대한진단검사의학회지제 27 권제 2 호 2007 Korean J Lab Med 2007;27:111-7 원저 임상미생물학 Imipenem 내성 Acinetobacter baumannii에서항균제병합요법의시험관내상승작용검사 성흥섭 최수진 유수진 김미나 울산의대서울아산병원진단검사의학과 In vitro Antimicrobial Synergy against Imipenem-Resistant Acinetobacter baumannii Heungsup Sung, M.D., Soo Jin Choi, M.D., Soojin Yoo, M.D., and Mi-Na Kim, M.D. Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Korea Background : Most imipenem-resistant Acinetobacter baumannii (IRAB) isolates are multiresistant, leaving few options for an effective antimicrobial therapy. We purposed to select possible candidates for the combinations of antimicrobials that are synergistic in vitro for inhibitory or bactericidal activities against IRAB and evaluate the usefulness of double disk synergy test (DDS) in predicting synergistic bactericidal activity. Methods : Fifty-five IRAB isolates recovered from patients during the period from August 1999 to November 2000 were tested for susceptibilities to amikacin, gentamicin, tobramycin, piperacillin, piperacillin/tazobactam, cefotaxime, cefepime, cefoperazone/sulbactam (C/S), imipenem, meropenem, ciprofloxacin, levofloxacin, trimethoprim/sulfamethoxazole, chloramphenicol, minocycline, and colistin by the Clinical and Laboratory Standard Institute agar dilution method. Three isolates showing different susceptibility profiles were tested for antimicrobial synergy by DDS and then by timekill study (TKS) using DDS-positive combinations. Results : Colistin, C/S, and minocycline were active in 50 (90.9%), 50, and 44 (80.0%) isolates, respectively, and all the other drugs were active in less than 20% of isolates. Minocycline-imipenem, minocycline-c/s, minocycline-amikacin, imipenem-tobramycin, C/S-amikacin, and C/S-tobramycin combinations showed synergistic inhibitory or bactericidal activity by TKS when the same combinations were synergistic in DDS; however, C/S-imipenem was found synergistic on DDS, but not by TKS. Conclusions : Colistin, C/S, and minocycline were relatively active against IRAB. DDS might help predict the synergistic antimicrobial effect of TKS if one of the combinations was susceptible. (Korean J Lab Med 2007;27:111-7) Key Words : Imipenem-resistant, Acinetobacter baumannii, Atimicrobial synergy, Double disk synergy, Time kill study 접 수 : 2006년 10월 30일 접수번호 : KJLM1998 수정본접수 : 2006년 12월 5일 게재승인일 : 2006년 12월 5일 교신저자 : 김미나 우 138-736 서울시송파구풍납2 동 388-1 서울아산병원진단검사의학과 전화 : 02-3010-4511, Fax: 02-478-0884 E-mail : mnkim@amc.seoul.kr * 본논문은 2001년도아산생명과학연구소연구비지원 (2001-229) 에의한 것임. 서론 Acinetobacter baumannii는호기성포도당비발효그람음성간균으로병원감염의주요원인균이다. 이균은폐렴, 패혈증, 요로감염, 창상감염, 수막염등의다양한형태의감염증을유발하며중환자실환자에서중증감염을일으킨다 [1, 2]. A. baumannii 는염색체성 AmpC -lactamase를생성하여일부 -lactam 항 111
112 성흥섭 최수진 유수진외 1 인 균제에내성이며다른여러항균제에도내재성혹은획득내성을지니고있기때문에치료항균제선택범위가매우좁다 [3, 4]. Imipenem은세포외막의 porin을잘투과하고, penicillin-binding protein (PBP) 과의친화도와 -lactamase에대한안정성이높아서항균제다제내성 A. baumannii에대해가장효과적인항균제로사용되어왔다 [5]. 서울아산병원에서는 1998년에 imipenem 내성 A. baumannii (imipenem-resistant A. baumannii, IRAB) 가처음검출된이래그비율이계속증가하여 2000년에는 5.6%, 2001년에는 8.7% 에달하였다. 국내의한 2차병원에서도 IRAB 의비율이 2000년 9% 에서 2001년 22% 로현저히증가하였다는보고가있으며 [6], 전국적인다기관조사연구에서도 1999년의 6.2% 에서 2003년에는 13% 로증가하였음이확인되었다 [7, 8]. IRAB 에의한감염은기존의항균제중에는효과적인약제가없는경우가대부분으로최근에는 colistin과같이부작용으로인해사용하지않던약제로치료하거나두가지이상의항균제를병합하여치료하려는시도가있다 [2, 5]. 이에본연구에서는 IRAB 에대한항균력이있는약제와 IRAB 균주를대상으로상승효과를보이는항균제병합요법을찾고, 실험실에서일상적으로사용할수있는이중디스크확산법 (double disk synergy) 검사로시간-살균검사 (time-kill study) 의결과를예측할수있는지를알아보고자하였다. 사용하였다. CLSI 기준 [10] 이없는 C/S는 cefoperazone의감수성기준을따랐다. Azithromycin, arbekacin, rifampin, sulbactam 등은감수성기준이없어감수성여부를결정하지않았다. 3. 이중디스크확산법검사이전연구에서 A. baumannii에상승작용을보였던항균제조합들을참조하여, C/S-imipenem, C/S-amikacin, C/S-minocycline, C/S-tobramycin, C/S-ciprofloxacin, minocycline-imipenem, minocycline-ciprofloxacin, minocycline-amikacin, minocycline-tobramycin, imipenem-tobramycin, imipenem-amikacin, imipenem-ciprofloxacin의조합에대해이중디스크확산법을실시하였다. 이중디스크확산법검사전디스크확산법을실시하여억제대직경을측정하고, 디스크주변억제대가서로겹치지않으면서근접하도록디스크를배치하였다. 배지는 Mueller-Hinton 한천배지를사용하였고, CLSI 디스크확산법조건에맞추어서균액을접종하였다 [11]. 35 항온기에하룻밤배양후결과를판독하였는데, 두디스크사이에서상승효과에의한억제대의확장현상이관찰되면양성으로판정하였다. 4. 시간-살균검사 재료및방법 1. 대상 1999년 8월부터 2000년 11월까지동일환자에서반복분리된균주를제외한 55주의 IRAB를 -70 에냉동보관하였다가연구에사용하였다. 균종동정과항균제감수성검사는 MicroScan Neg Combo type 21 (Dade Behring, West Sacramento, USA) 로시행하였다. 2. 항균제감수성시험 Clinical and Laboratory Standard Institute (CLSI) 의기준 [9] 에따라서한천희석법으로최소억제농도 (minimum inhibitory concentration, MIC) 를측정하였다. Azithromycin, amikacin, gentamicin, tobramycin, piperacillin, piperacillin/tazobactam, cefotaxime, ciprofloxacin, levofloxacin, chloramphenicol, minocycline, trimethoprim/sulfamethoxazole (SXT), colistin, rifampin은 Sigma-Aldrich (St. Louis, MO, USA) 에서구입하여사용하였고, imipenem (MSD, Elkton, VA, USA), arbekacin (Meiji Seika Co., Tokyo, Japan), cefepime (Bristol Myers Squibb Co., New York, NY, USA), cefoperazone/sulbactam (C/S; Pfizer Inc., New York, NY, USA), meropenem (AstraZeneca, Cheshire, UK) 등의항균제는제조사로부터기증받아 항균제감수성양상별로균주를하나씩선택하여이중디스크확산법검사를시행하고, 상승작용을보이는항균제조합에대해시간-살균검사를시행하였다. 시간 -살균검사를위한항균제농도는시험항균제에대하여감수성인경우 MIC 농도를, 비감수성인경우중간내성농도인 C/S 16 g/ml, amikacin 16 g/ml, tobramycin 1 g/ml, imipenem 8 g/ml 및 minocycline 2 g/ml를선택하였다. Mueller-Hinton broth (MHB) 에조합하는항균제와각각의항균제를적절한농도로희석한후, MHB에탁도가 McFarland No. 0.5가되도록균을부유하고최종균농도가10 6 CFU/mL가되도록균액을첨가하였다. 시험관들을 35 에서 4, 8, 24시간동안각각배양한후생균수를측정하였다. 선택된항균제조합중균의억제효과가가장큰항균제를단독으로사용했을때보다항균제병합시집락수가 2log 10 CFU/mL 이상감소하면상승작용으로판단하였다 [12]. 결과 1. 검체총 55주중 22주 (40.0%) 가호흡기검체에서분리되었고, 창상검체에서 8주 (14.5%), 담즙에서 7주 (12.7%), Jackson Pratt 배액관에서 6주 (10.9%), 뇌척수액에서 3주 (5.5%), 혈액, 소변, 복수에서각 2주 (3.6%), 기타검체에서 3주 (5.5%) 가분리되었다.
IRAB 에대한항균제상승작용 113 Antimicrobial (s) %S %I MIC50 ( g/ml) MIC90 ( g/ml) Azithromycin NA NA 64 128 Piperacillin 10.9 9.1 256 256 Piperacillin/tazobactam 16.3 3.6 128 256 Cefotaxime 0 0 >128 >128 Cefoperazone/sulbactam 90.9 0 16 16 Aztreonam 0 1.8 >128 >128 Cefepime 9.1 3.6 128 128 Meropenem 0 3.6 16 32 Imipenem 0 18.1 64 32 Ciprofloxacin 18.1 0 >32 >32 Levofloxacin 18.1 1.8 16 16 Gentamicin 0 1.8 >64 >64 Tobramycin 7.2 0 64 >64 Amikacin 5.4 23.6 64 128 Arbekacin NA NA 8 16 Minocycline 80 0 2 2 Colistin 90.9 0 0.5 1 Rifampin NA NA 4 8 Sulbactam NA NA 16 32 Trimethoprim/ 12.7 0 32 64 sulfamethoxazole Chloramphenicol 0 0 >128 >128 Abbreviations: NA, not available due to the lack of interpretative criteria; %S, percentage of susceptible isolates; %I, percentage of intermediate resistant isolates; MIC50 and MIC90, MICs at which 50% and 90% of isolates are inhibited, respectively. 2. 항균제감수성 A. baumannii 55주에대한항균제감수성검사에서 colistin 에 50주 (90.9%), C/S에 50주, minocycline에 44주 (80.0%) 가감수성으로높은감수성비율을보였다. 그외의항균제에대해서는 20% 미만이감수성을보였으며 cefotaxime, aztreonam, meropenem, gentamicin 및 chloramphenicol에감수성인균주는없었다 (Table 1). Arbekacin의 MIC 50 은 8 g/ml, MIC 90 은16 g/ml로 aminoglycoside계항균제중 MIC 분포가가장낮았다. 3. 항균제병합효과다양한항균제조합에대한상승작용검사를위해 colistin, C/S, minocycline에감수성을보이면서 amikacin에감수성인 3주, tobramycin에감수성인 4주, ciprofloxacin에감수성인 10주중에서각 1주씩 3주를선택하였다. 첫번째균주 (IRAB1) 는 imipenem MIC가 32 g/ml 로내성이었으며, amikacin, C/S, minocycline 의 MIC는각각 16 g/ml, 16 g/ml, 2 g/ml로감수성이었다. 두번째균주 (IRAB2) 는 C/S, minocycline, tobramycin MIC가각각 8 g/ml, 0.12 g/ml, 1 g/ml로감수성이었으며, imipenem, amikacin MIC가각각 32 g/ml, 64 g/ml 로내성인균주였다. 세번째균주 (IRAB3) 는 C/S, minocycline, ciprofloxacin MIC가각각 16 g/ml, 0.12 g/ml, 0.25 g/ ml로감수성이었으며, imipenem, amikacin MIC가각각 64 g/ Table 2. Antimicrobial susceptibility and synergy results of the isolates tested by double disk synergy tests and time-kill studies Strain No. MICs ( g/ml) IP C/S AK TM MC CI Antimicrobial combination tested by Double disk synergy tests Time-kill studies Synergistic Synergistic Table 1. MICs of 55 A. baumannii isolates against common antimicrobials Nonsynergistic Nonsynergistic IRAB1 32 16 16 16 2 4 MC+IP MC+AK MC+IP MC+C/S MC+C/S MC+AK IP+C/S IP+C/S IRAB2 32 8 64 1 0.12 4 MC+IP MC+TM MC+IP IP+AK MC+C/S MC+TM IP+C/S MC+AK MC+C/S IP+AK MC+AK IP+TM IP+TM IP+C/S C/S+TM C/S+TM IRAB3 64 16 128 16 0.12 0.25 MC+AK MC+IP None MC+IP IP+AK MC+CI MC+C/S IP+C/S MC+C/S MC+CI IP+CI IP+AK IP+C/S C/S+CI IP+CI CS+AK CS+CI Abbreviations: IP, imipenem; C/S, cefoperazone/sulbactam; AK, amikacin; TM, tobramycin; MC, minocycline; CI, ciprofloxacin.
114 성흥섭 최수진 유수진외 1 인 A Log CFU/mL 10 9 8 7 6 5 4 3 2 1 Control AK (16) C/S (16) IP (8) MC (2) MC (2)+IP (8) MC (2)+AK (16) C/S (16)+AK (16) MC (2)+C/S (16) IP (8)+C/S (16) Fig. 1. Double disk synergy tests of three A. baumannii isolates. (A) The isolate 1 showed synergy at the combination of MC+IP, IP+C/S, and. (B) The isolate 2 showed synergy at the combination of MC+IP, MC+C/S, MC+AK, IP+AK, IP+TM, IP+C/S, C/S +TM, and. (C) The isolate3 showed synergy at the combination of MC+AK, IP+AK, and IP+C/S. The black dots denote synergy between the two drugs. Abbreviations: See Table 2. ml, 128 g/ml 로내성이었다 (Table 2). IRAB1 은이중디스크확산법결과 minocycline-imipenem, C/Samikacin, C/S-imipenem에상승작용이있었고, minocyclineamikacin, C/S-minocycline에는상승작용이없었다 (Fig. 1A). 시간- 살균검사에서 minocycline-imipenem, minocycline-amikacin, C/S-amikacin은 24시간째살균적인상승작용이관찰되었다 (Fig. 2A). C/S-imipenem 조합은 C/S와동일한성장곡선을보여서상승작용이없었다. IRAB2는이중디스크확산법결과 minocycline-imipenem, minocycline-c/s, minocycline-amikacin, imipenem-amikacin, imipenem-tobramycin, imipenem-c/s, C/S-tobramycin, C/S-amikacin 조합에상승작용이있었으며, minocycline-tobramycin 사이에는상승작용이없었다 (Fig. 1B). 시간- 살균검사에서 imipenem-tobramycin에 4, 8, 24시간모두상승작용이관찰되었으며, minocycline-imipenem, minocycline-tobramycin, minocycline-c/s, C/S-tobramycin, C/S-amikacin은 24시간째상승작용이관찰되었다 (Fig. 2B). C/S-imipenem과 imipenem-amikacin 은이중디스크확산법결과와는달리상승작용이없었다. IRAB3은이중디스크확산법결과 minocycline-amikacin, imipenem-amikacin, imipenem-c/s 사이에상승작용이있었으며, C/S-amikacin, C/S-minocycline, C/S-ciprofloxacin, minocycline-colistin, imipenem-colistin, imipenem-minocycline 사이에 B C Log CFU/mL Log CFU/mL 0 0 4 8 24 Time (hr) 10 9 8 7 6 5 4 3 2 1 0 0 4 8 24 Time (hr) 10 9 8 7 6 5 4 3 2 1 0 0 4 8 24 Time (hr) Fig. 2. Time-kill tests for three A. baumannii isolates. (A) IRAB1 showed synergistic killing at the combination of MC+IP, MC+AK, and. (B) IRAB2 showed synergistic killing at the combination of MC+IP, MC+TM, MC+C/S, MC+AK, IP+TM, C/S+TM, and. (C) IRAB3 showed no synergistic killing at any combination of antimicrobials. The number in parentheses denotes the concentration ( g/ml) of antimicrobials tested. Abbreviations: See Table 2. 는상승작용이없었다 (Fig. 1C). 시간-살균검사에서는상승작용이있는조합이없었다 (Fig. 2C). A Control MC (0.12) AK (16) TM (1) IP (8) C/S (8) MC (0.12)+AK (16) MC (0.12)+TM (1) MC (0.12)+IP (8) IP (8)+AK (16) IP (8)+TM (1) IP (8)+C/S (8) C/S (8)+AK (16) C/S (16)+TM (1) MC (0.12)+C/S (8) B Control AK (16) CI (0.5) MC (0.5) IP (8) C/S (16) C/S (16)+AK (16) C/S (16)+CI (0.5) MC (0.5)+C/S (16) MC (0.5)+IP (8) MC (0.5)+CI (0.5) IP (8)+AK (16) IP (8)+CI (0.5) IP (8)+C/S (16) C
IRAB 에대한항균제상승작용 115 고찰본연구의 IRAB 55주는 colistin과 minocycline에각각 90.9% 와 80% 의감수성을보여대체약제의가능성을보였다. Colistin 은 1949년소개되었던 polymyxin 계열의항균제로신장독성과신경독성으로인해정주용으로는사용되지않았으나최근다제내성 A. baumannii와 Pseudomonas aeruginosa의치료에사용되고있다 [5, 13-15]. 다제내성또는 colistin에만감수성인 P. aeruginosa와 A. baumannii 감염을치료하기위해 colistimethate sodium을정주한결과패혈증의경우 60-100% ( 평균 69.7%, 23/33), 폐렴의경우 25-76% ( 평균 59.8%, 79/132), 복부감염의경우 50-83% ( 평균 75%, 12/16) 에서치료에성공하였음이보고된바있다 [16-20]. 본연구에서는 5균주의 colistin 내성 A. baumannii 가관찰되었으며, 모두 colistin 치료를받은적이없는환자에서분리되었다. 최근에야산발적으로 colistin 내성 A. baumannii가보고 [21, 22] 되었으며, rpob 유전자염기서열로구분한 A. baumannii subgroup에따라 colistin 내성률에차이가있어 [23], colistin 사용전에감수성검사가필요할것으로판단되었다. Imipenem과 sulbactam에내성인다제내성 A. baumannii에감염된 7 명의인공호흡기관련폐렴환자에서 minocycline이나 doxycycline 으로치료시 6명이치료되었다는보고가있어 [24], minocycline도감수성검사결과에따라 IRAB 인공호흡기관련폐렴에서단독으로사용이가능할것이다. CLSI에서는 C/S에대한 A. baumannii의판독기준을제시하지않았다. 본연구에서 cefoperazone의항균제감수성기준을적용했을때 90.9% 의 IRAB가 C/S에감수성이었다. Sulbactam은다제내성 A. baumannii에대해시험관내살균작용이있으며 [25], 호중성백혈구감소쥐의전신감염모델과폐렴모델에서생체내항균작용이있음 [26, 27] 이알려졌다. 또한 cefoperazone과 ampicillin 등과같은 -lactam 제제의항균력을증가시키므로, IRAB 중 ampicillin/sulbactam (A/S) 또는 C/S에감수성인경우 sulbactam 함유제제의사용을고려할수있겠다 [28]. IRAB에의한인공호흡기관련폐렴이나하기도감염에서 A/S가효과적이었다 [25, 27] 는보고와함께패혈증환자에서도 C/S가 imipenem/ cilastin과비교하여치료성적과사망률에서차이가없었다는보고가있어폐렴뿐만아니라패혈증에도사용이가능할것으로판단된다 [28]. Minocycline-imipenem, minocycline-c/s, minocycline-amikacin, imipenem-tobramycin, C/S-amikacin, C/S-tobramycin 항균제조합에서감수성인항균제들의조합인경우이중디스크확산법에서상승작용을보이면시간-살균검사에서도상승작용을관찰할수있었다. 내성인항균제가포함된조합을사용할때는살균적인상승작용을관찰할수없었다. 이런결과는 sulbactam을이용한연구에서 sulbactam에감수성인 A. baumannii 균주는 4 MIC에서살균작용을보인반면, 중간내성인균주는살균작용이없었다는보고와유사한결과이다 [29]. 본연구에서 IRAB1 과 IRAB2는 C/S-amikacin, minocycline-imipenem, minocycline-amikacin에살균적인상승작용을보였고, IRAB3는이중디스크확산법에서상승작용을보이는항균제조합이있었지만시간- 살균검사에서상승작용을나타내는조합은없었다. 이는 IRAB3 는 imipenem과 amikaicin의 MIC가 128 g/ml로고도내성이었기때문으로판단된다. 병합요법은내성균의발생을감소시키고항균제의독성을감소시키며항균력의상승효과를목적으로이용한다 [30]. 내성인항균제도 MIC까지항균제농도를높이면상승작용이나타날수있을것이다. 하지만항균제를안전한범위내에서사용해서효과가있어야진정한의미에서상승작용이있다고할수있기때문에본연구에서는내성인항균제의경우시간-살균검사에서중간내성에해당한농도를사용하였다. 이등 [31] 은 imipenem 내성또는중간내성인 29균주의 A. baumannii 균주를대상으로 checkerboard법으로항균제상승작용을검사한결과 A/S와 tobramycin, A/S와 meropenem, colistin과 rifampin에각 1균주및 colistin과 ceftazidime에대해 2균주에서만부가효과를보였다고하였다. 이연구에사용한균주들이이들항균제에내성이었기때문으로해석하였는데, 내성인항균제를조합하는것은효과가떨어짐을알수있다. 본연구에서서로다른감수성양상을보이는세균주의항균제병합효과검사에서균마다항균제병합의조합이나결과가달라서균주별로검사가필요한것을알수있었다. 특히 C/S-imipenem 조합은비록디스크확산법에서상승작용을보인다고해도시간 -살균검사에서 24시간에는재성장을보여 IRAB 치료에적합하지않을것으로판단된다. 시간 -살균검사로 sulbactam과 imipenem을병합하였을때 IRAB 두균주를포함한 4균주모두에서상승효과가있었다는보고 [32] 와 checkerboard법으로 meropenem과 sulbactam을병합하였을때 48균주중 37균주에서상승효과또는부분적인상승효과가있었다는보고 [33] 들을고려할때 C/S-imipenem 조합이이중디스크확산법에서상승작용을보인것은 sulbactam과 imipenem 사이의상승작용으로판단된다. 그러나 imipenem과 cefoperazone은둘다 -lactam 제제로서 C/Simipenem을병합하는것은 C/S 단독요법에비해상승작용을보일수없을것으로판단된다. 이처럼 IRAB에의한감염이문제가되는병원에서는환자들의항균제치료를결정하는데현재로서는기존항균제들의상승작용을기대하는수밖에없기때문에실시간상승작용검사가필요하다. 시간-살균검사는생체내조건을더잘반영한다고해도임상검사실에서통상적으로실시하기에는시간과인적소모가크다. 이중디스크확산법결과는시간-살균검사의결과를예측하는데도움이되기때문에임상검사실에서실시간으로상승작용검사를할때이용할수있을것으로판단되었다. 결론적으로 colistin, C/S, minocycline은대부분의 IRAB에대해감수성을유지하고있어대체약제의가능성이있었다. IRAB에의한심각한감염이발생했을때여러대체약제에대해광범위한디스크확산법을통해감수성이있는항균제를검색하고, 이들항
116 성흥섭 최수진 유수진외 1 인 균제를포함하여이중디스크확산법으로상승작용을보이는조합을찾아서항균제병합요법에사용하는것이도움을줄수있겠다. 요약목적 : Imipenem 내성 Acinetobacter baumannii (IRAB) 는다른항균제에도내성을지닌경우가많아서기존의항균제중에는효과적인약제를찾을수없는경우가대부분이다. 본연구에서는시간-살균검사를이용하여 IRAB 에유용한항균제병합을찾고이중디스크확산법검사로시간-살균검사의결과를예측할수있는지를알아보고자하였다. 재료및방법 : 1999년 8월부터 2000년 11월까지본원에서 55 명의환자에서분리된 IRAB 균주를대상으로하였다. Amikacin, gentamicin, tobramycin, piperacillin, piperacillin/tazobactam, cefotaxime, cefepime, cefoperazone/sulbactam (C/S), imipenem, meropenem, ciprofloxacin, levofloxacin, trimethoprim/ famethoxazole, chloramphenicol, minocycline, colistin 등에대해한천희석법에의한최소억제농도검사를실시하였다. 항균제감수성양상별로 3균주를선별하여이중디스크확산법에서상승작용을보이는항균제조합으로시간-살균검사를시행하였다. 결과 : Colistin에 50균주 (90.9%), C/S에 50균주, minocycline 에 44균주 (80.0%) 가감수성이었다. 다른항균제에대해서는 20% 미만의감수성을보였다. 감수성이있는항균제를조합하여 Minocycline-imipenem, minocycline-c/s, minocycline-amikacin, imipenem-tobramycin, C/S-amikacin, C/S-tobramycin 등의이중디스크확산법에서상승작용을보이면, 시간-살균검사에서도상승작용을관찰할수있었다. C/S-imipenem 조합은이중디스크확산법에서는상승작용을보였지만시간-살균검사에서는상승작용을관찰할수없었다. 결론 : Colistin, C/S, minocycline은대부분의 IRAB에대해감수성을유지하고있어대체약제의가능성이있었다. 감수성인항균제의조합으로이중디스크확산법검사를하는것으로시간- 살균검사의결과를예측할수있었다. 참고문헌 1. Afzal-Shah M and Livermore DM. Worldwide emergence of carbapenem-resistant Acinetobacter spp. J Antimicrob Chemother 1998; 41:576-7. 2. Appleman MD, Belzberg H, Citron DM, Heseltine PN, Yellin AE, Murray J, et al. In vitro activities of nontraditional antimicrobials against multiresistant Acinetobacter baumannii strains isolated in an intensive care unit outbreak. Antimicrob Agents Chemother 2000; 44:1035-40. 3. Henwood CJ, Gatward T, Warner M, James D, Stockdale MW, Spence RP, et al. Antibiotic resistance among clinical isolates of Acinetobacter in the UK, and in vitro evaluation of tigecycline (GAR-936). J Antimicrob Chemother 2002;49:479-87. 4. Oh SJ, Lee SU, Hwang HY, Bae IK, Jo HS, Lee BH, et al. Prevalence of class A extended-spectrum -lactamases in clinical isolates of Acinetobacter baumannii and Pseudomonas aeruginosa. Korean J Lab Med 2006;26:14-20. ( 오세진, 이상욱, 황현용, 배일권, 조현수, 이병호등. 임상검체에서분리된 Acinetobacter baumannii와 Pseudomonas aeruginosa의 class A extended-spectrum -lactamase 생성현황. 대한진단검사의학회지 2006;26:14-20.) 5. Murray CK and Hospenthal DR. Treatment of multidrug resistant Acinetobacter. Curr Opin Infect Dis 2005;18:502-6. 6. Park AJ and Hong HR. Evaluation of methods for detection of antimicrobial resistance of Acinetobacter baumannii to imipenem. Korean J Lab Med 2003;23:388-94. ( 박애자및홍혜림. Imipenem내성을보인 Acinetobacter baumannii의항균제감수성검사의신빙도조사. 대한진단검사의학회지 2003;23:388-94.) 7. Lee K, Lee HS, Jang SJ, Park AJ, Lee MH, Song WK, et al. Antimicrobial resistance surveillance of bacteria in 1999 in Korea with a special reference to resistance of enterococci to vancomycin and gramnegative bacilli to third generation cephalosporin, imipenem, and fluoroquinolone. J Korean Med Sci 2001;16:262-70. 8. Hong SG, Yong DE, Lee KW, Kim EJ, Lee WK, Jeung SH, et al. Antimicrobial resistance of clinically important bacteria isolated from hospitals located in representative provinces of Korea. Korean J Clin Microbiol 2003;6:29-36. ( 홍성근, 용동은, 이경원, 김의종, 이위교, 정석훈등. 국내여러지역병원의임상검체에서분리된주요세균의항균제내성율. 대한임상미생물학회지 2003;6:29-36.) 9. National Committee for Clinical Laboratory Standards. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically; approved standard-sixth edition, M7-A6. Wayne, Pa: National Committee for Clinical Laboratory Standards. 2003. 10. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial susceptibility testing; thirteen informational supplement, M100-S13 (M7). Wanye, Pa: National Committee for Clinical Laboratory Standards. 2003. 11. National Committee for Clinical Laboratory Standards. Performance standards for antimicrobial disk susceptibility tests; approved standard-eighth edition, M2-A8. Wayne, Pa: National Committee for Clinical Laboratory Standards. 2003. 12. Bonapace CR, White RL, Friedrich LV, Bosso JA. Evaluation of antibiotic synergy against Acinetobacter baumannii: a comparison with Etest, time-kill, and checkerboard methods. Diagn Microbiol Infect Dis 2000;38:43-50. 13. Falagas ME and Kasiakou SK. Colistin: the revival of polymyxins
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