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1 대한내과학회지 : 제 88 권제 5 호 특집 (Special Review) - 다제내성균감염의위협 침습성진균감염증과약제내성 전남대학교의과대학내과학교실 김어진 정숙인 Invasive Fungal Infections in the Era of Antifungal Resistance Uh Jin Kim and Sook-In Jung Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea Invasive fungal diseases are an important cause of morbidity and mortality in both immunocompromised and immunocompetent patients. The recent introduction of new antifungal agents seemed to open a new era for the treatment of invasive fungal infections. However, widespread use of prophylactic and therapeutic antifungal agents has lead to the emergence of antifungal resistance and potentially compromises their clinical utility. By understanding the mechanisms of drug resistance, new strategies can be utilized to minimize the emergence of drug resistance and to promote the development of innovative therapeutic approaches. In the meantime, close monitoring of antifungal resistance and its evolution is warranted in a clinical setting given the limited repertoire of antifungal drugs. (Korean J Med 2015;88: ) Keywords: Antifuangals; Resistance; Invasive fungal infection 서론 1956년에개발된 polyene계열의항진균제인 amphotericin B에서 1990년대에부터사용된 1세대및 2세대 triazole 항진균제와 2000년대의 echinocandin 항진균제까지 20세기의항진균제의발전은침습적진균감염증의치료에있어서커다란성과를거두었다. 그럼에도불구하고침습적진균감염증은여전히높은이환율과사망률을일으키는주요한원내감염균이며국내에서도입원기간의연장및막대한의료비지출을유발하는요인이다 [1]. 일반적인세균의높은항생제내성에비해서진균은항진균제에내성을띄는경우가드물지만, 1990년대후천성면역결핍증환자에서분리된칸디다 균주에서높은 fluconazole 내성이보고된이래항진균제내성이지속적으로보고되고있다 [2]. 더욱이최근항진균제예방요법, 항진균제의사용의증가및환경적요인등에의해항진균제에대한내성또한점차늘어가고있으며이는임상적으로는치료의실패및사망률을증가로이어지고있다 [3,4]. 본론칸디다증역학적현황현재까지정상면역체계를갖고있는환자들에서침습적 Correspondence to Sook-In Jung, M.D. Department of Internal Medicine, Chonnam National University Medical School, 160 Baekseo-ro, Dong-gu, Gwangju , Korea Tel: , Fax: , sijung@chonnam.ac.kr 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 - Uh Jin Kim, et al. Resistance in fungal infections - 진균감염증의가장흔한원인은칸디다종이다. 지난 10년간칸디다혈증은꾸준히증가추세를보이고있으며최근미국, 유럽에서는원내감염균 4-6위를차지하고있다. 균종별빈도는지역별로차이를보이나대부분의나라에서 C. albicans가 40-58% 로가장흔히동정된다 [5,6]. 그뒤를이어 non-albicans Candida에해당하는 C. parapsilosis, C. tropicalis, C. glabrata 등이동정되며 C. albicans에비해 non-albicans Candida의분리율이꾸준히증가하고있다 [6,7]. 특히 C. glabrata는미국에서 년도자료에서칸디다혈증의 12% 를차지한반면 년도에수집된자료에의하면 26.7% 로분리율이크게증가하였다 [8,9]. 국내에서도 C. albicans가가장흔히동정되며 년전국데이터에비해 년분석결과는 C. glabrata 분리율이 11% 에서 19% 로증가하는양상을보여이에대한지속적인추적관찰이필요하다 [10,11]. 칸디다균종의항진균제내성은세균의항생제에비해비교적낮은수준으로보고되고있다. 항진균제저항성은각균주별로차이가있지만 C. albicans는전반적으로 azole계항진균제에대부분감수성을보이며 echinocandin 계항진균제에는내성이거의없다 (Table 1) [3]. 그외 non-albicans candida 중 C. glabrata는 azole계항진균제에 % 및 echinocandin 계항진균제에 % 의비교적높은내성을 보이고 [12] C. krusei는 fluconazole에대해선천내성이다. 최근 년도국내자료에의하면혈액에서분리되는칸디다균종의내성률은여전히낮은상태로유지되고있으며, Clinical and Laboratory Standards Institute (CLSI) 기준에의해 fluconazole에대해 1.4%, voriconazole에대해서는 1% 의내성을보였다 [11]. 이외에도드물지만 azole계열에내성을보이는 C. haemulonii와 amphotericin-b에고도내성을보이는 C. pseudohaemulonii 혈증의증례가국내에서보고된바있으며이는항진균제노출력과관련이있었다 [13]. 내성기전 Azole 내성칸디다에서 azole계항진균제는세포막의 ergosterol 합성과정에서 C14a-demethylation 단계에작용해서항진균효과를나타낸다. 일반적으로 azole 저항성과관련하여 4가지주요기전이알려져있다 [14]. 첫째, MDR과 CDR 유전자의과발현 (overexpression) 으로이들유전자에의해조절되는유출펌프 (efflux pump) 가증가하고결과적으로작용부위에서항진균제의농도가감소한다. MDR 유전자의과발현은주로 fluconazole 저항성에관여하는반면 CDR 유전의과발현은대부분의 azole 계열의항진균제에내성을나타낸다. 둘째, 항진균제의표적효소 lanosterol C14a-demethylase를부호화하 Table 1. The spectrum of activity of systemic antifungal agents Polyenes Triazoles Echinocandins AMB FLU ITRA VORI POSA CAS MICA ANID Candida spp. C. albicans C. glabrata ++ +/- N C. tropicalis C. prapsilosis C. krusei + - +/ Cryptococcus neoformans Aspergillus spp. A. fumigatus N A. flavus N A. terreus N A. niger N A. nidulans N Mucorales + - +/ AMB, amphotericin B; FLU, fluconazole; ITRA, itraconazole; VORI, voriconazole; POSA, posaconazole; CAS, caspofungin; MICA, micafungin; ANID, anidulafungin; N, not assessed

3 - 대한내과학회지 : 제 88 권제 5 호통권제 657 호 는유전자인 ERG11 의돌연변이로인해효소부위에 azole 항진균제의결합이억제된다. 현재까지약 80여종의아미노산돌연변이가보고된바있으며서로다른돌연변이가공존하기도한다. 셋째, 일부에서는세포내 ERG11 단백의농도가과도하게증가되어일반적인치료농도로는 ergosterol 합성을효과적으로억제하지못하게되지만내성에미치는영향이미미할것으로여겨진다. 마지막으로, 측부로를발달시키는방법으로 azole 항진균제에노출되면세포막의 ergosterol이고갈되고독성산물인 C14a-demethyl-3,6-diol이축적되어성장정지를초래하게되는데 ERG3 유전자변형은 14a-metthylfecosterol로부터 C14a-demethyl-3,6-diol의형성을억제한다. 대부분 2가지이상의기전들이함께발현되는것으로알려졌으며기전들은서로부가효과 (additive effect) 를나타낸다는연구도있다 [15]. Polyene 내성 Ergosterol 생합성에서 ERG3 유전자의결손은진균세포막에다른 sterol들의축적을일으킨다. 결과적으로 polyene 내성 Candida균주는감수성균주에비해상대적으로낮은 ergosterol 성분을갖게되며 catalase 활성도가증가되어산화손상에대한감수성이떨어져 amphotericin B에내성을보이기도한다 [16]. Echinocandin 내성 Echinocandin계항진균제는진균세포벽의주요구성물질중하나인 1,3-β-D-glucan 합성을억제하여진균세포자멸사를초래한다. Echinocandin제재의표적인 1,3-β-D-glucan synthase 복합체를합성하는 FKS1 유전자의돌연변이가 echinocandin 제재의저항성을나타내는주요기전이다 [17]. 이러한 ecinocandin 계항진균계에대한내성은 echinocandin 계약제끼리교차내성을유발하여결과적으로는 echinocandin 계항진균제전체에대한내성을띌수있다. 생체막 (Biofilm) 칸디다감염증에서항진균제내성을발현하는주요기전중의하나는생체막 (biofilm) 이다. 생체막의저항기전은아직완벽하게밝혀진것은아니지만세균의생체막과마찬가지로생체내방어기전으로부터진균을보호하며항진균제에대해내성을증가시켜결과적으로항진균제치료실패를유발한다 [18]. 생체막은구강점막과같은인체내부또는카테터나인공관절등의표면에서형성될수있으며이로인하여혈관내카테타는칸디다혈류감염증을유발하는주요위험인자로알려져있다 [19]. 또한칸디다감염증에서생체막형 성은앞에서언급한항진균제내성과관련된 MDR, CDR 등의유전자를과발현과연관되어내성을높인다는보고도있다 [20]. 이러한생체막에대해서는 liposomal amphotericin B, echinocandin 계약제가효과적이다 [21]. 임상적의의실제임상현장에서환자의면역저하, 항진균제치료시작의지연과함께항진균제의내성은진균감염치료실패의원인중하나로지목되고있다 [22]. 항진균제내성과관련하여골수이식환자에서 fluconazole 예방요법중발생한 azole계내성 C. glabrata 전신감염증에대한보고 [23] 와칸디다혈증에서 fluconazole 내성 ( 최소억제농도 64 mg/ml) 이사망과관련이있다는 Baddley 등 [24] 의보고는항진균제예방요법중항진균제의내성으로인한돌파감염의발생과더불어항진균제내성이치료실패를유발할수있음을잘보여주고있다. 따라서항진균제사용력이있는칸디다혈증에서항진균제내성에대한고려가필요하다. 특히 C. glabrata의경우 echinocandin에저항성균주의최대 38% 가 fluconazole에도저항성을띄고있으므로치료약제선정에주의가필요하다 [3]. 치료칸디다감염증에서경험적항진균제는호중구감소증의유무, 감염의중증도, 항진균제사용의과거력에따라결정한다. 호중구감소증을동반하지않은중등도칸디다혈증에서 azole사용력이없는경우미국감염학회가이드라인에서는 fluconazole과 echinocandin계열중 1제를일차약제로, lipid formation amphotericin B, voriconazole을대체약제로권고하고있다. 유럽미생물학회에서는 echinocandin 계열을우선적으로권고하고, 다음으로 lipid formation amphotericin B, voriconazole을권고한다. Fluconazole 투여력이있는경우미국감염학회에서는 echinocandin 계열을우선권고하고, 유럽미생물학회에서도 echinocandin 계열을우선적으로권장하되 lipid formation amphotericin B, voriconazole 등도권고한다. 중환자실입원과같은중증의칸디다혈증에서는미국감염학회와유럽미생물학회에서 echinocandin 계열을우선적으로권고하였다. 반면호중구감소증이있는혈액질환환자에서는미국감염학회에서는 echinocandin계열이나 lipid formation amphotericin B를우선적으로추천하되균종에따라항진균제를조정할것을권장한다 [25,26]. 현재임상에서사용되는항진균제의용량과용법은표 2와같다. 국내에서항진균제사용은심사평가원의고시에따라칸디다감염증에 amphotericin B, fluconazole의사용을우선적으로인정하되, 중증환자또

4 - 김어진외 1 인. 진균감염과내성 - Table 2. Systemic antifungal agents and their dosing interval for adult patients with normal renal function Drug Azoles Fluconazole Itraconazole Voriconazole Posaconazole Echinocandins Caspofungin Micafungin Anidulafungin Polyenes AMB ABCD ABLC LAMB Others Flucytosoine Typical adult dosing 6-12 mg/kg/d 200 mg twice daily 6 mg/kg every 12 h for 2 doses, then 4 mg/kg every 12 h mg/d in divided doses 70 mg loading dose, then 50 mg/d mg/d 200 mg x 1 loading dose, then 100 mg/d mg/kg/d 4 mg/kg/d 5 mg/kg/d 3-5 mg/kg/d 100 mg/kg/d in divided doses AMB, amphotericin B; ABCD, amphotericin B colloidal dispersion; ABLC, amphotericin lipid complex; LAMB, liposomal AMB. 는최근에 azole 투여경험이있었던환자에서는 echinocandin 계약제도인정된다. Voriconazole은타항진균제에실패하였거나투여가불가능한경우에인정된다. 혈액배양결과가보고되면균종과항진균제감수성결과에따라항진균제를선택한다. 전신캔디다감염증에서의항진균제는혈액배양에서음전된시점을기준으로부터 14일간더투여할것을추천하고있다. 아스페르길루스증 역학적현황아스페르길루스종은면역체계가저하된환자에서침습성감염증을유발하는가장흔한원인이며 Aspergillus fumigatus 가가장흔하게검출된다 [12]. Aspergillus종은 fluconazole을제외한 azole계열과 echinocandin 계열항진균제에대한후천적내성이드문편이다. 2001년부터 2009년까지의전세계 63개의료기관에서수집된 A. fumigatus 1,312주를대상으로한연구결과에서최소억제농도 (minimal inhibitory concentration) 가 epidemiologic cutoff values (ECVs) 보다높은균주가 itraconazole, posaconazole, voriconazole에대해각각 2.0%, 3.5%, 1.4% 였고 기간별분석에서도증가추세를보이지는않았다 [27]. 반면, 네델란드의 2009년부터 2011년도에수집된 A. fumigatus 임상분리주의내성검사결과전체적으로 azole계열에대한내성률이 6.8% 였고, 이중 74.6% 에서 TR/L98H 유전자변이를가지고있었다 [28]. 특히주목할만한점은일부유전자변이가 voriconazole 고도내성을유발하여치료실패와관련이있을것으로보이고, 환경에서검출된균주에도동일한내성유전자변이가발견되어환경으로부터선택 (selection) 된내성이전파되었을가능성을제시하였다. 이러한 azole 내성은특히유럽에서증가추세를보이는데특히영국에서는 1997 년에처음 itraconazole 내성이보고된이래 azole계열내성이꾸준히증가하여 2009년도에는 20% 에이르고있다 [29]. 대부분의 Aspergillus분리주는 amphotericin B에감수성이지만 Aspergillus terreus 는선천성내성을가진것으로알려져있다 (Table 1). Aspergillus의 amphotericin B에대한임상적내성기준점 (clinical breakpoint) 이정해져있지않지만대략 1 mg/ml을초과하는경우를내성으로본다. 현재사용되는세가지의 echinocandin 에대한비교연구에서도 Aspergillus 임상분리균주의 99% 이상이낮은농도의 echinocandin 에억제되어매우우수한효과를보였다 [30]. 국내 Aspergillus종의내성현황은 년도에임상검체에서분리된 302주의검사결과 amphotericin-b, itraconazole, voriconazole, posaconazole에대해각각 5.1%, 1.3%, 1.7%, 4.0% 의낮은내성률을보였다 [31]. 내성기전및임상적의의다른종과마찬가지로 Aspergillus종의 azole계항진균제내성의대표적인기전은표적효소의변이이다. Aspergillus 에서 azole 표적효소인 lanosterol demethylase는 cyp51a 유전자에의해부호화된다. 흔한유전자변이로는 Gly54, TR/L98H 등이있다 [32]. Echinocandin계제재의저항성은 azole계제재의저항성보다더드물며 Candida종에서와마찬가지로 FKS1 의돌연변이로인해내성을보일수있으나임상균주에서는드물게나타난다. Aspergillus종의 azole계제재의내성은항진균제에노출되는환자들에서도종종발견되지만 [4] 이전의 azole 사용력이없는환자에서도 azole 내성균이보고되고있다. 특히 Aspergillus 감염증은사람간전파는드물고주로환경에서획득되는것으로알려져있다 [33]. 최근항진균제성분이포함된살충제를사용하면서환경에존재하는 Aspergillus에내성을획득함으로써내성균감염이증가될가능성이있어향후치료약제선택에있어주의가필요할것으로보인다

5 - The Korean Journal of Medicine: Vol. 88, No. 5, 치료침습성폐아스페르길루스감염증은가장흔한전신성아스페르길루스감염증으로이분야치료에대한연구가가장활발히진행되었으며이에근거하여다른부위의감염증의치료에도적용시킬수있다. Amphotericin B와의무작위배정연구에서 voriconazole이우월한치료효과를보여미국감염학회가이드라인에서 voriconazole을 1차약제로추천하고있다 [34]. 대체약제로는 liposomal amphotericin B, amphotericin lipid complex, caspofungin, micafungin, posaconazole, itraconazole 이있다. 단독약제사용을추천하며아직까지병합요법을추천할만한근거는미약하다. 항진균제선택시 Aspergillus종을고려해야한다. A. terreus는 amphotericin B에내성이므로이에대한 1차치료약제로 amphotericin B 대신 azole계열을사용해야한다. 드물지만일부 A. fumigatus가 itraconazole에내성이며, A. lentulus, A. nidulans, A. ustus, A. versicolar 등도 amphotericin B에내성을보일수있다. 향후기존에 azole 항진균제를사용한환자에서는항진균제감수성검사를고려해야하고 amphotericin 제제또는 echinocandin 과같은다른계열의항진균제가권장된다. 치료기간은확립되어있지않으나대부분의전문가들이모든임상증상과영상의학적소견이소실또는안정화될때까지사용을권장하고있다. 침습성아스페르길루증의예후에감염부위, 면역억제정도, 질병범위, 면역억제의회복가능성등이관여한다. 크립토코쿠스증역학적현황크립토코쿠스증은 Cryptococcus균종에의한감염증으로주로에이즈, 이식환자, 혈액암, 장기스테로이드사용자, 간경화같은기저질환이있는면역저하자에서감염을일으키지만드물게정상면역환자에서발생하기도한다. C. neoformans와 C. gatti가주요병원균으로폐질환이가장흔하며중추신경계로의침범은아급성뇌수막염양상을띄며높은이환률과사망률을유발한다. 그외피부, 안구, 전립선등신체모든부위에침범및감염을일으킬수있다. Cryptococcus의 amphotericin 과 flucytosine의감수성기준을제시하기위한대규모연구에서 amphotericin-b 1 mg/ml을기준으로 98.4%, flucytosine 16 mg/ml을기준으로 97.1% 의균주가감수성이었다 [35]. 또한 2012년도전세계 72개의료기관이참여한진균의항진균제감수성검사에서 Cryptococcus 52주모두 fluconazole에감수성 (100%, Epidemiologic cut-off value, 16 ug/ml) 을보였으며 voriconazole에도대부분감수 성 (98.1%) 을보였다 [12]. 국내에서는 년동안 3개병원에서수집된 C. neoformans 35주는 fluconazole에 97.1%, voriconazole에 97.2% 의감수성을보였다 [36]. 내성기전및임상적의의치료와예방목적으로 fluconazole을광범위한사용과더불어장기간부적절하게낮은농도의사용이크립토코쿠스증의재발에기여하는것으로보인다. 높은 fluconazole MIC 와치료실패의연관성은아직도논란의여지가있다 [37,38]. 항진균제표적유전자인 ERG11 의변이와유출펌프를부호화하는 CnAFR1의과발현이 azole계열내성과관련이있다 [32]. Flucytosine 내성은 pyrimidine 경로에관여하는 FCY1 또는 FCY2 유전자의돌연변이가알려져있지만 amphotericin B 에대한내성기전은잘알려져있지않다. 치료 Cryptococcus의주치료약제는 Amphotericin B과 flucytosine 의병합요법이추천되지만최근연구에서 amphotericin 과고용량의 fluconazole 또는 voriconazole의병합요법도고려할수있겠다 [39]. 그외사용가능한약제로는지질친화성 amphotericin B, posaconazole과 voriconazole을대체약제로사용해볼수있으나 echoncandin계제제는 Cryptococcus종에효과가없다. 현재까지 Cryptococcus종의항진균제내성검사방법과그기준이정립되지않았고항진균제내성이임상적치료반응과의관계도명확하지않아 2010년미국감염학회가이드라인에서는초치료시 C. neoformans의감수성검사는추천하지않는다 [40]. 그러나재발소견이보이는경우새로운경험적약제의시작과더불어재발시획득한균주로내성검사를고려할필요가있겠다. 결론세균과달리침습성진균감염증을일으키는주요진균들에서항진균제내성은현재까지는높지않다. 그러나치료및예방목적으로의광범위한항진균제의사용으로인한내성의획득과환경내에서내성의선택등으로인해내성이증가하는추세이며이로인한항진균제치료실패들이보고되고있다. 또한환자들의심각한기저질환이임상적내성의주요원인이되고있다. 더불어일부균주에대해서는항진균제내성검사의기준점이정립되어있지않을뿐아니라실제임상상황에서항진균제감수성검사를시행하기어려운경우가대부분이다. 향후침습성진균감염증의예후를개선

6 - Uh Jin Kim, et al. Resistance in fungal infections - 시키기위해내성추이에대한지속적인모니터링과적절한검체획득을통해정확한진단과빠른항진균제치료를해야한다. 또한치료실패가의심되는경우항진균제내성에대한검사및시기적절한항진균제교체를고려해야한다. 중심단어 : 항진균제 ; 내성 ; 침습성진균감염증 REFERENCES 1. Horn DL, Neofytos D, Anaissie EJ, et al. Epidemiology and outcomes of candidemia in 2019 patients: data from the prospective antifungal therapy alliance registry. Clin Infect Dis 2009;48: Law D, Moore CB, Wardle HM, Ganguli LA, Keaney MG, Denning DW. High prevalence of antifungal resistance in Candida spp. from patients with AIDS. J Antimicrob Chemother 1994;34: Pfaller MA, Messer SA, Woosley LN, Jones RN, Castanheira M. Echinocandin and triazole antifungal susceptibility profiles for clinical opportunistic yeast and mold isolates collected from 2010 to 2011: application of new CLSI clinical breakpoints and epidemiological cutoff values for characterization of geographic and temporal trends of antifungal resistance. J Clin Microbiol 2013;51: Howard SJ, Cerar D, Anderson MJ, et al. Frequency and evolution of Azole resistance in Aspergillus fumigatus associated with treatment failure. Emerg Infect Dis 2009;15: Wisplinghoff H, Ebbers J, Geurtz L, et al. Nosocomial bloodstream infections due to Candida spp. in the USA: species distribution, clinical features and antifungal susceptibilities. Int J Antimicrob Agents 2014;43: Bassetti M, Merelli M, Righi E, et al. Epidemiology, species distribution, antifungal susceptibility, and outcome of candidemia across five sites in Italy and Spain. J Clin Microbiol 2013;51: Morii D, Seki M, Binongo JN, et al. Distribution of Candida species isolated from blood cultures in hospitals in Osaka, Japan. J Infect Chemother 2014;20: Kao AS, Brandt ME, Pruitt WR, et al. The epidemiology of candidemia in two United States cities: results of a population-based active surveillance. Clin Infect Dis 1999;29: Pfaller M, Neofytos D, Diekema D, et al. Epidemiology and outcomes of candidemia in 3648 patients: data from the Prospective Antifungal Therapy (PATH Alliance ) registry, Diagn Microbiol Infect Dis 2012;74: Lee JS, Shin JH, Lee K, et al. Species distribution and susceptibility to azole antifungals of Candida bloodstream isolates from eight university hospitals in Korea. Yonsei Med J 2007;48: Jang MJ, Shin JH, Lee WG, et al. In vitro fluconazole and voriconazole susceptibilities of Candida bloodstream isolates in Korea: use of the CLSI and EUCAST epidemiological cutoff values. Ann Lab Med 2013;33: Castanheira M, Messer SA, Jones RN, et al. Activity of echinocandins and triazoles against a contemporary (2012) worldwide collection of yeast and moulds collected from invasive infections. Int J Antimicrob Agents 2014;44: Kim MN, Shin JH, Sung H, et al. Candida haemulonii and closely related species at 5 university hospitals in Korea: identification, antifungal susceptibility, and clinical features. Clin Infect Dis 2009;48:e Pemán J, Cantón E, Espinel-Ingroff A. Antifungal drug resistance mechanisms. Expert Rev Anti Infect Ther 2009; 7: MacCallum DM, Coste A, Ischer F, Jacobsen MD, Odds FC, Sanglard D. Genetic dissection of azole resistance mechanisms in Candida albicans and their validation in a mouse model of disseminated infection. Antimicrob Agents Chemother 2010; 54: Sokol-Anderson ML, Brajtburg J, Medoff G. Amphotericin B-induced oxidative damage and killing of Candida albicans. J Infect Dis 1986;154: Perlin DS. Resistance to echinocandin-class antifungal drugs. Drug Resist Updat 2007;10: Douglas LJ. Candida biofilms and their role in infection. Trends Microbiol 2003;11: Shin JH, Kee SJ, Shin MG, et al. Biofilm production by isolates of Candida species recovered from nonneutropenic patients: comparison of bloodstream isolates with isolates from other sources. J Clin Microbiol 2002;40: Ramage G, Bachmann S, Patterson TF, Wickes BL, López- Ribot JL. Investigation of multidrug efflux pumps in relation to fluconazole resistance in Candida albicans biofilms. J Antimicrob Chemother 2002;49: Kuhn DM, George T, Chandra J, Mukherjee PK, Ghannoum MA. Antifungal susceptibility of Candida biofilms: unique efficacy of amphotericin B lipid formulations and echinocandins. Antimicrob Agents Chemother 2002;46: Garey KW, Rege M, Pai MP, et al. Time to initiation of fluconazole therapy impacts mortality in patients with candidemia: a multi-institutional study. Clin Infect Dis 2006;43: Alexander BD, Schell WA, Miller JL, Long GD, Perfect JR. Candida glabrata fungemia in transplant patients receiving voriconazole after fluconazole. Transplantation 2005;80: Baddley JW, Patel M, Bhavnani SM, Moser SA, Andes DR

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편집순서 1 : 겉표지 학술연구용역사업최종결과보고서 과 국문과제명 제 영문과제명 명 주 의 ( 주의내용기재 ) 2 0 주관연구기관 : ( 글 14 point 고딕체 ) 질병관리본부 질병관리본부 - 1 -

편집순서 1 : 겉표지 학술연구용역사업최종결과보고서 과 국문과제명 제 영문과제명 명 주 의 ( 주의내용기재 ) 2 0 주관연구기관 : ( 글 14 point 고딕체 ) 질병관리본부 질병관리본부 - 1 - 주의내용 주 의 1. 이보고서는질병관리본부에서시행한학술연구용역사업의최종결 과보고서입니다. 2. 이보고서내용을발표할때에는반드시질병관리본부에서시행한 학술연구용역사업의연구결과임을밝혀야합니다.