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1 대한내과학회지 : 제 88 권제 5 호 특집 (Special Review) - 다제내성균감염의위협 다제내성그람음성균감염의항생제치료 성균관대학교의과대학삼성서울병원감염내과 강철인 Antimicrobial Therapy for Infections Caused by Multidrug-Resistant Gram-Negative Bacteria Cheol-In Kang Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea The incidence of infections caused by multidrug-resistant (MDR) Gram-negative bacteria has increased over the past decade and extensively drug-resistant (XDR) infections are now on the rise, especially in non-fermenters such as Pseudomonas and Acinetobacter species. Unfortunately, our therapeutic options for these pathogens are extremely limited. Infections due to antimicrobial-resistant bacteria are associated with a greater likelihood of inappropriate antimicrobial therapy, which has adverse effects on the outcomes of patients with serious infections. Physicians who are treating immunocompromised patients should be aware of not only the current epidemiological status of antimicrobial resistance but also appropriate antimicrobial therapy for MDR pathogens. Although carbapenems are considered a mainstay for the treatment of extended-spectrum beta-lactamase (ESBL) or AmpC β-lactamase-producing pathogens, antimicrobial stewardship for the appropriate use of carbapenems should be implemented to preserve these important antimicrobial agents. For carbapenem-resistant XDR infections, colistin and tigecycline could be considered a therapeutic option, based on the in vitro antibacterial spectrum, although the optimum treatment has not been established. This review provides a recent update of the antimicrobial therapeutic strategies for serious infections due to MDR or XDR Gram-negative bacteria, such as ESBL-producers and carbapenem-resistant pathogens. (Korean J Med 2015;88: ) Keywords: Gram-negative bacteria; Antimicrobial resistance; Multidrug resistance; Antimicrobial therapy; Treatment outcome 서 인류가항생제를세균성감염질환의치료제로사용한지 론 70여년이지났다. 항생제의도입으로인해감염질환의직접적인치료는물론이고외과적수술, 항암요법등감염합병증이많이발생하는의학적치료도급속하게발전할수 Correspondence to Cheol-In Kang, M.D. Division of Infectious Diseases, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul , Korea Tel: , Fax: , collacin@hotmail.com *This study was supported partly by the Basic Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Education, Science, and Technology (No ). Copyright c 2015 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 - Cheol-In Kang. Therapy for MDR Gram-negative pathogens - 있었다. 항생제를개발한후인류는세균성감염질환을쉽게정복할수있는듯했으나항생제를최초로개발한플레밍이경고한바대로인류는 항생제내성 이라는새로운문제에직면하게되었다 [1]. 특히 3가지계열이상의항생제에내성을보이는 다제내성균 의출현은효과적인항생제치료를어렵게만들고있고중증감염환자의치료경과에심각한악영향을미치고있다 [2,3]. 과거와달리다제내성균감염이증가하고있고내성기전도매우복잡해지고있어임상의사가항생제를적절하게사용하는것이점점어렵고힘들어지고있다. 더불어 21세기임상의사들에게는항생제내성기전과역학적현황에대한지식이필수적으로요구되고있다. 대장균, 녹농균등의그람음성균은요로감염, 복강감염, 폐렴등을일으킬수있는중요한병원균이며최근다제내성균이증가추세이다. 특히녹농균, Acinetobacter균은 carbapenem에도내성을보이는경우가흔해서임상적으로큰문제가된다 [4]. 본연제에서는최근의료관련감염에서심각한문제가되고있는다제내성그람음성균감염에대한적절한항생제치료에대해서논의하고자한다. 본론 Extended-spectrum beta-lactamase 생성장내세균 (ESBL-producing Enterobacteriaceae) 대장균, 폐렴간균등의장내세균에서 3세대 cephalosporin 계열항생제에내성을나타내는주된내성기전은 extendedspectrum beta-lactamase을생성하는것이다. ESBL 은세균이만들어내는효소이기때문에 ESBL의종류와생성정도에따라서 cefotaxime, ceftazidime, cefepime 의최소억제농도 (minimal inhibitory concentration, MIC) 가다를수있다. 하지만 MIC가감수성범위라고하더라도중증감염에서 cephalosporin계열항생제를사용하는경우치료실패위험성이높아서 ESBL 생성균은 cephalosporin계열항생제에내성으로간주하는것이안전하다. ESBL 생성균은 cefepime 에감수성을보이는경우가많아 cefepime 을치료에사용해볼수있는데 MIC가 2 μg/ml 이상인경우에는치료실패가능성이높아주의를요한다 [5-8]. ESBL 생성균중 cefepime 의 MIC가 1 μg/ml 이하로낮은경우에는 cefepime 을치료에사용할수있다는보고가있으나임상자료가충분하지않다 [6,8]. 국내 에서분리되는 ESBL 생성장내세균은 piperacillin/tazobactam 에감수성인경우가 60-70% 에달한다. ESBL 생성균이라고하더라도 piperacillin/tazobactam 감수성균인경우 piperacillin/ tazobactam을사용해볼수있으며후향적연구에서 carbapenem계열항생제를투여한경우에비해열등하지않은유사한치료효과가보고된바있다 [8-12]. 하지만 piperacillin/ tazobactam은 cephalosporin계열항생제와마찬가지로균주수가 100배이상증가하면 (10 5 cfu/ml 에서 10 7 cfu/ ml로 ) MIC 가 8배이상증가하는 inoculum effect 를보이므로중증감염에서 piperacillin/tazobactam 을사용할때는주의를요한다 [8,13]. 특히 high inoculum이예상되는감염증, 예를들면농양을동반한복강내감염, 중증폐렴등에서는 piperacillin/ tazobactam에감수성균이라도 ESBL생성균에서는 carbapenem계열항생제를투여하는것이안전하다. 국내에서분리되는 ESBL 생성균주의 amikacin에대한감수성은 90% 이상으로매우높다. 따라서 ESBL 생성균감염의위험성이높은환자에서경험적투여로 piperacillin/tazobactam 과 amikacin의병합요법을고려해볼수있으며이는 carbapenem의무분별한경험적사용을줄일수있는효과적인항생제치료전략이다. ESBL 생성균중 ciprofloxacin 또는 SMX/TMP 에감수성을나타내는경우가있는데, 이들항생제는요로감염에서효과적으로사용가능한항생제이므로 ESBL 생성균이라고하더라도이들항생제에감수성인경우투여가능하다. ESBL 생성균에서가장효과적으로사용할수있는항생제는 carbapenem계열항생제이며 ertapenem, imipenem, meropenem, doripenem 등이있다 [4]. 이중 ertapenem은녹농균, acinetobacter균에항균력이없어 group 1으로분류하고다른 carbapenems 을 group 2로분류한다 [3]. Ertapenem 은녹농균, acinetobacter균에항균력이없다는단점이있지만반감기가길어서 1일 1회투여가가능하다는장점이있어외래주사실이나가정간호로투여가가능하다. ESBL 생성균에의한상부요로감염, 복강내감염등의치료에주로사용한다. Imipenem, meropenem, doripenem의 ESBL 생성균에대한치료효과와부작용발현정도는비슷한것으로알려져있다. Carbapenem계열항생제의사용이증가하면서최근 carbapenem 내성균또한증가추세이며이를예방하기위해서는 carbapenem계열항생제의오남용을방지하고꼭필요한경우에적정기간동안적정용량으로사용하려는노력이필요하다. Carbapenem을대체할만한안전하고효과적인항생

3 - 대한내과학회지 : 제 88 권제 5 호통권제 657 호 제가현재없으며수년내에개발될가능성또한없기때문이다 [3]. AmpC β-lactamase 생성균 AmpC β-lactamase 생성은 ESBL 생성과함께 3세대 cephalosporin계열항생제내성을유발하는그람음성세균의주요내성기전이다. ESBL 은대장균, 폐렴간균의주된내성기전이고 plasmid 에위치하고있는데반해 AmpC β-lactamase는 chromosome에위치하고있고 Enterobacter, Citrobacter, Serratia 등의주된내성기전이다. 3세대 cephalosporin계열항생제에내성을나타내어임상적의미는 ESBL 생성균과유사하지만 cefepime 은 AmpC β-lactamase에의해잘분해되지않아서 ESBL 생성균과달리 AmpC β-lactamase 생성균에서는 cefepime을효과적으로사용할수있다 [14]. 하지만최근 ESBL 과 AmpC β-lactamase를함께생성하는균들이증가하고있어 Enterobacter 같은 AmpC β-lactamase 생성균감염에서 cefepime 을사용할경우 cefepime 의 MIC를확인할필요가있다. Cefepime 의 MIC가 1 μg/ml 이하인경우 cefepime 을투여해도문제가없겠지만 2-8 μg/ml로상승되어있는경우에는주의를요하며 cefepime 을투여할경우 2 g iv q 8 h 으로증량하는것이좋다. 최근한후향적연구에서 cefepime 을고용량으로투여한경우사망률이유의하게감소되었음을보고한바있으며이는최근분리되는균들의 cefepime MIC 가 2 μg/ml 이상으로상승되고있는경향과무관하지않다 [15]. ESBL 생성균과마찬가지로 AmpC β-lactamase 생성균에의한중증감염에가장효과적으로사용할수있는항생제는 carbapenem계열항생제이다 [4]. Carbapenem 내성장내세균 (Carbapenem-Resistant Enterobacteriaceae, CRE) ESBL 또는 AmpC β-lactamase 생성균에서세포막의 porin mutation이동반되면 carbapenem 내성을획득하며국내 carbapenem 내성장내세균의가장흔한내성기전이다. 최근 carbapenemase 라는효소를생성함으로써 carbapenem 내성을나타내는 carbapenemases-producing Enterobacteriaceae (CPE) 가의료관련감염위주로출현하고있으며이러한내성기전은 plasmid 를타고균주간전파가용이하다는점에서심각한문제가되고있다. Carbapenem 내성장내세균감염에서투여를고려해볼수있는항생제는 colistin과 tigecycline 이다 [16-19]. Amikacin 에감수성인경우투여를고려할수있으나장기간투여할경우신독성, 이독성이문제가된다. Colistin은 40여년전개발되어사용되었으나부작용으로생산이중단되었다가최근다제내성그람음성균감염이증가하면서다시재사용되기시작한약제이다. Carbapenem 내성균에서투여할만한다른효과적인항생제가없을때 colistin 의투여를고려하지만장기간투여할경우신독성, 신경독성등이문제가된다. 정상신기능환자에서 colistin 150 mg iv q 12 h 을투여하지만최근약동학 / 약력학연구결과체중, 체표면적, 신기능등을고려한새로운용량, 용법이권고되고있다 [20]. 최근제시되는용법에의하면 mg 정도의 loading dose를투여한후신기능, 체표면적을토대로계산된적정용량을하루 2-3회분할해서투여하게되는데, 60 kg 이상의정상신기능을가진성인에서는대부분 150 mg iv q 12 h 보다훨씬많은용량을투여해야한다. 고용량을투여할경우치료효과는높일수있겠지만필연적으로신독성이증가할것이므로환자상태에따라적정용량을결정하는것이필요하다. Tigecycline은그람양성균, 그람음성균, 혐기성균등복합감염의치료에사용할수있는광범위항생제로서복잡성피부연조직감염, 복잡성복강내감염에서사용하도록승인되었다 [21]. ESBL 또는 AmpC β-lactamase 생성균, carbapenem 내성장내세균감염증등의치료에서사용가능하다. Tigecycline은조직투과도가좋고담즙에고용량으로배출되어피부연조직감염, 복강내감염에서는효과적으로투여할수있으나혈중농도가낮아서균혈증을동반한경우에사용하는경우에는주의를요한다 [21]. Atypical pathogen 과폐렴알균에항균력이좋아서지역사회획득폐렴의경험적항생제로사용가능하나녹농균등의그람음성균을고려해야하는의료관련폐렴에서는 tigecycline의사용을추천하지않는다. 100 mg을 loading dose로투여한후 50 mg iv q 12 h 로유지한다. 주된부작용은구역등의위장증상인데 5명중 1명정도의빈도로비교적흔하게발생한다. 최근연구에서 carbapenem 내성장내세균에의한중증감염의치료에 tigecycline, colistin, carbapenem 을병합투여한경우유의하게생존율이증가했음을보고한바있어중증감염에서세가지약제의병합요법을고려할수있겠으나국내의경우보험적용의문제가있겠다 [2,22]

4 - 강철인. 다제내성그람음성균감염의항생제치료 - 다제내성녹농균, Acinetobacter 녹농균, Acinetobacter균등을 non-fermenters로분류하며 non-fermenters에사용할수있는항생제는제한되어있다. Penicillin계열항생제중 piperacillin, ticarcillin, cephalosporin 계열항생제중 ceftazidime, cefepime, group 2 carbapenem계열항생제, fluoroquinolone계열항생제중 ciprofloxacin, levofloxacin, 그리고 aztreonam이있다. 이중 3가지계열항생제에내성을보이는경우다제내성균으로분류하는데 non-fermenters 균주들은 carbapenem 내성을포함한다제내성균이흔하다. Carbapenem에내성이라고하더라도다른계열항생제중감수성이있는것이있으면투여가가능하지만다른항생제에도모두내성이라면결국 colistin을투여해야한다. Amikacin, tobramycin 등 aminoglycosides에감수성인경우가있지만 aminoglycoside 단독요법은녹농균, Acinetobacter균감염에서는추천하지않는다. 하지만 β-lactam계열항생제와 aminoglycoside 계열항생제를병합해서투여하는경우 synergy 가있으므로항균제감수성검사에서 intermediate 감수성을보인 β-lactam계열항생제가있다면 amikacin, tobramycin 등과병합해서투여를고려해볼수있겠다. β-lactam계열항생제는살균효과에 time over MIC 가중요한약제이므로감수성이저하된균주에서투여하는경우 4시간에걸쳐투여하는 prolonged infusion 을시도해볼수있다 [23]. 녹농균에대한 carbapenem계열항생제의 MIC 분포를보면, imipenem, meropenem, doripenem 중 doripenem의 MIC가가장낮은경향을보이지만임상적으로 doripenem의치료효과가더우월한지여부는명확하지않다 [24,25]. Acinetobacter균은녹농균과달리 minocycline, tigecycline에감수성을보이는경우가있어이들항생제의투여를고려할수있다. 하지만이들항생제는혈중농도가낮아서중증감염에서단독요법으로투여하는경우주의를요한다. 최근 minocycline 주사제가외국에서는사용되고있으나아직국내에서는경구제제만사용가능하며 100 mg 하루 2회 경구투여한다 [26]. Colistin을 carbapenem, tigecycline, amikacin, rifampin, minocycline 등의다른항생제와병용해서투여하려는연구와시도가많이이루어졌으나실제임상에서병용요법의효과가명확하게증명된바는없다 [16,19,27]. Carbapenems 중 meropenem과 doripenem에서비교적일관성있는 in vitro synergy 자료가보고되어 colistin과병합을고려할 수있고 rifampin 또한동물모델에서 synergy가잘확인된약제이다 [28,29]. 하지만최근 colistin, rifampin의병합요법과 colistin 단독요법을비교한임상연구가진행되었으나사망률에서두군간의유의한차이는없었다 [30]. Colistin은혈중농도가낮고투여중내성이발현되기쉬워중증감염에서 colistin을투여할경우 carbapenem 같은광범위 β-lactam계열항생제와병합해서투여하는것을고려할수있다 [17,31]. Stenotrophomonas maltophilia Stenotrophomonas maltophilia균은내재적으로다제내성균으로서사용할수있는항생제가매우제한되어있다. 중증감염에서가장효과적인항생제는 sulfamethoxazole/trimethoprim (SMX/TMP) 이지만최근내성균주가증가추세이므로주의를요한다. 또한 SMX/TMP는과민반응, 골수억제, 신독성, 간독성등의부작용이흔하다. Ticarcillin/clavulanate 도사용가능한항생제이지만국내분리균주의내성률이 50% 이상으로높아서항균제감수성결과를확인해야한다 [32]. Fluoroquinolone계열항생제중 levofloxacin, moxifloxacin 의감수성이좋다. 최근 levofloxacin의치료결과가 SMX/TMP 의치료결과와유사하였다는연구결과가보고되었으며부작용발현정도는 levofloxacin이더적었다 [33,34]. 하지만최근 levofloxacin 내성균주가증가추세라서주의를요한다. 다제내성그람음성균감염에투여가능한적절한항생제를표 1에정리하였다 (Table 1). 새로개발중인항생제그람음성세균의항생제내성기전중가장중요한것이 β- lactamase이므로기존의 β-lactam계열항생제에새로운 β- lactamase inhibitor 를결합시켜서신항생제를개발하려는노력을많이하고있다. 현재사용중인 β-lactamase inhibitors는 clavulanic acid, tazobactam, sulbactam인데, 이에대한내성균이점점증가하고있어문제가된다. 최근새롭게개발되어 3상임상연구중인 β-lactamase inhibitors 는 avibactam과 MK- 7655가대표적이며 Ceftazidime/Avibactam 과 Imipenem/MK-7655 제형으로연구개발중이다 [3,35]. 녹농균을포함한그람음성균에항균력이좋은새로운 cephalosporin계열항생제로서 ceftolozane이개발되었는데 ceftolozane/tazobactam 제형으로연구개발되어 2014년 12월미국 FDA의승인을받았다 [36]. Aminoglycoside계열항생제로서 plazomicin이개발되어 2상

5 - The Korean Journal of Medicine: Vol. 88, No. 5, 임상연구중이며, 새로운 carbapenem계열항생제로서 tomopenem, razupenem이연구개발중이다 [3]. 이들 tomopenem, razupenem은 methicillin-resistant Staphylococcus aureus에도항균력을갖는광범위 carbapenems 로주목을받고있다. 결론광범위 cephalosporin계열항생제에내성을나타내는 ESBL 또는 AmpC β-lactamase 생성균에의한중증감염에서효과적으로사용할수있는항생제는 carbapenem계열항생제이다. 하지만최근 carbapenem계열항생제사용의증가에따라 carbapenem 내성그람음성균감염의발생빈도가증가하고있다. Carbapenem 내성균의발생을억제하기위해서는 carbapenems 의사용을줄여야하며가능하면대체항생제를사 용할필요가있다. Carbapenem 대체항생제로서 cefepime, piperacillin/tazobactam, amikacin, tigecycline 등을적절한상황에서투여하도록노력해야한다. Carbapenem 내성다제내성균의중증감염증에서투여를고려할수있는항생제는 colistin이며장내세균과 acinetobacter균에서는 tigecycline도감수성에따라투여를고려할수있다. 하지만 colistin과 tigecycline은혈중농도가낮아서중증감염에서투여할경우내성이쉽게유발될수있고치료실패위험성이높다. Carbapenems, rifampin, minocycline 등과병합해서투여해볼수있지만병용요법에관한임상자료가부족한실정이다. 현실적으로 carbapenems 외다제내성그람음성균감염에서사용가능한안전하고효과적인약제가거의없고향후수년내에개발될가능성도없기때문에 carbapenem계열항생제를적절하게사용해서 carbapenem 내성균발현을줄이는것이 Table 1. Antimicrobial therapy for serious infections caused by multidrug-resistant gram-negative pathogens Pathogens ESBL-producing pathogens AmpC β-lactamase-producing pathogens Carbapenem-resistant Enterobacteriaceae Extensively drug-resistant non-fermenters (carbapenem-resistant) Stenotrophomonas maltophilia Primary Suggested regimens Ertapenem 1 g iv q 24 h Imipenem/cilastatin 500 mg iv q 6 h Meropenem 1 g iv q 8 h Doripenem 500 mg iv q 8 h Colistin for mild-to-moderate infections: 150 mg iv q 12 h Colistin for severe systemic infections: - Loading dose: 3.5 x 2 x ideal body weight in kg - Maintenance dose: 3.5 [(1.5 CrCln) + 30] = total daily dose. Divide and give q 8-12 h Colistin as above SMX/TMP, doses based on TMP component, 5-20 mg/kg/day divided q 6-12 h Alternative Cefepime 2 g iv q 8 h Piperacillin/tazobactam 4.5 g iv q 6-8 h Ciprofloxacin 400 mg iv q 12 h Amikacin 15 mg/kg iv q 24 h, need therapeutic drug monitoring (TDM) Tigecycline 100 mg iv loading, then 50 mg iv q 12 h Amikacin 15 mg/kg iv q 24 h, need therapeutic drug monitoring (TDM) Aztreonam 2 g iv q 6-8 h, if susceptible In Acinetobacter infections, tigecycline 100 mg iv loading, then 50 mg iv q 12 h, or highdose of amp/sulbactam Levofloxacin 750 mg iv q 24h Ticarcillin/clavulanate 3.2 g iv q 4-6 h Comments Check MICs of alternative antimicrobials Consider prolonged infusion of β-lactams 3.5 = targeted average serum steady state level of colistin base CrCln = normalized CrCl based on body surface area (BSA): Pt BSA in m 2 /1.73 m 2 The maximum suggested daily dose of colistin: 475 mg Consider combination therapy including carbapenem, rifampin, or minocycline ESBL, extended-spectrum beta-lactamase; MIC, minimal inhibitory concentration; SMX, sulfamethoxazole; TMP, trimethoprim.

6 - Cheol-In Kang. Therapy for MDR Gram-negative pathogens - 매우중요하다. 중심단어 : 그람음성균 ; 항생제내성 ; 다제내성 ; 항생제치료 ; 치료결과 REFERENCES 1. Kang CI, Song JH. Antimicrobial resistance in Asia: current epidemiology and clinical implications. Infect Chemother 2013;45: Munoz-Price LS, Poirel L, Bonomo RA, et al. Clinical epidemiology of the global expansion of Klebsiella pneumoniae carbapenemases. Lancet Infect Dis 2013;13: Bassetti M, Merelli M, Temperoni C, Astilean A. New antibiotics for bad bugs: where are we? Ann Clin Microbiol Antimicrob 2013;12: Papp-Wallace KM, Endimiani A, Taracila MA, Bonomo RA. Carbapenems: past, present, and future. Antimicrob Agents Chemother 2011;55: Endimiani A, Perez F, Bonomo RA. Cefepime: a reappraisal in an era of increasing antimicrobial resistance. Expert Rev Anti Infect Ther 2008;6: Lee NY, Lee CC, Huang WH, Tsui KC, Hsueh PR, Ko WC. Cefepime therapy for monomicrobial bacteremia caused by cefepime-susceptible extended-spectrum beta-lactamase-producing Enterobacteriaceae: MIC matters. Clin Infect Dis 2013;56: Wi YM, Kang CI, Cheong HS, et al. Failure of cefepime therapy in neutropenic patients with extended-spectrum beta-lactamase-producing Gram-negative bacteraemia. Int J Antimicrob Agents 2009;33: Nguyen HM, Shier KL, Graber CJ. Determining a clinical framework for use of cefepime and β-lactam/β-lactamase inhibitors in the treatment of infections caused by extendedspectrum-β-lactamase-producing Enterobacteriaceae. J Antimicrob Chemother 2014;69: Kang CI, Park SY, Chung DR, Peck KR, Song JH. Piperacillin-tazobactam as an initial empirical therapy of bacteremia caused by extended-spectrum β-lactamase-producing Escherichia coli and Klebsiella pneumoniae. J Infect 2012;64: Park SH, Choi SM, Chang YK, et al. The efficacy of non-carbapenem antibiotics for the treatment of community-onset acute pyelonephritis due to extended-spectrum β -lactamase-producing Escherichia coli. J Antimicrob Chemother 2014;69: Rodríguez-Baño J, Navarro MD, Retamar P, Picón E, Pascual Á; Extended-Spectrum Beta-Lactamases Red Española de Investigación en Patología Infecciosa/Grupo de Estudio de Infección Hospitalaria Group. β-lactam/β-lactam inhibitor combinations for the treatment of bacteremia due to extended-spectrum β-lactamase-producing Escherichia coli: a post hoc analysis of prospective cohorts. Clin Infect Dis 2012;54: Retamar P, López-Cerero L, Muniain MA, Pascual Á, Rodríguez-Baño J; ESBL-REIPI/GEIH Group. Impact of the MIC of piperacillin-tazobactam on the outcome of patients with bacteremia due to extended-spectrum-β-lactamase-producing Escherichia coli. Antimicrob Agents Chemother 2013;57: Kang CI, Cha MK, Kim SH, et al. Extended-spectrum cephalosporins and the inoculum effect in tests with CTX-Mtype extended-spectrum β-lactamase-producing Escherichia coli: potential clinical implications of the revised CLSI interpretive criteria. Int J Antimicrob Agents 2014;43: Tamma PD, Girdwood SC, Gopaul R, et al. The use of cefepime for treating AmpC β-lactamase-producing Enterobacteriaceae. Clin Infect Dis 2013;57: Alves MD, Ribeiro VB, Tessari JP, et al. Effect of cefepime dose on mortality of patients with Gram-negative bacterial bloodstream infections: a prospective cohort study. J Antimicrob Chemother 2014;69: Lee CS, Doi Y. Therapy of Infections due to Carbapenem- Resistant Gram-Negative Pathogens. Infect Chemother 2014;46: Falagas ME, Lourida P, Poulikakos P, Rafailidis PI, Tansarli GS. Antibiotic treatment of infections due to carbapenemresistant Enterobacteriaceae: systematic evaluation of the available evidence. Antimicrob Agents Chemother 2014;58: van Duin D, Kaye KS, Neuner EA, Bonomo RA. Carbapenem-resistant Enterobacteriaceae: a review of treatment and outcomes. Diagn Microbiol Infect Dis 2013;75: Zavascki AP, Bulitta JB, Landersdorfer CB. Combination therapy for carbapenem-resistant Gram-negative bacteria. Expert Rev Anti Infect Ther 2013;11: Garonzik SM, Li J, Thamlikitkul V, et al. Population pharmacokinetics of colistin methanesulfonate and formed colistin in critically ill patients from a multicenter study provide dosing suggestions for various categories of patients. Antimicrob Agents Chemother 2011;55: Stein GE, Babinchak T. Tigecycline: an update. Diagn Microbiol Infect Dis 2013;75: Tumbarello M, Viale P, Viscoli C, et al. Predictors of mortality in bloodstream infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae: importance of combination therapy. Clin Infect Dis 2012;55: Bauer KA, West JE, O'Brien JM, Goff DA. Extended-in

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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