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1 대한내과학회지 : 제 72 권제 6 호 2007 Clostridium difficile 연관설사에대한 metronidazole의치료효과 성균관대학교의과대학삼성서울병원감염내과, 진단검사의학과 2, 아시아태평양감염연구재단 3, 계명대학교동산의료원감염내과 4, 제주대학교병원내과 5 정혜숙 김종규 임태규 권기태 류성열 4 허상택 5 고관수 3 오원섭 백경란 이남용 2 송재훈 =Abstract= Therapeutic efficacy of metronidazole for patients with Clostridium difficileassociated diarrhea Hae Suk Cheong, M.D., Jong Kyu Kim, M.D., Tae Kyu Lim, M.D. 1, Ki Tae Kwon, M.D., Seong Yeol Ryu, M.D. 4, Sang Taek Heo, M.D. 5, Kwan Soo Ko, PhD. 3, Won Sup Oh, M.D., Kyong Ran Peck, M.D., Nam Yong Lee, M.D. 2 and Jae Hoon Song, M.D. Division of Infectious Diseases and Department of Laboratory Medicine 2, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; AsianPacific 3 Research Foundation for Infectious Diseases (ARFID), Seoul, Korea; Division of Infectious Diseases 4 and Department of Internal Medicine, Keimyung University, Dongsan Medical Center, Taegu, Korea; and Department of Internal Medicine 5, Cheju National University Hospital, Cheju, Korea Background : The rate of treatment failure with metronidazole for C. difficileassociated diarrhea (CDAD) has been recently increasing in Western countries. A retrospective study was performed to evaluate the clinical outcome of metronidazole treatment and determine the risk factors for treatment failure for patients with CDAD in Korea. Methods : From January 2000 to May 2005, patients who had shown a positive result for C. difficile toxin A assay in feces were considered for the study. Patients who had diarrhea and one or more symptoms of fever, abdominal pain or leukocytosis after 48 hours of hospitalization were included. The medical records of the patients and laboratory data were reviewed. Results : A total of 476 patients (mean age, 56.7 years old) were enrolled in the study. Of these, 382 patients (80.3%) were treated with metronidazole as an initial regimen for CDAD; 316 patients (82.7%) received successful treatment within 14 days, 29 patients (6.3%) had persistent symptoms and signs of colitis and 37 patients (9.7%) had a recurrence of symptoms and signs within 4 weeks after completion of treatment. There were no significant differences in the rates of treatment success for each 5year period (p>0.05). Among 66 patients who failed to respond to an initial course of metronidazole, 48 patients underwent prolonged or additional courses of metronidazole treatment. Of these, 34 patients (70.8%) were successfully treated. By multivariate analysis, severe diarrhea (p=0.02), prior use of fluroquinolones (p=0.02) and enteral tube feeding (p=0.02) were the risk factors for treatment failure of CDAD with metronidazole. Conclusions : Contrary to a recent survey in Western countries, metronidazole is still useful as a primary regimen for the treatment of patients with CDAD in our institution. In CDAD patients with tube feeding, severe diarrhea or the prior use of quinolones, precautions for treatment failure should be taken.(korean J Med 72:639646, 2007) Key Words : Clostridium difficile, Diarrhea, Metronidazole, Fluoroquinolones Received : Accepted : Correspondence to : Won Sup Oh, M.D., Division of infectious disease, Samsung medical center, Sungkyunkwan University School of Medicine, 50 Ilwondong, Gangnamgu, Seoul , Korea wsoh@smc.samsung.co.kr 639

2 The Korean Journal of Medicine : Vol. 72, No. 6, 2007 서론 Clostridium difficile 연관설사 (C. difficileassociated diarrhea, CDAD) 는병원성설사의가장흔한원인으로전체병원성설사의약 15~20% 가 C. difficile 에의하여발생한다 1, 2). CDAD는대부분항생제사용으로인해장내정상세균총이파괴되어오염된주위환경을통하여섭취된 C. difficile 이장내에군집화되면서발생하게된다. 따라서항생제사용량이높거나주위환경이 C. difficile 포자로오염된경우에 CDAD의발생빈도는증가하게된다 3). 1970년대에위막성대장염 (Pseudomen branous colitis, PMC) 이 C. difficile에의한것이라고처음으로밝혀진후반코마이신경구투여가위막성대장염의치료에효과적이라는것이알려졌다 4). 이후에 CDAD에대한반코마이신과메트로니다졸의치료효과를비교한무작위임상연구에서반코마이신과메트로니다졸은각각 88%, 90% 의치료율을보여두약제간에유의한차이가없었지만, 반코마이신내성장구균 (vancomycinresistant Enterococcus) 과같은내성균의출현및약제비의상승등으로인하여현재는메트로니다졸이 CDAD 치료의일차약제로추천되고있다 5. 6). 최근외국연구들에의하면이전에비하여 CDAD에대한메트로니다졸의치료효과가감소하고재발률이증가하고있다 7. 8). CDAD의메트로니다졸치료실패의증가는결국반코마이신의사용을증가시키게되고, 이에연이은항생제내성균의발생은임상적으로심각한문제가아닐수없다. 하지만국내에서 CDAD의치료효과에대한최근연구가없는실정이다. 따라서본연구에서는최근 5년간 1개의대학병원에서 CDAD로진단된환자를대상으로메트로니다졸의임상적치료효과를조사하고메트로니다졸초치료에대한치료실패의위험인자들을분석하고자하였다. 대상및방법본연구는 2000년 1월 1일부터 2005년 5월 31일까지삼성서울병원에서시행한대변검사에서 C. difficile toxin A (Enzymelinked fluorescent immunoassay, VIDAS, BioMerieux, SA, France) 양성인 15세이상의환자를대상으로하였다. 이들환자의의무기록및검사결과를토대로성별, 연령, 기저질환, 2개월이내의수술여부, 경관유동의여부, CDAD 발생 8주전부터의사용된항생제, 환자의활동정도, 설사기간, CDAD에대한치료항생제등을후향적으로조사하였고, CDAD에대한치료를시작후 6주까지임상경과및재발여부를추적하였다. 입원 48시간이후에설사가발생한환자중에서발열, 복통또는백혈구증가가있으면서대변검사상 C. difficile toxin A가양성으로나오는경우에 CDAD로정의하였다. 또한 CDAD에대하여치료를시행한경우에는메트로니다졸 (250 mg 1일 4회또는 500 mg 1일 3회 ) 또는반코마이신 (125 mg 1일 4회또는 250 mg 1일 3회 ) 을 10~14일간경구투여하였다. 경험적항생제투여후 14일이내에설사및동반된증상이호전되는경우를치료성공 (success) 으로정의하였고, 적절한경험적항생제치료에도불구하고설사및동반된증상이지속되거나악화되는경우에치료실패 (treatment failure) 로정의하였다. CDAD에대한치료를종결한후 4주이내에다시발열이나복통또는백혈구증가가동반된설사가다시발생하면서 C. difficile toxin A이양성으로나오는경우를재발 (recurrence) 로정의하였다 10). 면역억제상태 (immunosuppressive status) 는악성종양으로최근 30일이내에항암화학요법을받았거나호중구수가 500 cells/mm 3 미만또는 500 cells/mm 3 이상이지만 48시간이내에 500 cells/mm 3 미만으로감소하리라예상되는경우로정의하였다 10). 설사횟수 (frequency of diarrhea) 는진단당시일일설사횟수가가장높은경우로나타내었고, 이것이설사의중증도를나타낸다고판단하였다 1). 모든자료는 SPSS statistical software package (SPSS 11.5, SPSS Inc, Chicago, USA) 를이용하여분석하였다. 기술적인통계분석을위하여범주형자료의기술은분율의형태로나타내었으며, 연속형자료의분석은평균이나중앙값으로기술하였다. 변수간의비교분석을위해서연속형변수인경우에는 student ttest를시행하였으며, 범주형변수인경우에는 chisquare test 또는 Fishers Exact test를시행하였고, 이를토대로위험인자에대한회귀분석을시행하였다. 분석한자료의통계적인유의성은 p<0.05으로정의하였다. 640

3 Hae Suk Cheong, et al : Clostridiumdifficile associated diarrhea 결과 1. 임상적특성 2000년 1월 1일부터 2005년 5월 31일까지 C. difficile toxin A 양성으로나온환자는모두 525명이었고, 이중에서 CDAD의정의를만족하지않은경우, 연령이 15세미만인경우, 환자의의무기록으로임상양상을추적할수없었던경우등을제외한총 476명을본연구에포함 시켰다. 이중 28명이입원중사망하였다. 사망환자중 2명을제외하고는 CDAD가직접적인사인은아니었다. 그리고사망환자를제외한 39명이 6주까지추적관찰이이루어지지않았다. CDAD로진단된환자들의평균연령은 56.7세이었고남녀비는 242:234이었다 ( 표 1). CDAD로진단될때까지의재원기간의중앙값은 16일이었고, 기저질환으로는악성종양이 236예 (49.6%) 로가장흔하였다. CDAD로진단된 8주이내에항생제를사용하였던경우가 431예 Table 1. Clinical characteristics of patients with C. difficileassociated diarrhea (CDAD) Clinical characteristics No. of patients (%) Age (years, mean±sd * ) Sex (M : F) Hospital stay before onset of CDAD (days, median; range) Underlying conditions Malignancy Chronic renal failure Immunosuppressive status Recent ( 2 months) operation Enteric tube feeding Prior use of antimicrobial agents Penicillins 1 st generation cephalosporins 2 nd generation cephalosporins 3 rd generation cephalosporins 4 th generation cephalosporins Carbapenems Fluoroquinolones Aminoglycosides Glycopeptides Metronidazole Clindamycin Others Clinical or laboratory findings Fever (oral temperature >38 ) Abdominal pain Leukocytosis (white cell count > 10,000 cells/ìl) Frequency of diarrhea (times/day) Duration of diarrhea (days, median ; range) * SD, standard deviation This denoted the maximal occurrences of diarrhea per day before diagnosis of CDAD This denoted the duration of diarrhea before the diagnosis of CDAD 56.7± : (2~922) 236 (49.6) 56 (11.8) 162 (34) 137 (28.5) 119 (24.8) 431 (90.5) 68 (18.3) 28 (5.8) 36 (7.5) 205 (45.7) 72 (15) 71 (14.9) 129 (27.1) 64 (13.4) 129 (27.1) 41 (8.5) 41 (8.5) 84 (19.5) 196 (41.2) 73 (15.3) 149 (35.1) 4.7±4.0 3 (1~25) 641

4 대한내과학회지 : 제 72 권제 6 호통권제 562 호 2007 (90.5%) 이었고, 이중에서세팔로스포린계항생제가 71.6% 로가장사용빈도가높았고, 그다음으로퀴놀론계항생제 (27.1%) 이었다. 세팔로스포린계항생제중에서도 3세대세팔로스포린이 205예 (45.7%) 로가장많이사용되었으며, 그뒤로 4세대세팔로스포린 (15%) 이었다. 또한전체 476명의환자중 57.1% 에서 2개이상의항생제가동시에사용되었다. 임상양상중에서설사를제외하고발열이 196예 (41.2%) 로가장흔하였다. 2. 치료효과전체 476명의환자중에서 CDAD에대한초치료로메트로니다졸을투여한경우가 382예 (80.3%), 반코마이신을투여한경우는 9예 (1.9%), 메트로니다졸과반코마이신을병합투여한경우는 3예 (0.6%) 이었고, 나머지 82 예 (17.2%) 에는항생제를투여하지않았다. 메트로니다졸초치료군 382예중에서치료성공은 316예 (82.7%), 치료실패는 66예 (17.3%) 이었다. 반코마이신초치료군 9예중치료성공은 7예 (77.8%), 치료실패는 2예 (22.2%) 이었고재발은없었다. 메트로니다졸과반코마이신동시에병합투여한 3예는모두치료성공을나타내었다. CDAD에대한초치료로서메트로니다졸과반코마이신의치료효과는통계학적으로유의한차이를보이지않았다 (p=0.659) ( 표 2). 메트로니다졸초치료에대한치료성공률은 2000년에 82.8%, 2001년에 83.7%, 2002년에 84.3%, 2003년에 76.9%, 2004년에 86.1%, 2005년에 88.9% 이었고, 이들치료성공률은발생연도에따라서통계학적으로유의한차이를보이지않았다 (p=0.755). CDAD의초치료실패와재발한군을비반응군으로정의하였고, 비반응군 66예중에서재치료로메트로니다졸을투여한경우가 48예 (70.6%), 반코마이신을투여한경우는 11예 (16.2%), 메트로니다졸과반코마이신을병합투여한경우는 1예 (1.5%) 이었고, 나머지 8예 (11.7%) 에는항생제를투여하지않았다. 메트로니다졸초치료비반응군 66예중에서 48예 (72.7%) 는초치료와동일한방법으로메트로니다졸로재치료를시행하였는데, 이중에서치료성공은 34예 (70.8%), 치료실패는 4예 (8.4%) 그리고재발이 10예 (20.8%) 이었다. 그러한반면반코마이신재치료군은 90.9% 의치료성공률을나타내었다. 메트로니다졸초치료실패군에있어메트로니다졸과반코마이신의치료성공률은 70.8% 와 90.9% 로높은차이가있었지만, 통계학적으로는유의한차이를보이지않았다 (p=0.070). 하지만메트로니다졸초치료의치료성공율에비하여메트로니다졸재치료의치료성공율은통계학적으로유의하게낮았다 (p=0.005). CDAD 진단시에초치료로메트로니다졸과반코마이신으로치료하지않았던 82예중에 8예는사용항생제를중지하였고, 2예는다른항생제로약제를변경하였다. 이들중에서 79예 (96.3%) 가증상호전을보였고, 2예는증상호전을보였다가 4주이내증상이악화되었고, 1예는 2주이상증상호전을보이지않다가결국메트로니다졸로치료하여증상이호전되었다. 3. 메트로니다졸초치료비반응군에대한위험인자분석메트로니다졸치료실패에대한위험인자를조사하기 Table 2. Clinical outcomes of CDAD patients treated with primary or rescue therapy Antimicrobial regimens (n) Primary therapy (394) Metronidazole (382) Vancomycin (9) Metronidazole + vancomycin (3) No. of patients (%) Success Treatment failure Recurrence 316 (82.7) 29 (6.3) 37 (9.7) 7 (77.8) 2 (22.2) 0 (0.0) 3 (100.0) 0 (0.0) 0 (0.0) Rescue therapy * (66) Metronidazole (48) Vancomycin (11) Metronidazole + vancomycin (1) 34 (70.8) 10 (90.9) 1 (100) 4 (8.4) 0 (0) 0 (0) 10 (20.8) 1 (8.9) 0 (0) * In the group with initial metronidazole therapy, patients who had a treatment failure or recurrence 642

5 정혜숙외 10 인 : Clostridiumdifficile 연관설사 위한단변량분석에서는경관유동식 (p=0.006), bedridden 상태 (p=0.001), 이전에퀴놀론계항생제의사용 (p=0.002) 및하루당설사횟수 (p=0.42) 가메트로니다졸치료실패에대하여유의하게관련이있는것으로나타났다 ( 표 3). 이에대하여다시시행한다변량분석에서는경관유동식 (OR, 1.979; 95% CI, ; p=0.018), 이전퀴놀론계항생제의사용 (OR, 1.953; 95% CI ; p=0.019) 및설사횟수 (OR, 1.069; 95% CI ; p=0.022) 가치료실패와유의하게연관이있는것으로나타났다. 고찰 C. difficile은혐기성그람양성연쇄균으로 1935년에처음으로동정되었고, 1974년에 Tedesco 등에의해클린다마이신사용에의한위막성대장염의원인으로밝혀졌으며, 현재는항생제연관장염 (antibioticsassociated diarrhea) 의 15~25% 를차지하고있는중요한원내병원균이다 1214). 현재까지 CDAD에대해서메트로니다졸과반코마이신은효과적인치료제로알려져있다 15, 16). 그러나최근외국의연구결과에따르면기존의알려진 바와는다르게 CDAD의일차항생제로알려진메트로니다졸의치료효과가예전보다좋지않다는결과들이보고되고있다. Nair 등은 36명의 CDAD로진단된환자를메트로니다졸로치료한결과 22% 에해당하는환자에서치료에반응하지않고 19% 에해당하는환자에서치료를끝낸시점에서 3개월이내에재발하였다고보고하였다 8). 또한 Daniel 등은 CDAD로진단된 207명의환자들을메트로니다졸로치료한결과 50% 의환자에서치료반응을, 보였고 22% 의환자는치료에도불구하고 10일이상증상이지속되었고, 28% 의환자에서치료종결후 3 개월이내에재발하였다고보고하였다 7). 메트로니다졸의치료효과가떨어지는이유로는과거에비해병원에입원하는환자들의고령화와기저질환의중증도가증가하고있으며, 새로운세팔로스포린또는퀴놀론과같은광범위항생제사용의증가에기인한다고추정하고있다 1719). 실제로본연구에서도 CDAD 환자들의평균연령이 61 세로비교적높게나타났으며, CDAD의발생이전에사용하였던항생제중에서세팔로스포린계항생제가많이사용되었고, 그중에서특히 3세대이상의세팔로스포린계항생제가더많이사용되었음을알수있었다. 하지 Table 3. Comparison of clinical and laboratory findings between treatment success group and treatment failure group Characteristics Response group * (%) (N=316) 54.6± (28.5) 83 (26.3) 68 (21.6) 66 (20.9) 170 (53.8) 78 (24.7) 32 (10.1) 4.5±4.1 No. of patients Nonresponse group (%) (N=66) 57.7± (39.4) 24 (33.3) 28 (42.4) 25 (47.9) 31 (47.0) 28 (47.0) 6 (9.1) 5.6±3.2 Univariate analysis pvalue Multivariate analysis Odds ratio (95% CI) pvalue Age (years) Prior hospital stay > 28 days Recent operation (< 2 month) Bedridden state Enteral tube feeding Prior use of 3 rd generation cephalosporins Prior use of fluoroquinolones Prior use of clindamycin Frequency of diarrhea (occurrences/day) ( ) 2.0 ( ) 1.1 ( ) (per 1 times increment) * Response group denoted a group of treatment success Nonresponse group included a group of treatement failure and recurrence pvalue calculated using the student ttest or χ 2 test pvalue calculated using logistic regression. Variables with a p value of <0.05 in the univariate analysis were candidates for multivariate analysis. We excluded overlap data (i.e., enteral tube feeding including a bedridden state) from this analysis. 643

6 The Korean Journal of Medicine : Vol. 72, No. 6, 2007 만본연구에서 CDAD로진단된환자에대해서메트로니다졸을사용한경우치료성공률은 84% 로이는최근서구에서보고된것보다는좋은결과를보였다. 하지만이는초기에보고되었던성공률보다는떨어지는수치로향후이에대한추적관찰은아주중요할것으로보여진다. CDAD의치료실패또는재발에관련된위험인자로여성, 만성신부전, 최근의복부수술, 지속적인항생제의노출그리고기저질환의중증도등으로알려져있다 14, 20). 본연구에서단변량분석에서는치료실패나재발의위험인자로경관영양의여부, bedridden 상태, 이전에퀴놀론계항생제의사용및설사지속기간이긴경우로나타났지만, 다변량분석에서는경관유동식, 이전에퀴놀론계항생제의사용그리고설사횟수가의미있는위험인자로나타났다. 이중에서퀴놀론계항생제가 CDAD에미치는영향에관한보고들이최근에증가하고있다. 퀴놀론계항생제와 CDAD 치료실패와의연관성에대한대한연구들로서 Pepin 등에따르면 CDAD가발생한 293명의환자에대한코호트연구에서퀴놀론계항생제의사용이 CDAD 발생의가장중요한위험인자로나타났고, Loo 등은높은이환율과사망률을보인 CDAD의발병에퀴놀론계항생제에내성을보인 C. difficile 이주요역할을하며퀴놀론계항생제의사용이 CDAD 발생의위험인자라고보고하고있으며, Yip 등도 CDAD의가장강력한위험인자로퀴놀론계항생제를지적하였다 2123). 이는세팔로스포린계항생제나클린다마이신이 CDAD에발생에주요원인이라고알려져있던기존의연구결과와는상이하다 22). 일반적으로장내정상세균총은 C. difficile 감염에대해서보호능력이있다. 그러나 ciprofloxacin 등과같은경구용퀴놀론계항생제는많은종류의장내세균에대해살균력이있고대변내에높은농도로존재하기때문에 C. difficile에상대적으로감수성이떨어지는것을볼수있었다. 특히, moxifloxacin 이나 gatifloxacin 과같은혐기성세균에효과가있는퀴놀론계항생제의경우장내정상세균총의증식을강력하게억제하므로 CDAD의발생을더높이게된다고한다 19, 23, 24). 위중 Gaynes 등은장기요양원에서 levofloxacin에서 gatifloxacin 으로사용항생제를바꾼후 CDAD의증가가많아져다시 levofloxacin으로항생제를바꾼뒤 CDAD의발생이감소하였다는보고를하였다. 퀴놀론계항생제는광범위항균작용을가지 고있으며경구생체이용률 (oral bioavailability) 이뛰어나서현재임상에서많이사용되어지고있지만, 이들항생제가다른항생제에비하여 CDAD의발생을증가시킬뿐만아니라 CDAD의치료실패의위험성도높이므로이들항생제의사용을엄격히제한할필요가있다고사료된다 18). 이전항생제의사용이 CDAD의중요한위험인자이다 1, 2, 20, 25). 따라서 CDAD의일반적인치료원칙은가능한원인이되는항생제를중단하는것이다 26). 하지만본연구에서발열을동반한호중구감수증, 패혈증, 폐렴등과같이원인항생제를중단하기어려운경우가많아서메트로니다졸이나경구반코마이신을추가하는경우가매우많았다. 또한본연구에서전체환자의 90.5% 의환자에서발병 8주이내에항생제를사용하였던과거력이있었다. 이와같은사실로볼때 CDAD의발병을줄이기위해서는불필요한항생제의사용을억제하는것이매우중요할것으로생각된다. 이와병행하여 CDAD의전파를억제하는것이중요한데, 이를위해 CDAD 환자의격리, 장갑착용, 손씻기, 주변환경의위생등이필요하다. C. difficile 포자는환경에서수개월간생존가능하며비교적알코올이나다른항균제에대해서도저항성이있어, CDAD의발생기간동안에는진찰시장갑을착용하고, 장갑을벗어낸후에는물과비누로손을씻는것이권고되고있다 20). 비록본연구가한개의국내의료기관에서후향적으로진행한연구이고, C. difficile에대한항생제감수성검사를시행하지않았기때문에실제로항생제내성이치료실패에작용하였는지의여부를확인할수없었지만최근서구에서의연구결과와는달리본원에서의 CDAD 의치료에메트로니다졸은아직까지효과적인것으로나타났다. 또한경관유동, 이전에퀴놀론계항생제의사용, 설사횟수가많을수록 CDAD에대한치료실패율이 증가한다. 하지만향후 CDAD의치료효과에대해국내의다기관전향적인연구가필요하며, C. difficile에대한항생제감수성검사와치료반응과관계그리고실제 CDAD의발생과관계가있다고알려진 binary toxin 과관련된유전자에대한연구도필요할것으로사료된다. 요약목적 : 본연구는국내에서 CDAD에대한메트로니 644

7 Hae Suk Cheong, et al : Clostridiumdifficile associated diarrhea 다졸초치료의치료효과를조사하고, CDAD의치료실패및재발에관련된위험인자를분석하고자하였다. 방법 : 2000년 1월 1일부터 2005년 5월 31일까지대변검사상 C. difficile toxin A 양성인 15세이상의성인환자를대상으로의무기록및검사결과를후향적으로분석하였다. 결과 : 총 476예가연구에포함되었고, 대상환자의평균나이는 56.7세였으며남녀간의차이는보이지않았다. 이중에서 382예 (80.3%) 는초치료로메트로니다졸을사용하였고, 9예 (1.9%) 는반코마이신을사용하였다. 메트로니다졸초치료군 382예중에서 316예 (82.7%) 는치료성공, 29예 (6.3%) 는치료실패그리고 37예 (9.7%) 는재발을보였고, 이러한치료성공률은발생연도에따라서통계학적으로유의한차이를보이지않았다. 그리고경관영양, 이전에퀴놀론계항생제의사용및설사횟수가메트로니다졸초치료에대한치료실패에유의한연관성이있는것으로나타났다. 결론 : 서구의경우와는달리본원에서 CDAD의치료에있어서메트로니다졸이아직까지효과적이지만이에대한지속적인감시가필요할것으로사료된다. 또한경관유동, 이전에퀴놀론계항생제의사용, 설사횟수가많을수록 CDAD에대한메트로니다졸초치료의치료실패율이높아진다. 중심단어 : Clostridium difficile, 설사, 메트로니다졸, 퀴놀론계 REFERENCES 1) Gerding DN, Olson MM, Peterson LR, Teasley DG, Gebhard RL, Schwartz ML, Lee JT Jr. Clostridium difficileassociated diarrhea and colitis in adults: a prospective casecontrolled epidemiologic study. Arch Intern Med 146:95100, ) Kelly CP, LaMont JT. Clostridium difficile infection. Annu Rev Med 49:375390, ) Morris AM, Jobe BA, Stoney M, Sheppard BC, Deveney CW, Deveney KE. Clostridium difficile colitis: an increasingly aggressive iatrogenic disease? Arch Surg 137: , ) Keighley MR, Burdon DW, Arabi Y, Williams JA, Thompson H, Youngs D, Johnson M, Bentley S, George RH, Mogg GA. Randomised controlled trial of vancomycin for pseudomembranous colitis and postoperative diarrhoea. Br Med J 2: , ) Dever LL, Smith SM, Handwerger S, Eng RH. Vancomycindependent Enterococcus faecium isolated from stool following oral vancomycin therapy. J Clin Microbiol 33: , ) Teasley DG, Gerding DN, Olson MM, Peterson LR, Gebhard RL, Schwartz MJ, Lee JT Jr. Prospective randomised trial of metronidazole versus vancomycin for Clostridiumdifficileassociated diarrhoea and colitis. Lancet 2: , ) Musher DM, Aslam S, Logan N, Nallacheru S, Bhaila I, Borchert F, Hamill RJ. Relatively poor outcome after treatment of Clostridium difficile colitis with metronidazole. Clin Infect Dis 40: , ) Nair S, Yadav D, Corpuz M, Pitchumoni CS. Clostridium difficile colitis: factors influencing treatment failure and relapse: a prospective evaluation. Am J Gastroenterol 93: , ) Gorschluter M, Glasmacher A, Hahn C, Schakowski F, Ziske C, Molitor E, Marklein G, Sauerbruch T, SchmidtWolf IG. Clostridium difficile infection in patients with neutropenia. Clin Infect Dis 33:786791, ) Hughes WT, Armstrong D, Bodey GP, Bow EJ, Brown AE, Calandra T, Feld R, Pizzo PA, Rolston KV, Shenep JL, Young LS guidelines for the use of antimicrobial agents in neutropenic patients with cancer. Clin Infect Dis 34:730751, ) Gilbert DN, Moellering RC, Eliopoulos GM, Sande MA. The sanford guide to antimicrobial therapy th ed. p. 13, ) Barbut F, Corthier G, Charpak Y, Cerf M, Monteil H, Fosse T, Trevoux A, de Barbeyrac B, Boussougant Y, Tigaud S, Tytgat F, Sedallian A, Duborgel S, Collignon A, le Guern ME, Bernasconi P, Petit JC. Prevalence and pathogenicity of Clostridium difficile in hospitalized patients. Arch Intern Med 156: , ) Bartlett JG. Clostridium difficile: history of its role as an enteric pathogen and the current state of knowledge about the organism. Clin Infect Dis 18(Suppl 4):S265S272, ) Oldfield EC 3rd. Clostridium difficileassociated diarrhea: risk factors, diagnostic methods, and treatment. Rev Gastroenterol Disord 4:186195, ) Fekety R. Guidelines for the diagnosis and management of Clostridium difficileassociated diarrhea and colitis. Am J Gastroenterol 92:739750, ) Wilcox MH. Treatment of Clostridium difficile infection. J Antimicrob Chemother 41(Suppl C):41 46, ) Gerding DN. Clindamycin, cephalosporins, fluoroqu 645

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012임수진

012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar