84 계명의대학술지제 31 권 1 호 2012 μg /ml). Isolation frequency of MDRAB strains was 97.7% (172 strains) and was highly prevalent. Fifty eight (33.0%) strains

Transcription

1 계명의대학술지제 31 권 1 호 Keimyung Med J Vol. 31, No. 1, June, 2012 다약제내성 Acinetobacter baumannii 의 유병율과항균제감수성 계명대학교의과대학미생물학교실, 의과학연구소 서성일 백원기 서민호 High Prevalence and Antimicrobial Drug Susceptibility of Multidrug Resistant Acinetobacter baumannii Seong Il Suh, M.D., Won Ki Baek, M.D., Min Ho Suh, M.D. Department of Microbiology, Institute for Medical Science, Keimyung University School of Medicine, Daegu, Korea Abstract Acinetobacter baumannii is a typical nosocomial pathogen causing infections and high mortality, almost exclusively in compromised hospital patients. Multidrug resistant Acinetobacter baumannii (MDRAB) is currently causing one of the most difficult infections to treat, because efficacious antimicrobial choices have been highly limited. A total of 176 strains of Acinetobacter baumannii isolated from various clinical specimens in a university medical center were tested for antimicrobial drug susceptibility to 24 drugs including imipenem, meropenem, levofloxacin, colistin and minocycline. Acinetobacter baumannii were most frequently isolated from sputum (84.1%), followed by wound discharge (8.0%), urine (2.8%), pus (2.3%) and etc. Most of the strains were resistant to all the ß-lactams tested, imipenem, meropenem, aztreonam, gentamicin, netilmicin, fluoroquinolones and trimethoprim-sulfamethoxazole. MIC90 of these drugs were more than 512 μg /ml, except carbapenems (MIC90: μg /ml). The resistance frequencies of amikacin and tobramycin were 63.1% and 60.8%, respectively (MIC90: more than 512 μg /ml). Most of the strains were susceptible to colistin and minocycline, and MIC90 was 1 and 4 μg /ml, respectively. The resistance frequency of doxycycline was 10.8% (MIC90: 32 교신저자 : 서민호, 대구광역시달서구달구벌대로 1095, 계명대학교의과대학미생물학교실, 의과학연구소 Min Ho Suh, M.D., Department of Microbiology, Institute for Medical Science, Keimyung University School of Medicine 1095 Dalgubeol-daero, Dalseo-gu, Daegu , Korea Tel: minho@dsmc.or.kr

2 84 계명의대학술지제 31 권 1 호 2012 μg /ml). Isolation frequency of MDRAB strains was 97.7% (172 strains) and was highly prevalent. Fifty eight (33.0%) strains were multiply resistant to 20 drugs, and twenty eight (15.9%) strains were multiply resistant to 19 drugs. All of the MDRAB were multiply resistant to more than 16 drugs. We need concerted multidisciplinary efforts to preserve the efficacy of currently available antimicrobial agents, by continued surveillance of MDRAB prevalence and antimicrobial resistance patterns that is important to choose effective drugs for MDRAB infections. Key Words : Antimicrobial susceptibility, Colistin, Minocycline, Doxycycline, Imipenem, Levofloxacin, Multidrug resistant Acinetobacter baumannii (MDRAB), Prevalence 서론 Acinetobacter baumannii는 Acinetobacter속의대표적세균으로원내감염의주요원인균으로서, 폐감염, 요로감염, 창상감염, 혈액감염등을일으키며, 특히중환자실에서호발한다 [1,2]. 그중에서도원내감염으로인한폐렴은환자의생명을위협하는가장흔한감염병이며, Acinetobacter baumannii와녹농균이주된원인균으로밝혀져있다 [3]. Acinetobacter baumannii는다양한환경에서서식가능하며특히온도및습도가적절한병원환경에서잘서식한다 [4,5]. 이러한특성때문에병원내에서집단발병을초래하는경우가종종있으며공중보건학적으로위협이되고있다 [1,2,6,7]. Acinetobacter baumannii는 ß-lactams, aminoglycosides, fluoroquinolones 등의주요항균제에흔히내성을가지고있으며, 강력한항균력을가진 carbapenem계에도내성을나타내고있는것으로보고되고있다 [2,8,9]. 특히최근에다약제내성 Acinetobacter baumannii (multidrug resistant Acinetobacter baumannii, MDRAB) 의출현이증가하고있는데, 항균제사용빈도의증가와부적절한항균제선택등이주요원인으로알려져있다 [10,11,12]. MDRAB의증가는감염병치료에있어서적절한항균제선택에어려움을초래하여치료가어렵고, 치료기간연장과유병율및사망율증가의주된원인으로간주되고있다 [8,13]. 항균제를 사용하게되면내성균의출현은불가피하므로내성균의출현을최소화하고, 현재유효한항균제의효능을최대한오랫동안보호하기위한노력을기울여야한다 [14,15]. 이연구는원내감염의주요원인균인 Acinetobacter baumannii의 colistin, minocycline, imipenem, meropenem 및 levofloxacin을포함한각종항균제에대한감수성과내성양상및최소억제농도를조사하여 MDRAB의분리빈도및유행정도를파악하고, MDRAB에대한최선의항균제를선택할수있는정보를제공하고, 향후항균제내성기전규명에필요한기본자료를확보하기위해수행되었다. 재료및방법 1. 균주분리및동정균주분리는객담, 창상가검물, 뇨, 농및기타가검물에서분리된 Acinetobacter baumannii 176주를대상으로실시하였다. 이균들은계명대학교동산의료원에서 2011년에분리된균으로서, 동정기준은 Murray 등의재래적인방법과 16S rrna 유전자염기서열분석, 그리고 Acinetobacter baumannii 염색체 DNA에내재하는 OXA51 유전자검사결과를기준으로동정하였다 [16-19].

3 다약제내성 Acinetobacter baumannii 의유병율과항균제감수성 85 16S rrna 유전자는 primer 16S-8F 5'-AGA GTT TGA TCC TGG CTC AG-3' 및 16S-1541R 5'-AAG GAG GTG ATC CAG CCG CA-3' 을이용하여 PCR로증폭후 SolGent사 (Daejeon, Korea) 에의뢰하여 big dye-terminator cycle 법과 ABI PRISM 3730XL DNA analyzer (Applied Biosystems, Foster City, CA, USA) 를이용하여 DNA 염기서열을분석하였다. OXA51 유전자는 primer OXA-51-likeF 5'-TAA TGC TTT GAT CGG CCT TG-3' 및 OXA-51-likeR 5'-TGG ATT GCA CTT CAT CTT GG-3' 을이용하여 PCR로증폭후 agarose gel 전기영동을실시하여 353 base pair의 amplicon을확인하였다. 35 에서하루배양시킨다음균발육유무를보아최소억제농도 (Minimal Inhibitory Concentration: MIC) 를결정하였다. 내성균판정기준은 Clinical and Laboratory Standard Institute (CLSI) 의기준에 [21] 따랐으며, 매실험마다정도관리를위하여 Escherichia coli ATCC25922와 Pseudomonas aeruginosa ATCC 27853을함께공시하였다 [20,21]. MDRAB 의판정기준은 Adams-Haduch 등, Lee 등및 Peleg 등의기준을 [2,8,22] 적용하여, ß-lactam계, carbapenem계, aminoglycoside계및 fluoroquinolone계항균제들중에서적어도 3계열이상의항균제에동시내성인균을 MDRAB로판정하였다. 2. 항균제 ß-lactam계항균제 10종 (amoxicillin-clavulanic acid, carbenicillin, ticarcillin, piperacillin, ceftazidime, cefotaxime, ceftizoxime, cefoperazone, cefepime, aztreonam), carbapenem계 2종 (imipenem, meropenem), aminoglycoside계 4종 (amikacin, gentamicin, tobramycin, netilmicin), fluoroquinolone계 2종 (ciprofloxacin, levofloxacin), colistin, tetracycline, minocycline, doxycycline, trimethoprim-sulfamethoxazole, chloramphenicol 등 24종의항균제를사용하여실험하였다. 각항균제는규정된용매에용해시켜고농도의용액을만들어소분하여 -70 에냉동보관하면서필요시 1개씩취하여사용하였다. 3. 항균제감수성검사항균제감수성검사는평판희석법및디스크확산법으로검사하였다 [20]. 평판희석법에서는순차적으로희석된소정농도의항균제가함유된 Mueller-Hinton agar (Becton, Dickinson and Co., Sparks, MD, USA) 를사용하였고, 공시균을 tryptic soy broth (Becton, Dickinson and Co., Sparks, MD, USA) 에하루배양한후생리식염수로 100배희석하여 Steers' multiple inoculator로접종하여 성적 각종임상가검물에서분리된 Acinetobacter baumannii의가검물별분리빈도는, 총 176주중 148주 (84.1%) 가객담에서분리되어그빈도가가장높았으며, 다음으로창상가검물 14주 (8.0%), 요 5주 (2.8%), 농 4주 (2.3%) 등의순서로분리빈도를나타내었다 (Table 1). ß-lactam계, carbapenem계및관련항균제에 Table 1. Isolation frequency of Acinetobacter baumannii from various specimens Specimens No. (%) of strains Sputum 148 (84.1) Wound Discharge 14 ( 8.0) Urine 5 ( 2.8) Pus 4 ( 2.3) Bile 2 ( 1.1) Bronchial Lavage 2 ( 1.1) Pleural Fluids 1 ( 0.6) Total 176 (100)

4 86 계명의대학술지제 31 권 1 호 2012 대한 Acinetobacter baumannii의내성율은 amoxicillin-clavulanic acid에는 98.3%, carbenicillin에는 98.9%, ticarcillin에는 94.9%, piperacillin 및 ceftazidime에는 98.3%, cefotaxime 및 ceftizoxime에는 99.4%, cefoperazone에는 98.9%, cefepime에는 95.5%, aztreonam에는 100%, imipenem 및 meropenem에는 97.7% 였다 (Table 2). 실질적인내성화정도를파악할수있는 90% MIC (90% 의균을억제하는항균제농도 ) 는 meropenem 은 128 μg /ml, imipenem은 256 μg /ml이었으며, 그외의 ß-lactam 계항균제들은 512 μg /ml 이상으로매우높았다 (Table 2). Aminoglycoside계열항균제에대한 Acinetobacter baumannii의내성율은 amikacin 및 tobramycin에는 63.1%, 60.8% 가각각내성을나타내었고, gentamicin 및 netilmicin에는 83.0%, 84.1% 가각각내성을나타내었다 (Table 3). 90% MIC는 4종의 aminoglycoside계항균제모두가 512 μg /ml 이상으로서 매우높았다 (Table 3). Fluoroquinolone계열항균제에대한 Acinetobacter baumannii의내성율은 ciprofloxacin 및 levofloxacin에 98.3%, 96.6% 가각각내성을나타내었고, 90% MIC는 levofloxacin은 32 μg /ml이었고, ciprofloxacin은 256 μg /ml로매우높았다 (Table 3). Colistin, minocycline 및기타항균제에대한 Acinetobacter baumannii의내성율은 colistin과 minocycline에는 1.1%, 1.7% 만이각각내성을나타내었으며, doxycycline에는 10.8% 가내성을나타내었다 (Table 4). Tetracycline에는 67.0% 가내성을나타내었으며, trimethoprimsulfamethoxazole과 chloramphenicol에는 97.2%, 99.4% 가각각내성을나타내었다 (Table 4). 90% MIC는 colistin과 minocycline에는각각 1 μg /ml, 4 μg /ml로낮았고, doxycycline에는 32 μg /ml이었으며, tetracycline, trimethoprim-sulfamethoxazole 및 chloramphenicol에는 512 μg /ml 이상으로매우높았다 (Table 4). Table 2. Antimicrobial activities of ß-lactams, carbapenems and related drugs to isolated Acinetobacter baumannii Antimicrobial agents No. (%) of resistant strains Range MIC (µg/ml) a 50% 90% amoxicillin/clavulanate 173 (98.3) 12 ->512/256 >512/256 >512/256 carbenicillin 174 (98.9) 8 - >512 >512 >512 ticarcillin 167 (94.9) 4 - >512 >512 >512 piperacillin 173 (98.3) 4 - >512 >512 >512 ceftazidime 173 (98.3) 2 - > >512 cefotaxime 175 (99.4) 4 - >512 >512 >512 ceftizoxime 175 (99.4) 2 - >512 >512 >512 cefoperazone 174 (98.9) 16 - >512 >512 >512 cefepime 168 (95.5) 2 - > >512 aztreonam 176 (100) 16 - > >512 imipenem 172 (97.7) meropenem 172 (97.7) a; 50% and 90% are MICs required to inhibit 50 and 90% of the strains, respectively.

5 다약제내성 Acinetobacter baumannii 의유병율과항균제감수성 87 Table 3. Antimicrobial activities of aminoglycosides and fluoroquinolones to isolated Acinetobacter baumannii Antimicrobial agents No. (%) of resistant strains Range MIC (µg/ml) a 50% 90% amikacin 111 (63.1) > >512 gentamicin 146 (83.0) >512 >512 >512 tobramycin 107 (60.8) > >512 netilmicin 148 (84.1) > >512 ciprofloxacin 173 (98.3) levofloxacin 170 (96.6) a; 50% and 90% are MICs required to inhibit 50 and 90% of the strains, respectively. Table 4. Antimicrobial activities of other antimicrobial agents to isolated Acinetobacter baumannii Antimicrobial agents No. (%) of resistant strains Range MIC (µg/ml) a 50% 90% colistin 2 ( 1.1) > tetracycline 118 (67.0) 1 - > >512 minocycline 3 ( 1.7) doxycycline 19 (10.8) trimethoprim/ 171 (97.2) 20- >128/512 >128/512 >128/512 sulfamethoxazole chloramphenicol 175 (99.4) 16 - >512 >512 >512 a; 50% and 90% are MICs required to inhibit 50 and 90% of the strains, respectively. ß-lactam계열, carbapenem계열, aminoglycoside계열및 fluoroquinolone계열중에서 3계열이상의약제에동시내성인 Acinetobacter baumannii를계수한결과 172주가 MDRAB로판정되었고, 분리빈도는 97.7% 로매우높았다 (Table 5). MDRAB의분리빈도와내성약제수의분포를보면, 20종항균제에동시내성인것이 58주 (33.0%) 로가장많았고, 21종항균제에동시내성인것이 41주 (23.3%) 이었으며, 19종항균제에 동시내성인것이 28주 (15.9%) 였다 (Table 5). 모든 MDRAB는적어도 16종이상의항균제에동시내성이었고, 23종항균제에동시내성인것도 3주 (1.7%) 가있었다 (Table 5). 고찰 Acinetobacter baumannii는다양한원내감염을

6 88 계명의대학술지제 31 권 1 호 2012 Table 5. Isolation frequencies of multidrug resistant Acinetobacter baumannii (MDRAB a ) No. of resistant drugs No. (%) of strains Cumulative percentage of MDRAB 23 3 ( 1.7) ( 5.1) (23.3) (33.0) (15.9) ( 6.8) (10.8) ( 1.1) 97.7 Total a; The definition of MDRAB was established as resistant to at least three drugs in the following classes: ß-lactams, carbapenems, aminoglycosides and fluoroquinolones. 일으키는대표적인세균으로서다약제내성 Acinetobacter baumannii (multidrug resistant Acinetobacter baumannii, MDRAB) 의출현이증가하고있으며집단발병을일으키는경우가흔하고, 사망률이높다 [6,7]. Acinetobacter baumannii는습한곳과건조한곳모두에서생존하는데, 이러한특성은이균이병원환경에서서식하면서감염을일으키기에유리하게한다 [4]. 중환자실에서의원내감염유병율은높게는 25% 까지도보고되어있는데 [23], Acinetobacter baumannii는포도알균이나녹농균에비하여개달물이나중환자실근무자들의손에서더흔히검출되고, 면역력이저하된환자들에게자주감염을일으킨다 [4,5]. Acinetobacter 속들을표현형분석을이용한재래식감별법으로동정하는것은대단히어려우므로 Acinetobacter 속들의정확한동정을위해서는 16S rrna 혹은 16S-23S rrna intergenic spacer (ITS) 염기서열분석등의분자생물학적동정법이요구된다 [17-19,24,25]. 따라서이연구에서는재래적인표현형검사상 Acinetobacter baumannii로추정되는 202주의균을 16S rrna 유전자 염기서열분석과 Acinetobacter baumannii 염색체 DNA에내재하는 OXA-51 유전자검사를실시하였으며, 그결과 176주 (87.1%) 가최종적으로 Acinetobacter baumannii로동정되었다. 이것은분자생물학적방법으로 % 의동정율을보인국내외연구자들의보고와유사하였다 [24,26]. 이연구에서가검물에서의 Acinetobacter baumannii의분리빈도는객담에서 148주 (84.16%), 창상가검물에서 14주 (8%), 요에서 5주 (2.8%), 농에서 4주 (2.3%) 등으로, 객담에서가장빈도가높았으며, 국내외다른연구자들의보고와 [27,28] 유사하였다. 그러나분리균주의수는임상가검물의숫자차이에따라나타났을가능성이높으므로, 향후충분한검체수를확보하여각각의검체별로분리균의빈도및내성율을알게되면임상각분야에서전공질환별로내성율을파악하는데도움이될것으로생각된다. Acinetobacter baumannii는대부분의항균제에내성을가지고있어서치료에어려움을주고있으며, 한국을포함한아시아지역이미국과유럽에비하여 Acinetobacter baumannii 감염이더욱흔하고내성율이더높다 [8,29].

7 다약제내성 Acinetobacter baumannii 의유병율과항균제감수성 89 이연구에서 ß-lactam계항균제인 amoxicillinclavulanic acid, carbenicillin, ticarcillin, piperacillin, ceftazidime, cefotaxime, ceftizoxime, cefoperazone 및 cefepime과,monobactam계항균제인 aztreonam에대한 Acinetobacter baumannii의내성율을조사한결과 94.9% 이상의균주가각각내성이었고, 90% MIC는 512 μg /ml 이상으로서매우높았다. 이러한사실은 Acinetobacter baumannii 감염증치료에 ß-lactam계항균제는효과가거의없음을시사하며, 연구자에따라 82.2%-100% 사이의내성율을보고한국내외다른연구성적들과유사하였다 [25,30-32]. Carbapenem계항균제인 imipenem 및 meropenem에는이연구에서 97.7% 의균이내성을나타내었고, 90% MIC는각각 128 μg /ml, 256 μg /ml로서매우높았다. 국내외다른연구자들은국가나지역에따라 60.7%-90.5% 사이의다양한내성율을보고하였는데, 대체로한국을포함한아시아지역과중남미지역의내성율이높았다 [8,11,32,33]. 국내외적으로내성율이차이가나는이유중하나로서국가나지역별로항균제선택의선호도가달라서지역별감수성의차이가있을것으로일반적으로고찰하고 [34] 있으나, 추후다국적-다기관이참여하여지역별로선호하는항균제종류의차이등을포함한구체적인연구가요망된다. Carbapenem은대부분의세균에효과가있는중요한항균제로서, 1997년에는 imipenem 내성율이 1% 에불과하였으나, 2009년에는 60.9% 로급속히증가하였고, 2010년에는최대 90.5% 까지내성이증가하였다 [8,33]. Carbapenem에대한내성이증가하게된이유는 3세대세파로스포린내성균의치료를위해 carbapenem의사용빈도가증가하게된것과, 의료인들의부적절한사용이그원인으로간주되고있다 [9-12,32]. 이연구에서 aminoglycoside계항균제인 amikacin, gentamicin, tobramycin 및 netilmicin에는 % 의균이내성을나타내었고, 90% MIC는 4종의 aminoglycoside 계항균제모두가 512 μg /ml 이상으로서매우높았으며, % 의내성율을보고한국내외연구자들의성적과유사하였다 [25,30-32]. 따라서이약제들은투약전에반드시항균제감수성검사를시행하여야하며, 그결과에따라적절히사용했을시항균효과를기대할수있을것으로판단된다. 이연구에서 fluoroquinolone계항균제인 ciprofloxacin 및 levofloxacin에는 98.3%, 96.6% 의균이각각내성을나타내었으며, 90% MIC는각각 256 μg /ml 및 32 μg /ml로서매우높았다. 이러한사실은 Acinetobacter baumannii 감염증치료에 fluoroquinolone계항균제는효과가거의없음을시사하며, % 의내성율을보고한국내외연구자들의성적과유사하였다 [25,30-32]. Colistin은 polypeptide계항균제로서대부분의그람음성균에효과가있으나신장독성과신경독성때문에거의사용되지않고있는데, 최근에 MDRAB 감염치료에효과가있어서사용이증가하고있다 [2,8]. 이연구에서 colistin에는 1.1% 의균주만이내성을나타내었으며, 90% MIC는 1 μg /ml로낮아서항균효과가매우우수함을알수있었고, 국내외다른연구자들의보고에서도 0-1.8% 의균주가내성을나타내어유사한결과를볼수있었다 [35,36]. 그러나국내의한연구에서는 colistin 내성율이 30.6% 까지보고되어있어서, 가까운미래에국내에서 colistin 내성균이확산될수도있을것으로우려된다 [37]. 이연구에서 tetracycline에는 67% 의균이내성을나타내었고, 90% MIC는 512 μg /ml 이상으로매우높았으며, 국내외다른연구자들의보고에서도 % 의균주가내성을나타내어유사한결과를볼수있었다 [38,39]. 그러나이연구에서 minocycline 에는 1.7% 만이내성을나타내었고, 90% MIC는 4 μg /ml 로낮아서항균효과가매우우수함을알수있었으며, 국내외다른연구자들의보고에서도 0-8.8% 의균주가감수성을나타내어유사한결과를볼수있었다 [7]. 이연구에서 doxycycline에는 10.8% 가내성이었고 90% MIC는 32 μg /ml로서항균효과가비교적우수함을알수있었으며, 다른연구자의보고에서도 8.3% 의균주가감수성을나타내어유사한결과를볼수있었다 [41]. Trimethoprim-sulfamethoxazole과 chloramphenicol에는 97.2%, 99.4% 가각각내성이었고

8 90 계명의대학술지제 31 권 1 호 % MIC는 128/512 μg /ml 이상으로매우높아서, 이항균제들은 Acinetobacter baumannii 감염증치료에효과가거의없음을시사하였고, % 의내성율을보고한국내외연구자들의성적과유사하였다 [7,39]. Acinetobacter baumannii는여러가지항균제에내성을매우빨리획득하는특성을가지고있으며, 최근에 MDRAB의출현이증가하고있다 [1,8,32,33,39]. 이연구에서도 Adams-Haduch 등, Lee 등및 Peleg 등의기준에 [2,8,22] 준하여 ß-lactam계열, carbapenem계열, aminoglycoside계열및 fluoroquinolone계열중에서 3계열이상의약제에동시내성인 MDRAB를계수한결과 172주가 MDRAB로판정되었고, 분리빈도는 97.7% 로매우높았다. 국내외다른연구자들의 MDRAB 분리율은 % 로서이연구에서의분리율이다른연구자들의보고에비해매우높았다 [8,32,33,39]. MDRAB의분리율이계속증가추세임을고려할때, 이연구에사용된균은 2011년도분리균이고, 다른연구자들은 년도분리균을사용했기때문에 MDRAB의분리율에차이가있을것으로판단된다 년도분리균을이용한연구결과와 2011년도분리균을사용한본연구결과를비교해볼때 MDRAB가최근급격히증가하고있음을알수있었으며, 향후 MDRAB에관한지속적감시가필요할것으로판단된다. MDRAB의다약제내성패턴을분석한결과, 20종항균제에동시내성인것이 58주 (33.0%) 로가장많았고, 21종항균제에동시내성인것이 41주 (23.3%) 이었으며, 모든 MDRAB는적어도 16종이상의항균제에동시내성이어서, MDRAB 감염증에서추측에의한임의적항균제선택은효과를기대하기어려울것으로사료된다. 이연구를통해 MDRAB 감염증의치료에유용하게쓰일수있는항균제로서 colistin과 minocycline이가장우수할것으로사료되며, doxycycline도효과가양호할것으로판단된다 [7,35,40,41]. 그러나현재임상에서널리사용되고있는 carbapenem계, aminoglycoside계, fluoroquinolone계및 ß-lactam계항균제들은 MDRAB 감염의치료에효과가거의없을것으로판단되며, 투약전항균제감수성검사를실시후선별적으로항균효과를기대할수있을것으로사료된다. MDRAB의효과적인치료를위해서는다약제내성획득기전연구를통하여내성균에효과를나타내는새로운항균제가개발되어야하지만새로운항균제개발은매우어려운현실이다 [42]. 따라서신속하고도정확한미생물진단법을개발하여원인균을조기에진단함으로써치료시기를앞당기고, 항균제사용시사용지침을잘따르며, 잘협력된감염관리활동을펼치는등의다양한노력을기울임으로써항균제내성화를최소로억제하고항균제의효능을잘보호하도록힘써야할것으로사료된다 [43]. 요약원내감염의중요한원인이되고있는다약제내성 Acinetobacter baumannii (MDRAB) 의분리빈도를파악하고최선의항균제를선택할수있는정보를제공하기위해 176주의 Acinetobacter baumannii를대상으로 imipenem, meropenem, amikacin, levofloxacin, colistin, minocycline 등 24종의항균제에대한감수성검사및내성양상분석을실시하였다. 가검물에서의분리빈도는객담에서 148주 (84.1%), 창상가검물에서 14주 (8.0%) 요에서 5주 (2.8%), 농 4주 (2.3%) 등으로객담에서가장높은분리율을보였다. 24종의항균제에대한감수성검사를시행한결과 colistin과 minocycline에는거의모든균주가감수성을나타내었고, 90% MIC는각각 1 μg /ml, 4 μg /ml이었으며, doxycycline에는 10.8% 의균이내성을나타내었고, 90% MIC는 32 μg /ml이었다. Amikacin 및 tobramycin에는 63.1%, 60.8% 가각각내성을나타내었고, gentamicin 및 netilmicin에는 83.0%, 84.1% 가각각내성을나타내었으며, 90% MIC는 512 μg /ml 이상으로서매우높았다. Ciprofloxacin 및 levofloxacin에는 98.3%, 96.6% 가각각내성을나타내었고, 90% MIC는 levofloxacin은

9 다약제내성 Acinetobacter baumannii 의유병율과항균제감수성 μg /ml이었고, ciprofloxacin은 256 μg /ml로매우높았다. Meropenem 을포함한 12종의 ß-lactam 계및 carbapenem계항균제에는 94.9% 이상의균이각각내성을나타내었고, 90% MIC는 meropenem은 128 μg /ml, imipenem은 256 μg /ml이었으며, 그외의 ß-lactam 계항균제들은 512 μg /ml 이상으로매우높았다. ß-lactam계열, carbapenem계열, aminoglycoside계열및 fluoroquinolone계열중에서 3계열이상의약제에동시내성인 MDRAB의분리빈도는 97.7% (172주) 로매우높아서 MDRAB가유행상태임을알수있었으며, 이에대한지속적감시와대책수립이필요할것으로사료된다. MDRAB의다약제내성양상을분석한결과, 20종항균제에동시내성인것이 58주 (33.0%) 로가장많았고, 21종항균제에동시내성인것이 41주 (23.3%), 19종항균제에동시내성인것이 28주 (15.9%) 였으며, 모든 MDRAB는적어도 16종이상의항균제에동시내성으로나타났다. 따라서 MDRAB 감염증에서추측에의한임의적항균제선택은효과를기대하기어려울것으로사료되며, 투약전항균제감수성검사실시가요망된다. 결론적으로, MDRAB 감염증의치료에유용하게쓰일수있는항균제는 colistin과 minocycline이가장우수하며, doxycycline도효과가양호함을알수있었고, amikacin 및 tobramycin은투약전항균제감수성검사를실시후선별적으로항균효과를기대할수있을것으로사료된다. 그러나현재임상에서널리사용되고있는 carbapenem계열및 fluoroquinolone계열의항균제들은기대와는달리 MDRAB 감염의치료에효과가없을것으로판단되며, 유전적및분자생물학적내성기전분석을통하여다약제내성균만연에대한대책개발이요망된다. 참고문헌 1. Bergogne-Bérézin E, Towner KJ. Acinetobacter spp. as nosocomial pathogens: microbiological, clinical, and epidemiological features. Clin Microbiol Rev 1996;9: Peleg AY, Seifert H, Paterson DL. Acinetobacter baumannii: emergence of a successful pathogen. Clin Microbiol Rev 2008;21: Gaynes R, Edwards JR. Overview of nosocomial infections caused by gram-negative bacilli. Clin Infect Dis 2005;41: Getchell-White SI, Donowitz LG, Gröschel DH. The inanimate environment of an intensive care unit as a potential source of nosocomial bacteria: evidence for long survival of Acinetobacter calcoaceticus. Infect Control Hosp Epidemiol 1989;10: Petersen K, Cannegieter SC, van der Reijden TJ, van Strijen B, You DM, Babel BS, et al. Diversity and clinical impact of Acinetobacter baumannii colonization and infection at a military medical center. J Clin Microbiol 2011;49: Song JY, Cheong HJ, Choi WS, Heo JY, Noh JY, Kim WJ. Clinical and microbiological characterization of carbapenem-resistant Acinetobacter baumannii bloodstream infections. J Med Microbiol 2011;60: Kim JW, Heo ST, Jin JS, Choi CH, Lee YC, Jeong YG, et al. Characterization of Acinetobacter baumannii carrying blaoxa-23, blaper-1 and arma in a Korean hospital. Clin Microbiol Infect 2008;14: Lee K, Yong D, Jeong SH, Chong Y. Multidrugresistant Acinetobacter spp: increasingly problematic nosocomial pathogens. Yonsei Med J 2011;52: Kempf M, Rolain M. Emergence of resistance to carbaphenems in Acinetobacter baumannii in Europe: clinical impact and therapeutic options. Int J Antimicrob agents 2012;39: Paterson DL. The Epidemiological profile of infections with multidrug-resistant Pseudomonas aeruginosa and Acinetobacter species. Clin Infect Dis 2006;43(Suppl 2):S Kuo HY, Chang KC, Kuo JW, Yueh HW, Liou ML. Imipenem: a potent inducer of multidrug resistance in Acinetobacter baumannii. Int J Antimicrob agents

10 92 계명의대학술지제 31 권 1 호 ;39: Liew YX, Lee W, Kwa AL, Lye DC, Yeo CL, Hsu LY. Inappropriate carbapenem use in Singapore public hospitals: opportunities for antimicrobial stewardship. Int J Antimicrob Agents 2011;37: Peleg AY, Hooper DC. Hospital-acquired infections due to Gram-negative bacteria. N Engl J Med 2010;362: Woodford N, Livermore DM. Infections caused by Gram-positive bacteria: a review of the global challenge. J Infect 2009;59(Suppl 1):S Talbot GH. The antibiotic development pipeline for multidrug-resistant Gram-negative bacilli: current and future landscapes. Infect Control Hosp Epidemiol 2010;31(Suppl 1):S Murray PR, Baron EJ, Jorgensen JH, Landry ML, Pfaller MA. Manual of Clinical Microbiology. 9th ed. Washington, DC, ASM Press; 2007, p Loffler FE, Sun Q, Li J, Tiedje JM. 16S rrna genebased detection of tetrachloroethene-dechlorinating Desulfuromonas and Dehalococcoides species. Appl Environ Microbiol 2000;66: Chang HC, Wei YF, Dijkshoorn L, Vaneechoutte M, Tang CT, Chang TC. Species-level identification of isolates of the Acinetobacter calcoaceticus- Acinetobacter baumannii complex by sequence analysis of the 16S-23S rrna gene spacer region. J Clin Microbiol 2005;43: Turton JF, Woodford N, Glover J, Yarde S, Kaufmann ME, Pitt TL. Identification of Acinetobacter baumannii by detection of the blaoxa-51-like carbapenemase gene intrinsic to this species. J Clin Microbiol 2006;44: Murray PR, Baron EJ, Jorgensen JH, Landry ML, Pfaller MA. Manual of Clinical Microbiology. 9th ed. Washington, DC, ASM Press; 2007, p Clinical and Laboratory Standard Institute. Performance standards for antimicrobial susceptibility testing: Twenty-first informational supplement M100-S21. CLSI, Wayne, PA, USA, Adams-Haduch JM, Paterson DL, Sidjabat HE, Pasculle AW, Potoski BA, Muto CA, et al. Genetic basis of multidrug resistance in Acinetobacter baumannii clinical isolates at a tertiary medical center in Pennsylvania. Antimicrob Agents Chemother 2008;52: Carlet J, Fabry J, Amalberti R, Degos L. The "zero risk" concept for hospital-acquired infections: a risky business. Clin Infect Dis 2009;49: Dortet L, Legrand P, Soussy CJ, Cattoir V. Bacterial identification, clinical significance, and antimicrobial susceptibilities of Acinetobacter ursingii and Acinetobacter schindleri, two frequently misidentified opportunistic pathogens. J Clin Microbiol 2006;44: Lim YM, Shin KS, Kim J. Distinct antimicrobial resistance patterns and antimicrobial resistanceharboring genes according to genomic species of Acinetobacter isolates. J Clin Microbiol 2007;45: Lee Y, Lee J, Jeong SH, Lee J, Bae IK, Lee K. Carbapenem-non-susceptible Acinetobacter baumannii of sequence type 92 or its single-locus variants with a G428T substitution in zone 2 of the rpob gene. J Antimicrob Chemother 2011;66: Ryoo NH, Ha JS, Jeon DS, Kim JR. Prevalence of metallo-beta-lactamases in imipenem-non-susceptible Pseudomonas aeruginosa and Acinetobacter baumannii. Korean J Clin Microbiol 2010;13: Mera RM, Miller LA, Amrine-Madsen H, Sahm DF. Acinetobacter baumannii : increase of carbapenem-associated multiclass resistance in the United States. Microb Drug Resist 2010;16: Jean SS, Hsueh PR. High burden of antimicrobial resistance in Asia. Int J Antimicrob Agents 2011;37: Yang HY, Lee HJ, Suh JT, Lee KM. Outbreaks of imipenem resistant Acinetobacter baumannii producing OXA-23 beta-lactamase in a tertiary care

11 다약제내성 Acinetobacter baumannii 의유병율과항균제감수성 93 hospital in Korea. Yonsei Med J 2009;50: Hujer KM, Hujer AM, Hulten EA, Bajaksouzian S, Adams JM, Donskey CJ, et al. Analysis of antibiotic resistance genes in multidrug-resistant Acinetobacter sp. isolates from military and civilian patients treated at the Walter Reed Army Medical Center. Antimicrob Agents Chemother 2006;50: Cao J, Song W, Gu B, Mei Y, Tang J, Meng L, et al. Correlation between carbapenem consumption and antimicrobial resistance rates of Acinetobacter baumannii in a university-affiliated hospital in China. J Clin Pharmacol 2012.doi: / Kiratisin P, Chongthaleong A, Tan TY, Lagamayo E, Roberts S, Garcia J, et al. Comparative in vitro activity of carbapenems against major Gram-negative pathogens: results of asia-pacific surveillance from the COMPACT II study. Int J Antimicrob Agents 2012;39: Jones RN, Kirby JT, Beach ML, Biedenbach DJ, Pfaller MA. Geographic variations in activity of broad-spectrum beta-lactams against Pseudomonas aeruginosa: summary of the worldwide SENTRY Antimicrobial Surveillance Program ( ). Diagn Microbiol Infect Dis 2002;43: Roh KH, Kim CK, Yum JH, Yong D, Jeong SH, Lim CS, et al. Carbapenem resistance mechanisms and molecular epidemiology of Acinetobacter spp. from four hospitals in Seoul and Gyeonggi province in Korean J Clin Microbiol 2010;13: Dueñas-Díez AI, Bratos-Pérez MA, Eiros-Bouza JM, Almaraz-Gómez A, Gutiérrez-Rodríguez P, Miguel- Gómez MA, et al. Susceptibility of the Acinetobacter calcoaceticus-a. baumannii complex to imipenem, meropenem, sulbactam and colistin. Int J Antimicrob Agents 2004;23: Ko KS, Suh JY, Kwon KT, Jung SI, Park KH, Kang CI, et al. High rates of resistance to colistin and polymyxin B in subgroups of Acinetobacter baumannii isolates from Korea. J Antimicrob Chemother 2007;60: Lee H, Kim CK, Lee J, Lee SH, Ahn JY, Hong SG, et al. Antimicrobial resistance of clinically important bacteria isolated from 12 hospitals in Korea in 2005 and Korean J Clin Microbiol 2007;10: Hamzeh AR, Al Najjar M, Mahfoud M. Prevalence of antibiotic resistance among Acinetobacter baumannii isolates from Aleppo, Syria. Am J Infect Control 2012.doi: /j.ajic Morfin-Otero R, Dowzicky MJ. Changes in MIC within a global collection of Acinetobacter baumannii collected as part of the tigecycline evaluation and surveillance trial, 2004 to Clin Ther 2012;34: Gales AC, Reis AO, Jones RN. Contemporary assessment of antimicrobial susceptibility testing methods for polymyxin B and colistin: review of available interpretative criteria and quality control guidelines. J Clin Microbiol 2001;39: Brötz-Oesterhelt H, Sass P. Postgenomic strategies in antibacterial drug discovery. Future Microbiol 2010;5: Fishman N. Antimicrobial stewardship. Am J Med 2006;119:S53 61.