/06. 27. Song JH JK, Kang MW, Kim DJ, Pai H, Suh JY, Shim TS, Ahn JH, Ahn CM, Woo JH, Lee NY, Lee DG, Lee MS, Lee SM, Lee YS, Lee H, Chung DR; A Joint committee for CAP Treatment Guideline. Treatment Guidelines for Community-acquired Pneumonia in Korea: An Evidence-based Approach to Appropriate Antimicrobial Therapy. Infection and Chemotherapy. 2009; 41(3):133-53. 28. Leroy O, Saux P, Bedos JP, Caulin E. Comparison of levofloxacin and cefotaxime combined with ofloxacin for ICU patients with community-acquired pneumonia who do not require vasopressors. Chest. 2005;128(1):172-83. Epub 2005/07/09. 29. Baddour LM, Yu VL, Klugman KP, Feldman C, Ortqvist A, Rello J, et al. Combination antibiotic therapy lowers mortality among severely ill patients with pneumococcal bacteremia. American journal of respiratory and critical care medicine. 2004;170(4): 440-4. Epub 2004/06/09. 30. Waterer GW, Somes GW, Wunderink RG. Monotherapy may be suboptimal for severe bacteremic pneumococcal pneumonia. Archives of internal medicine. 2001;161(15):1837-42. Epub 2001/08/30. 31. Martinez JA, Horcajada JP, Almela M, Marco F, Soriano A, Garcia E, et al. Addition of a macrolide to a beta-lactam-based empirical antibiotic regimen is associated with lower in-hospital mortality for patients with bacteremic pneumococcal pneumonia. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2003;36(4):389-95. Epub 2003/02/05. 32. Rodriguez A, Mendia A, Sirvent JM, Barcenilla F, de la Torre-Prados MV, Sole-Violan J, et al. Combination antibiotic therapy improves survival in patients with community-acquired pneumonia and shock. Critical care medicine. 2007;35(6):1493-8. Epub 2007/04/25. 33. Lodise TP, Kwa A, Cosler L, Gupta R, Smith RP. Comparison of beta-lactam and macrolide combination therapy versus fluoroquinolone monotherapy in hospitalized Veterans Affairs patients with community-acquired pneumonia. Antimicrobial agents and chemotherapy. 2007;51(11):3977-82. Epub 2007/08/22. 34. Feldman C, Anderson R. Therapy for pneumococcal bacteremia: monotherapy or combination therapy? Current opinion in infectious diseases. 2009;22(2):137-42. Epub 2009/03/12. 35. Martin-Loeches I, Lisboa T, Rodriguez A, Putensen C, Annane D, Garnacho-Montero J, et al. Combination antibiotic therapy with macrolides improves survival in intubated patients with community-acquired pneumonia. Intensive care medicine. 2010;36(4):612-20. Epub 2009/12/03. 36. Restrepo MI, Mortensen EM, Waterer GW, Wunderink RG, Coalson JJ, Anzueto A. Impact of macrolide therapy on mortality for patients with severe sepsis due to pneumonia. The European respiratory journal: official journal of the European Society for Clinical Respiratory Physiology. 2009;33(1):153-9. Epub 2008/ 09/05. 37. Garnacho-Montero J, Sa-Borges M, Sole-Violan J, Barcenilla F, Escoresca-Ortega A, Ochoa M, et al. Optimal management therapy for Pseudomonas aeruginosa ventilator-associated pneumonia: an observational, multicenter study comparing monotherapy with combination antibiotic therapy. Critical care medicine. 2007;35(8):1888-95. Epub 2007/06/22. 38. Lee SJ, Lee DS, Choe HS, Shim BS, Kim CS, Kim ME, et al. Antimicrobial resistance in community-acquired urinary tract infections: results from the Korean Antimicrobial Resistance Monitoring System. Journal of infection and chemotherapy: official journal of the Japan Society of Chemotherapy. 2011; 17(3):440-6. Epub 2010/12/09. 39. Byl B, Clevenbergh P, Kentos A, Jacobs F, Marchant A, Vincent JL, et al. Ceftazidime- and imipenem-induced endotoxin release during treatment of gram-negative infections. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology. 2001;20(11): 804-7. Epub 2002/01/11. 40. Luchi M, Morrison DC, Opal S, Yoneda K, Slotman G, Chambers H, et al. A comparative trial of imipenem versus ceftazidime in the release of endotoxin and cytokine generation in patients with gram-negative urosepsis. Urosepsis Study Group. Journal of endotoxin research. 2000;6(1):25-31. Epub 2000/11/04. 41. McKinnon PS, Paladino JA, Schentag JJ. Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. International journal of antimicrobial agents. 2008;31(4):345-51. Epub 2008/03/04. 42. Bin C, Hui W, Renyuan Z, Yongzhong N, Xiuli X, Yingchun X, et al. Outcome of cephalosporin treatment of bacteremia due to CTX-M-type extended-spectrum beta-lactamase-producing Escherichia coli. Diagnostic microbiology and infectious disease. 2006;56(4):351-7. Epub 2006/08/29. 43. Vidal L, Gafter-Gvili A, Borok S, Fraser A, Leibovici L, Paul M. Efficacy and safety of aminoglycoside monotherapy: systematic review and meta-analysis of randomized controlled trials. The Journal of antimicrobial chemotherapy. 2007;60(2):247-57. Epub 2007/06/15. 44. Siegman-Igra Y, Ravona R, Primerman H, Giladi M. - 219 -
- 2012 년제 63 차대한내과학회추계학술대회 - Pseudomonas aeruginosa bacteremia: an analysis of 123 episodes, with particular emphasis on the effect of antibiotic therapy. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 1998;2(4):211-5. Epub 1998/10/08. 45. Leibovici L, Paul M, Poznanski O, Drucker M, Samra Z, Konigsberger H, et al. Monotherapy versus beta-lactam-aminoglycoside combination treatment for gram-negative bacteremia: a prospective, observational study. Antimicrobial agents and chemotherapy. 1997;41(5):1127-33. Epub 1997/05/01. 46. Solomkin JS, Wilson SE, Christou NV, Rotstein OD, Dellinger EP, Bennion RS, et al. Results of a clinical trial of clinafloxacin versus imipenem/cilastatin for intraabdominal infections. Annals of surgery. 2001;233(1):79-87. Epub 2001/01/05. 47. Solomkin JS, Yellin AE, Rotstein OD, Christou NV, Dellinger EP, Tellado JM, et al. Ertapenem versus piperacillin/tazobactam in the treatment of complicated intraabdominal infections: results of a double-blind, randomized comparative phase III trial. Annals of surgery. 2003;237(2):235-45. Epub 2003/02/01. 48. Solomkin JS, Reinhart HH, Dellinger EP, Bohnen JM, Rotstein OD, Vogel SB, et al. Results of a randomized trial comparing sequential intravenous/oral treatment with ciprofloxacin plus metronidazole to imipenem/cilastatin for intra-abdominal infections. The Intra-Abdominal Infection Study Group. Annals of surgery. 1996;223(3):303-15. Epub 1996/03/01. 49. Ahn IK SW, Ryu JW, Lee HG, Park JK, Chung M, Park DK, Kim JT, Lee DS, Lee CY. Bacteriologic Study and Prophylactic Antibiotics in the Acute and Complicated Appendicitis. J Korean Surg Soc. 1998;55(2):235-41. 50. Park SW PJ, Lee SI. Analysis on the Etiology and Prognostic Factors of Community-Acquired Bacteremia in a Community- Based Tertiary Hospital. Infect Chemother. 2005;37(5):255-64. 51. Bae WK MY, Kim JH, Lee SH, Kim NH, Kim KA, Lee JS, Um TH, Cho CR. Microbiologic Study of the Bile Culture and Antimicrobial Susceptibility in Patients with Biliary Tract Infection. Korean J Gastroenterol. 2008;51(4):248-54. 52. Kang CI, Chung DR, Ko KS, Peck KR, Song JH. Clinical predictors for enterococcal bacteraemia in patients with bacteraemic intra-abdominal infections. Scandinavian journal of infectious diseases. 2010;42(11-12):817-20. Epub 2010/06/22. 53. Cheong HS, Kang CI, Kwon KT, Heo ST, Wi YM, Kim ES, et al. Clinical significance of healthcare-associated infections in community-onset Escherichia coli bacteraemia. The Journal of antimicrobial chemotherapy. 2007;60(6):1355-60. Epub 2007/ 10/10. 54. Roh KH, Kim S, Kim CK, Yum JH, Kim MS, Yong D, et al. Resistance trends of Bacteroides fragilis group over an 8-year period, 1997-2004, in Korea. Korean J Lab Med. 2009;29(4): 293-8. Epub 2009/09/04. 55. Lee K, Kim MN, Kim JS, Hong HL, Kang JO, Shin JH, et al. Further increases in carbapenem-, amikacin-, and fluoroquinolone-resistant isolates of Acinetobacter spp. and P. aeruginosa in Korea: KONSAR study 2009. Yonsei medical journal. 2011;52(5):793-802. Epub 2011/07/26. 56. Solomkin JS, Mazuski JE, Bradley JS, Rodvold KA, Goldstein EJ, Baron EJ, et al. Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America. 2010;50(2):133-64. Epub 2009/12/26. 57. Bailey JA, Virgo KS, DiPiro JT, Nathens AB, Sawyer RG, Mazuski JE. Aminoglycosides for intra-abdominal infection: equal to the challenge? Surgical infections. 2002;3(4):315-35. Epub 2003/04/17. 58. Paul M, Silbiger I, Grozinsky S, Soares-Weiser K, Leibovici L. Beta lactam antibiotic monotherapy versus beta lactam-aminoglycoside antibiotic combination therapy for sepsis. Cochrane Database Syst Rev. 2006(1):CD003344. Epub 2006/01/27. 59. Simon D, Trenholme G. Antibiotic selection for patients with septic shock. Critical care clinics. 2000;16(2):215-31. Epub 2000/ 04/18. 60. Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein EJ, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2005;41(10):1373-406. Epub 2005/10/19. 61. Liu JW, Lee IK, Tang HJ, Ko WC, Lee HC, Liu YC, et al. Prognostic factors and antibiotics in Vibrio vulnificus septicemia. Archives of internal medicine. 2006;166(19):2117-23. Epub 2006/10/25. 62. Tang HJ, Chang MC, Ko WC, Huang KY, Lee CL, Chuang YC. In vitro and in vivo activities of newer fluoroquinolones against Vibrio vulnificus. Antimicrobial agents and chemotherapy. 2002; 46(11):3580-4. Epub 2002/10/18. 63. Kim ES, Song JS, Lee HJ, Choe PG, Park KH, Cho JH, et al. A survey of community-associated methicillin-resistant Staphylococcus aureus in Korea. The Journal of antimicrobial chemotherapy. 2007;60(5):1108-14. Epub 2007/09/22. 64. Heo ST, Peck KR, Ryu SY, Kwon KT, Ko KS, Oh WS, et al. Analysis of methicillin resistance among Staphylococcus aureus blood isolates in an emergency department. Journal of Korean medical science. 2007;22(4):682-6. Epub 2007/08/31. - 220 -