Kang CI 문제가되고있는주요병원균으로는소위 ESKAPE 균주들 이있는데, 이는 Enterococci, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aerugino

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1 DOI: /jkma pissn: eissn: Pharmacotherapeutics 다제내성그람음성균감염의치료전략 강철인 * 성균관대학교의과대학삼성서울병원감염내과 Therapeutic strategy for the management of multidrug-resistant gram-negative bacterial infections Cheol - In Kang, MD* Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea *Corresponding author: Cheol-In Kang, collacin@hotmail.com Received February 8, 2011 Accepted February 22, 2011 Over the past decade, infections caused by antimicrobial-resistant bacteria have increased and continued to challenge physicians. Recent data show rapidly increasing rates of infection due to multidrug-resistant (MDR) gram-negative bacilli. Furthermore, pandrug-resistant infections now occur, especially due to gram-negative bacilli, and our therapeutic options for these pathogens are extremely limited. Infection caused by MDR bacteria was associated with a greater likelihood of inappropriate antimicrobial therapy, and inappropriate antimicrobial therapy has an adverse effect on survival in patients with serious infections. Consequently, it may be presumed that serious infections caused by MDR bacteria have a worse prognosis because of the delay in initiation of appropriate antimicrobial therapy. Empirical antibiotics for serious infections should be recommended on the basis of the distribution of pathogens and their susceptibility patterns in the institution where the regimen is administered. Therefore, physicians who are caring for patients with bacterial infection should be familiar with local antimicrobial susceptibility patterns and the epidemiology of MDR bacterial infections, in order to improve the treatment outcome of the patients. This comprehensive review aims to describe the epidemiology and clinical implications of MDR gram-negative bacterial infections in Korea, a country with a high prevalence of antimicrobial-resistant pathogens. Keywords: Multidrug-resistant bacteria; Gram-negative bacterial infections; Epidemiology; Anti-infective agents 서 론 항생제가개발된이후세균성감염질환은의사들이쉽게치료할수있는질환으로인식되었고항생제는의사들 이가장많이처방하는약중한가지가되었다. 하지만항생 제사용에따른세균의내성획득으로인해세균성감염질환의치료가점점더어려워지고있으며항생제를처방할때에도항생제내성균감염에대한지식이필수적인시대가되었다. 세균의항생제내성은의료현장에서뿐만아니라공중보건학적으로도큰문제를야기하고있다. 항생제내성이특히 c Korean Medical Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 대한의사협회지 325

2 Kang CI 문제가되고있는주요병원균으로는소위 ESKAPE 균주들 이있는데, 이는 Enterococci, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species 를지칭 한다. 최근 New Delhi metallo-β-lactamase 1 (NDM-1) 을 생성하는대장균과폐렴간균이보고되었다 [1]. 인도뉴델리 에위치한병원에서분리된균주라서 NDM-1 이라는명칭을 얻었으며이균주들은 carbapenem 계열항생제에내성을 나타낸다. 인도와파키스탄병원에서진료받은후유럽으로 돌아간환자들을통해이균주가영국을포함한유럽국가에 전파되었음이보고됨으로써언론의주목을받았고여러언 론들은소위슈퍼박테리아라는명칭을사용하였다 [2]. 슈퍼 박테리아는일반인들이사용하는용어로서학술용어가아 니며다제내성균또는다약제내성균이보다적절한표현이 다. 본약물요법에서는병원감염에서최근크게문제가되 고있는다제내성그람음성균감염의국내임상및역학자 료를토대로항생제내성현황과치료및예방에관하여기 술하고자한다. 다제내성그람음성균감염의국내역학및임상적의미 1. 폐렴간균및대장균 국내항생제내성균의모니터링을위한병원네트워크로 서 Korean Nationwide Surveillance of Antimicrobial Resistance (KONSAR) 프로그램이있다. 주기적으로국내 병원에서분리된균주들의항생제내성률을보고하고있는 데, 최근발표된국내 KONSAR 자료에따르면폐렴간균의 ceftazidime 내성률은 25-35% 에이르고있고, 대장균의 quinolone 내성률은 2002 년까지 10% 이하로유지되던것 이 2007 년에는 27% 에이르렀다 [3,4]. Extended-spectrum β-lactamase (ESBL) 생성균주에의한균혈증의위험인자 로는담즙배액관거치, 이전항생제사용력, 도뇨관거치, 이전에침습적처치를받은경우등이알려져있다 [5,6]. ESBL 생성과 ciprofloxacin 내성이연관되어있다는것 은알려져있다. ESBL을생성하는폐렴간균또는대장균균혈증 133예를분석한국내연구에서 ESBL 생성균주의 60% 가 ciprofloxacin 내성을가지고있었고, 이전 quinolone 사용력, 배뇨관거치, 72시간이전에침습적처치를받은경우가 ciprofloxacin 내성의위험인자로확인되었다 [7]. ESBL 생성폐렴간균균주들이 plasmid-mediated AmpC enzyme을함께보유하고있는경우가있다. 이러한균주들은통상적인 ESBL 확진검사에서확인되지못하는경우가있다. ESBL 생성균주와비교하였을때임상적인의의가비슷하며광범위 cephalosporin을투여받는경우에치료실패를경험할수있어문제가된다 [8]. Carbapenem 내성폐렴간균은드물게보고되고있다. Carbapenem 내성폐렴간균이분리된환자들의임상적특성을분석하였을때, 이전 carbapenem 사용력과 cephalosporin 사용력이위험인자로확인되었다 [9]. 서구, 특히스페인에서지역사회획득 ESBL 생성대장균감염증에관한연구들이많이보고되고있다 [10-12]. 90% 이상이소변검체에서분리되었으나, 일부혈액에서배양된균주들도보고된다. 위험인자로서고령, 여성, 당뇨병, 재발성요로감염, 이전항생제사용력들이확인되었다 [10]. 국내 2개의 3차병원에서지역사회획득대장균균혈증 929예를분석하였을때, 4% 가 ESBL 생성균주에의한균혈증이었으며이중 60% 가량은의료관련감염이었다 [13]. 최근국내 18개종합병원에서수집된균혈증자료를토대로지역사회에서발생한 ESBL 생성대장균에의한균혈증의위험인자가분석되었는데, 9.8% 가 ESBL 생성균주에의한균혈증이었고위험인자로서의료관련감염, 간질환, 감염부위가확인되지않은균혈증이확인되었다. ESBL 생성균에의한균혈증이사망의독립적인위험인자로확인되었다 [14]. Enterobacteriaceae 균주에의한감염증에서 ESBL 생성균주가치료결과및예후에미치는영향에대한연구가많이이루어졌다. 연구에따라차이가있지만최근시행된메타분석에서는 ESBL 생성균주에의한균혈증의경우사망률이 1.85배증가하는것으로보고되었다 [15]. ESBL 생성균주에의한감염의경우적절한항생제투여가지연될위험도가 5.56배증가하는것으로나타났다 [15]. 326 다제내성그람음성균감염의치료전략

3 MDR gram-negative bacterial infections 약물요법 Table 1. Antimicrobial therapy for serious infections caused by multidrug-resistant-klebsiella pneumoniae or Escherichia coli Antimicrobial agents Dose Adverse drug reaction Commentary For ESBL or AmpC producers Imipenem/cilastatin 0.5 g iv q 6h CNS toxicity Meropenem 1g iv q 8h Preferred in patients with neurologic disorder Ertapenem 1g iv q 24h Long half-life For carbapenem-resistant Enterobacteriaceae Colistin (polymyxin E) mg/kg per day, divided into 2-4 doses Nephrotoxicity, neurotoxicity Available in colistimethate sodium salt Tigecycline ESBL, extended-spectrum β-lactamase. After 100 mg iv loading, 50 mg iv q 12h Nausea, vomiting, hepatotoxicity Approved for complicated intraabdominal infection and soft tissue infections 2. 녹농균및아시네토박터균최근발표된 KONSAR 자료에따르면, 국내에서분리된녹농균 (Pseudomonas aeruginosa) 의 ceftazidime 내성률은 20%, piperacillin 내성률은 30-35%, quinolone 내성률은 40-50%, imipenem 내성률은 15-20% 에달한다 [3,4]. 병원에서시행된검사자료와 commercial labs에서시행된검사자료에서큰차이는없는것으로보고된다. 3차병원이아닌의료기관에서분리된균주를대상으로항생제감수성검사를시행하였을때에도항생제내성률이이전보고와유사하게높게보고되고있어, 항생제내성녹농균은국내의료기관에널리퍼져있는것으로생각된다 [15]. 3가지약제이상에내성을보이는다제내성균주는전체녹농균분리균주중 20-30% 가량을차지하는것으로보고되고있다 [16]. 내성균에의한위험인자를분석한보고에따르면, imipenem 내성균에의한균혈증의위험인자로서 carbapenem 사용력, quinolone 사용력, 이전에침습적처치를받은경우가확인되었다 [17]. 국내에서분리되는아시네토박터균 (Acinetobacter) 의 ceftazidime, quinolone 내성률은이미 1997년부터 50% 이상으로높게보고되고있다 [3,4]. Imipenem 내성률역시 2002년까지는 10% 이하로유지되다가이후증가추세를보인다 [3,18]. 최근에는 polymyxin 계열항생제에내성을보이는균주들이보고되고있으며, 한연구에서는 colistin 내성률이 30% 가량임을보고하였다 [19]. 하지만분리균주의 특정 subgroup만이높은 colistin 내성률을보였으며이들의임상적의미는현재까지규명된바없다. 녹농균에서항생제내성의임상적의미에관한연구가많이시행되었는데특히 imipenem 내성녹농균감염은사망률증가, 재원기간의연장, 의료비상승과관련있는것으로보고되었다 [20]. 국내 3개대학병원에서발생한아시네토박터균에의한균혈증환자들을대상으로 imipenem 내성이사망률에미치는영향을평가하였는데, imipenem 내성과초기부적절한항생제투여가사망의독립적인위험인자로규명되었다 [18]. 다제내성그람음성균감염의치료 1. 폐렴간균및대장균 ESBL 또는 AmpC beta- lactamase를생성하는그람음성균에의한감염증에서우선적으로사용할수있는항생제는 carbapenem 계열항생제이다. Carbapenem 계열항생제에는 imipenem, meropenem, ertapenem이있으며이중 ertapenem은하루 1회투여가가능하여외래주사치료실에서투여가능하다는장점이있다. 하지만 ertapenem은녹농균과아시네토박터균에효과가없다는제한점이있다. Imipenem과 meropenem의치료효과에는차이가없으나 imipenem에서간질발작같은중추신경계부작용이더흔하여신경과또는신경외과환자들에서는 meropenem이더 대한의사협회지 327

4 Kang CI Table 2. Antimicrobial therapy for serious infections caused by carbapenem-resistant- Pseudomonas aeruginosa or Acinetobacter baumannii Antimicrobial agents Dose Adverse drug reaction Commentary Colistin (polymyxin E) mg/kg per day, divided into 2-4 doses Nephrotoxicity, neurotoxicity Available in colistimethate sodium salt Aztreonam 2 g iv q 8h-6h Some isolates may be susceptible to aztreonam. Amikacin 7.5 mg/kg iv q 12h Nephrotoxicity, ototoxicity Tobramycin 1.7 mg/kg iv q 8h Nephrotoxicity, ototoxicity Combination with other susceptible antibiotics Combination with other susceptible antibiotics Carbapenem-resistant-P. aeruginosa or A. baumannii isolates might be susceptible to other classes of antibiotics (e.g., cefepime, piperacillin/ tazobactam, and ciprofloxacin), particularly in isolates with porin mutation as the main mechanism of carbapenem resistance. In such cases, those antibiotics susceptible in vitro can be used. 우선적으로추천된다. 최근에 carbapenem-resistant Enterobacteriaceae가산발적으로발생하고있어전세계적인문제가되고있다 [2]. 이균주에대해서 colistin과 tigecycline이사용가능한약제이다. Colistin은 40여년전개발되었으나부작용으로인하여시장에서퇴출된약이지만최근다제내성그람음성균감염이증가하면서다시생산을시작한약제이다. Carbapenem을포함한모든항생제에내성을보이는경우사용가능한항생제이다. 신독성과신경독성이문제가되므로혈청크레아티닌의모니터링이필요하다. 최근에개발된약제로서 tigecycline이있다. Tigecycline은간에서대사되어담도를통해배설되기때문에혈중농도의 100배이상의약물농도가담즙액에서검출되며대장상피세포에서도높은농도를유지한다. 따라서복강내감염에서사용가능한항생제로승인받았다. 그람양성균, 그람음성균, 혐기균에대해항균력이있는광범위항생제이며병원내감염에서문제가되고있는 methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus, ESBL 생성균주에도항균력이있어 tigecycline은단일요법으로만으로도여러가지내성균주들을치료할수있다. 하지만 tigecycline은녹농균, Proteus 균에항균력이부족하므로이들균주감염에대해서사용해서는안되고혈중농도가낮기때문에균혈증을동반한경우에는주의해서투여해야한다. 다제내성 Enterobacteriaceae 감염증에사용가능한항생제를 Table 1에기술하였다. 2. 녹농균및아시네토박터균 Carbapenem 내성녹농균및아시네토박터균은다른계열항생제에도내성을보이는경우가흔하여사용가능한항생제에제한이있다. 일부균주들은 cefepime, aztreonam, ciprofloxacin 등에감수성을보이는경우가있어감수성항생제를사용할수있다 [21]. 하지만대부분의 carbapenem 내성균은다른항생제에모두내성을보이는경우가흔하므로이경우 colistin을투여해야한다. Amikacin, tobramycin에감수성균주라면다른항생제와병합해서 aminoglycoside 투여를고려할수있다. 녹농균과달리아시네토박터균은 tigecycline에감수성이있다. Tigecycline은 tetracycline 계열항생제이므로 minocycline의감수성으로 tigecycline의감수성을추정해볼수있다. Carbapenem 내성녹농균과아시네토박터균감염증에사용가능한항생제를 Table 2에기술하였다. 3. 적극적인배농또는수술모든화농성감염의치료원칙은적절한배농후항생제치료이다. 좋은항생제가많이개발됨에따라감염질환의치료를위해항생제에만의존하려는경향이있는데, 항생제가현대의학에도입된지 70년가량밖에되지않았음을생각해보면항생제외의치료법의중요성을미루어짐작할수있다. 특히모든항생제에내성을보이는균주에의한감염이발생하고있다는것은항생제가개발되기이전의시대로돌아갈수있음을의미한다. 항생제가개발되기전의사들이화농성 328 다제내성그람음성균감염의치료전략

5 MDR gram-negative bacterial infections 약물요법 감염질환을수술로치료했듯이다제내성균감염에는보다적극적인배농또는수술이필요하다. 특히투여가능한항생제가제한되어있는경우제한된항생제를계속유지하는것보다적극적인배농과수술을통해감염원을제거해서항생제내성균의발생을억제하는것이중요하다. 항생제내성의감소는의료인개개인의노력만으로이루어지는것은아니다. 의료인, 의료기관, 의료인단체, 보건관련단체, 보건의료정책부서모두의포괄적이고적극적인노력이뒷받침되어야한국가의항생제내성률을감소시키고아울러항생제내성균에의한병원감염을줄일수있을것이다 [23]. 다제내성그람음성균감염의예방및대책 모든감염질환은치료보다예방이중요하다. 다제내성그 람음성균감염을예방하기위해서항생제내성균의발생을 억제해야한다. 항생제내성률을감소시키기위한방안은 적절한항생제사용과철저한병원감염관리로대변할수있 다 [22]. 이전항생제의사용력은항생제내성균발생의중요 한위험인자로알려져있고, 항생제사용량과내성률의상관 관계가밝혀져있다. 따라서꼭필요한경우에만항생제를 사용함으로써항생제오남용을줄이는것이항생제내성의 감소에중요하며, 항생제를투여할때는적절한용량과치료 기간을지켜서균의내성획득을막아야한다. 병원내에서내성균의전파는환자들사이또는환자와 의료인사이에서이루어지며손, 의료기기등매개체를통해 서이루어진다. 따라서병원내내성균을감소시키기위해 서는환자접촉전후로손위생관리를철저히하는것이중 요하며병원감염관리원칙을준수하는것이필요하다. 특 히다제내성균이분리된환자들을격리하거나접촉격리주 의 (contact precaution) 를하는것이필요하다. 항생제내성균에효과적인새로운항생제를개발하는것 이시급한과제이지만항생제개발에오랜시간과비용이들 어가고새롭게개발되었다고하더라도다시내성을획득하 는문제로인하여많은제약회사들이항생제개발을포기하 고있다. 그결과현재까지다제내성세균에효과적인새로 운항생제는매우드문실정이며특히그람음성다제내성균 에대한새로운항생제는거의전무한실정이다. 따라서현 실적으로신약의개발을기대하는것보다현재사용가능한 항생제의효능을유지시키도록노력하는것이무엇보다도 중요하다. 결 론 국내에서분리되는임상적으로중요한그람음성간균들 에서항생제내성률이매우높음을확인할수있다. 특히녹 농균, 아시네토박터균같은그람음성세균감염에서다제내 성균주가문제가되고있으며, 이는병원규모와상관없는 전반적인의료기관의문제가되고있다. 전통적으로 ESBL 생성이중요한내성기전이었던대장균과폐렴간균에서 carbapenem 내성은드물었지만최근 carbapenem 내성균 이발생하여문제가되고있다. Colistin 과 tigecycline 이이 러한다제내성그람음성균감염에서사용가능한항생제이 다. 환자를진료하는임상의사들은항생제내성문제의심 각성에대해잘인지해야하며서구와다른국내현실의독 특한상황을잘파악하고있는것이중요하다. Acknowledgement This study was supported by Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology ( ). 핵심용어 : 항생제내성 ; 그람음성균 ; 역학 ; 항생제 REFERENCES 21. Yong D, Toleman MA, Giske CG, Cho HS, Sundman K, Lee K, Walsh TR. Characterization of a new metallo-beta-lactamase gene, bla(ndm-1), and a novel erythromycin esterase gene carried on a unique genetic structure in Klebsiella pneumoniae sequence type 14 from India. Antimicrob Agents Chemother 2009;53: Kumarasamy KK, Toleman MA, Walsh TR, Bagaria J, Butt F, Balakrishnan R, Chaudhary U, Doumith M, Giske CG, Irfan S, Krishnan P, Kumar AV, Maharjan S, Mushtaq S, Noorie T, 대한의사협회지 329

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7 MDR gram-negative bacterial infections 약물요법 Peer Reviewers Commentary 본논문은최근문제가되고있는다제내성균의국내현황과이로인한감염증을치료할수있는항생제에대해기술하고있다. 또한, 다제내성균의확산을막기위한전략에대해서도소개하고있다. 항생제내성은단지 3 차의료기관에만국한된문제가아니며, 최근에는 1 2 차의료기관이나지역사회에서도심심치않게다제내성균이분리되고있다. 다제내성그람음성간균감염증을치료할수항생제는매우제한적이므로각의료기관의상황이나환자의위험요인에따라적절한항생제를선택하여사용해야하며, 항생제오남용을피하고손씻기등기본적인수칙을준수하여다제내성균이전파되는것을차단하기위해노력해야한다. [ 정리 : 편집위원회 ] 대한의사협회지 331

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untitled J Korean Soc Transplant 2013;27:81-86 http://dx.doi.org/10.4285/jkstn.2013.27.3.81 Review Article 다제내성세균의시대에세균성감염질환에대한항생제치료의최근발전들 성균관대학교의과대학삼성서울병원감염내과 강철인 What s New in the Management of Bacterial Infections