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1 다제내성 A. baumannii 에의한병원획득폐렴에서 Colistin 분무치료의시도 한림대학교의과대학 1 내과학교실, 2 흉부외과학교실 김창환 1, 김동규 1, 강혜련 1, 최정희 1, 이창률 1, 황용일 1, 신태림 1, 박상면 1, 박용범 1, 이재영 1, 장승훈 1, 김철홍 1, 모은경 1, 이명구 1, 현인규 1, 정기석 1, 최영진 1, 이재웅 2 A Trial of Aerosolized Colistin for the Treatment of Nosocomial Pneumonia due to Multidrug-resistant Acinetobacter baumannii Changhwan Kim, M.D. 1, Dong-Gyu Kim, M.D. 1, Hye-Ryun Kang, M.D. 1, Jeong-Hee Choi, M.D. 1, Chang Youl Lee, M.D. 1, Yong Il Hwang, M.D. 1, Tae Rim Shin, M.D. 1, Sang Myeon Park, M.D. 1, Yong Bum Park, M.D. 1, Jae Young Lee, M.D. 1, Seung Hun Jang, M.D. 1, Cheol Hong Kim, M.D. 1, Eun Kyung Mo, M.D. 1, Myung Goo Lee, M.D. 1, In-Gyu Hyun, M.D. 1, Ki-Suck Jung, M.D. 1, Young-Jin Choi, M.D. 1, Jae Woong Lee, M.D. 2 Departments of 1 Internal Medicine, and 2 Thoracic & Cardiovascular Surgery, Hallym University College of Medicine, Chuncheon, Korea Background: Recently, multidrug-resistant (MDR) A. baumannii has been implicated for a significant proportion of nosocominal pneumonia in many intensive care units (ICUs), and its acquisition may increase mortality and the length of stay in the ICU. Aerosolized colistin has been successfully used in patients with cystic fibrosis, but there is a lack of data regarding the use of aerosolized colistin in patients with nosocomial pneumonia. Methods: We conducted the present study to assess the effectiveness of aerosolized colistin for the treatment of MDR A. baumannii nosocomial pneumonia. We retrospectively reviewed the medical records of 10 patients who had been hospitalized in the medical ICU and had received aerosolized colistin as a therapy for MDR A. baumannii pneumonia. Results: The mean duration of aerosolized colistin therapy was 12.7±2.4 days. Nine (90%) of 10 patients showed a favorable response to the therapy. Follow-up cultures were available for all patients, and the responsible pathogen was completely eradicated. One patient suffered from bronchospasm, which resolved after treatment with nebulized salbutamol. Conclusion: Our results corroborate previous reports that aerosolized colistin may be an effective and safe choice for the treatment of nosocomial pneumonia caused by MDR A. baumannii. Larger prospective controlled clinical studies are warranted to validate further the effectiveness and safety of aerosolized colistin therapy. (Tuberc Respir Dis 2008;64: ) Key Words: Acinetobacter baumannii, Aerosolized colistin, Nosocomial pneumonia 서 Acinetobacter baumannii는병원내환경에널리분포하는그람음성구간균으로, Pseudomonas aeruginosa에비 Address for correspondence: Dong-Gyu Kim, M.D. Division of Pulmonary, Allergy & Critical Care Medicine, Hallym University Sacred Heart Hospital, 896, Pyeongchondong, Dongan-gu, Anyang , Korea Phone: , Fax: dongyu@hallym.ac.kr Received: Jan. 5, 2008 Accepted: Jan. 29, 2008 론 해병독성이높지않음에도불구하고흔히사용하는항생제에대한내성이증가하고있어문제가되는병원균이다 1,2. 또한 A. baumannii 는병원내환경에서장기간생존할수있어인공호흡기등을비롯한병원내기구를오염시킬수있으므로감염이쉽게전파되고지속되는특징이있다 년 Carbapenem 내성 A. baumannii의병원내유행이처음으로보고된이후세계여러나라에서발생의빈도가증가하고있으며 4, 본원에서도지난수년간중환자실에서발생한병원획득폐렴에서다제내성 A. baumannii의분리율이지속적으로증가하고있는실정이다. 102

2 Tuberculosis and Respiratory Diseases Vol. 64. No. 2, Feb 이러한다제내성 A. baumannii 감염은기계환기치료를받고있는중환자실환자에서기관기관지염또는폐렴의발생을유발하여기계환기이탈및발관을지연시키는상황을초래하기도한다. 일부보고에서도중환자실환자의 A. baumannii 감염의획득이중환자실재원기간및사망률을증가시킨다는것을입증한바있다 5-7. 이들다제내성 A. baumannii 감염증의치료를위해지난수년간여러시도들이있었으며, ampicillin/sulbactam 이나 doxycycline, colistin 등의항균제가치료의옵션으로제시되어왔다 8. 하지만 A. baumannii를포함한그람음성균중에는다른모든약제가효과적이지않고오로지 colistin만이작용하는경우가있으며, colistin에대한내성균주는거의발생하지않는다는점에서새롭게주목받고있다 9. Colistin 은폴리펩티드계항생제인 polymyxin E로 1960 년대에처음으로임상에사용된후신독성등의부작용문제로 1970년대다른항생제로대치되었으나, 다제내성 P. aeruginosa와 A. baumannii 등에의한감염증이증가하면서이들에대한새로운치료로 polymyxin B와 colistin이다시주목받기시작하였다 10,11. Colistin 분무치료는낭성섬유증환자에서광범위하고지속적인연구가이루어지고있으나 12-15, 병원획득폐렴에대한치료경험은매우희박하다 이에본연구는한대학병원중환자실에서발생한다제내성 A. baumannii에의한병원획득폐렴에서 colistin 분무치료의적용가능성을평가해보고자하였다. 대상및방법 1. 대상환자 2007 년 4월 1일부터 2007 년 11월 30일까지총 8개월간한림대학교성심병원내과계중환자실에서다제내성 A. baumannii에의한병원획득폐렴의발생이확인된환자들중 colistin 분무치료를시행한환자를대상으로후향적분석을하였다. 총 11명의병원획득폐렴환자에서 colistin 분무치료가시행되었으며, 그중 1명은치료 2일째감염증과무관한이유로사망하여분석에서제외되었다. 다음의세가지조건을만족하는경우다제내성 A. baumannii에의한병원획득폐렴으로정의하였다 21. 1) 임상적으로감염을시사하는소견이동반되는경우 : 이상체온 (>38 o C 또는 <36 o C), 화농성객담의증가, 백혈구증다증 (>10,000/mm 3 ) 또는감소증 (<4,000/mm 3 ) 2) 흉부단순촬영에서새로운침윤의발생또는기존침윤의진행이의심되고흉부 CT 에서폐렴병소가확인되는경우 3) 병변부위에서얻은기관지폐포세척액배양에서상기균주의집락수가 10 4 CFU/ml 이상인경우 2. 방법대상환자에대해성별과연령, 중환자실재원기간및총입원기간, 중환자실입실후기도분비물에서다제내성 A. baumannii가처음으로분리되기까지의시간, 치료종료후시행한객담배양검사에서동정된균주, 중환자실입실시상병, 동반질환, colistin 분무치료에대한반응및부작용, 치료시병용한항생제, 그리고치료후경과등을조사하였다. Colistin 분무치료에이용한약제는콜리스티메테이트주 (Colistimethate for injection U.S.P., SteriMax, Mississauga, Canada) 였으며, mg (12,500 units per milligram) 의용량을증류수 4 6 cc에혼합하여하루 3 회 8시간간격으로투여하였다. 매번 colistin 이투여되기전에 salbutamol 과 ipratropium bromide 분무를먼저시행하였다. 3. 치료반응의판정및부작용의판정치료에대한반응은다음의세경우로구분하여판정하였다 16,22. 1) 호전 (improvement): 기도분비물의양감소및양상의호전, 흉부단순촬영또는흉부 CT에서폐렴병변의감소또는소실, 그리고백혈구증다증과 CRP 상승의호전을보이는경우 2) 완치 (cure): 호전의조건을만족하며, 체온이정상화되고자발호흡회복되어중환자실에서벗어나는경우 3) 악화 (deterioration): 호전이나완치에포함되지않는경우정상신기능은혈청크레아니틴농도 1.3 mg/dl 이하로정의하였고, colistin 치료에의한신독성은혈청크레아티닌농도가치료시작전과비교하여 50% 이상상승하여 1.3 mg/dl 를초과하거나신대체요법을필요로하는신기능저하가발생한경우로정의하였다 23. 한편천명음을동반한호흡음의증가가 colistin 분무치료중또는치료후 30분이내에새롭게발생한경우 colistin 치료에의한기관지연축으로정의하였다

3 CH Kim et al: Aerosolized colistin for the treatment of MDR A. baumannii pneumonia 결과 1. 대상환자의특성분석대상환자총 10명의평균연령은 61.8±15.5 세였으며, 남녀비는 6:4였다. 중환자실입실시상병은폐렴에의한급성호흡부전증후군이 4명으로가장많았으며, 폐결핵이 3명, 중증지역사회획득폐렴이 2명, 그리고흡인성폐렴이 1명으로, 모두감염성폐질환으로인해기관삽관후인공호흡기치료를받은환자였다. 입실당시및입실후치료경과에서동반된질환은 Table 1과같다. 환자들의평균중환자실재원기간은 68.4±31.3 일, 평균총입원기간은 94.3±44.4 일로매우길었고, 중환자실입실후기도분비물에서다제내성 A. baumannii가처음으로확인되기까지의시간은평균 10.8±8.4 일로, 2주이내에 80% 의환자에서균이분리되었다. 메티실린내성황색포도상구균객담에서함께분리되거나복강내감염증 과같은동반질환으로인해 glycopeptides, carbapenem 등의광범위항균제를함께사용한환자가 6명이었고, 1 명에서는거대세포바이러스폐렴의치료만병행하였으며, 나머지 3명의폐결핵환자에서는항결핵제만병용투여하였다 (Table 1). 2. 치료에대한반응및부작용 Colistin 분무치료기간은평균 12.7±2.4일이었다. 치료종료후시행한객담배양검사에서다제내성 A. baumannii가지속적으로분리된환자는한명도없었다. 치료결과 10명의대상환자중 5명의환자에서호전, 4명의환자에서완치를보여총 9명 (90.0%) 의환자에서효과적인반응을나타내었다. 사망한환자는총 4명으로, 그중 2명은복강내감염증의악화가원인이었으며, 나머지 2명은메티실린내성황색포도상구균에의한폐렴으로사망하였다. 치료에대한반응을악화로판정하였던환자 1명 Table 1. Demographic and clinical characteristics of patients No. Sex Age Diagnosis at ICU admission Comorbidities ICU stay* Hospital Isolation stay days IV antibiotics 1 M 71 Pneumonia, ARDS CMV pneumonia Ganciclovir 2 F 50 Pneumonia, ARDS Intestinal obstruction, Spontaneous Tazocin, Aztreonam pneumothorax 3 M 71 Aspiration pneumonia CBD & colon cancer, Intraabdominal Teicoplanin, Imipenem abscess, ARF, Drug induced eosinophilic pneumonia 4 F 82 Pulmonary TB DM, ARF, acalculous cholecystitis, Antituberculous agents Renal tubular acidosis, Toxic hepatitis, Sacral sore, Dementia 5 F 65 Pulmonary TB DM, Toxic hepatitis, Dermatomyositis, Antituberculous agents Sacral sore 6 M 52 Pneumonia, ARDS DM, ARF, Alcoholic liver disease Teicoplanin, Metronidazole 7 F 70 Pulmonary TB Interstitial lung disease, DM, CIP Antituberculous agents 8 M 38 Severe CAP End stage renal disease, Ganciclovir, Teicoplanin, CMV pneumonia, CIP Meropenem, Moxifloxacin 9 M 78 Severe CAP COPD, Liver cirrhosis, CRF, Teicoplanin, Heart failure, Atrial fibrillation meropenem 10 M 41 Pneumonia, ARDS Small bowel perforation, Peritonitis, Teicoplanin, Dieulafoy's ulcer meropenem AVR ICU: Intensive Care Unit; IV: Intravenous; ARDS: Acute Respiratory Distress Syndrome; CMV: Cytomegalovirus; CBD: Common Bile Duct; ARF: Acute Renal Failure; TB: Tuberculosis; DM: Diabetes Mellitus; CIP: Critical Illness Polyneuropathy; CAP: Community- Acquired Pneumonia; COPD: Chronic Obstructive Pulmonary Disease; CRF: Chronic Renal Failure; AVR: Average. *Duration of ICU stay (days), Duration of hospitalization (days), Time from ICU admission to first isolation of A. baumannii from tracheal secretions of patients (days), Concomitant intravenous antibiotic treatment with aerosolized colistin. 104

4 Table 2. Clinical outcomes of patients treated with aerosolized colistin Tuberculosis and Respiratory Diseases Vol. 64. No. 2, Feb No. Sex Age Treatment days* Dosage Follow-up culture Outcome Clinical course Adverse effect 1 M mg 8 hrs Pseudomonas aeruginosa Cure Discharge 2 F mg 8 hrs Stenotrophomonas maltophilia Cure Discharge 3 M mg 8 hrs No bacteria Cure Death (Intraabdominal infection) 4 F mg 8 hrs No bacteria Improvement Discharge 5 F mg 8 hrs No bacteria Cure Discharge 6 M mg 8 hrs Pseudomonas aeruginosa Improvement Death (MRSA pneumonia) 7 F mg 8 hrs Stenotrophomonas maltophilia Improvement Hospitalization Bronchospasm 8 M mg 8 hrs No bacteria Improvement Hospitalization 9 M mg 8 hrs MRSA Deterioration Death (MRSA pneumonia) 10 M mg 8 hrs No bacteria Improvement Death (Intraabdominal infection) AVR 12.7 *Duration of aerosolized colistin (days), Dosage of aerosolized colistin per day, Posttreatment isolated organism from tracheal secretions of patients, She was transferred to the ICU of another hospital, so her clinical outcome was classified as improvement. 은 colistin 분무치료를시행하던중메티실린내성황색포도상구균폐렴에중복감염되어 colistin 분무치료의효과는불분명하였다 (Table 2). Colistin 분무치료시 1명의환자에서기관지연축이발생하였으나기관지확장제치료후호전되었고, 이후 colistin 분무용량을감량하여투여한결과더이상의연축은없었다. 그외에 colistin 정주시에나타날수있는신독성등의다른부작용은관찰되지않았다 (Table 2). 고찰앞서언급한바대로다제내성그람음성균에의한병원획득감염증의치료에 colistin이다시사용되기시작하였고비교적좋은치료성과를나타내고있으나, 정주투여시신독성의부작용이여전히문제가되고있다. 60명의다제내성 P. aeruginosa와 A. baumannii에의한병원획득감염증환자에대해 colistin 정주치료를시도한한연구에서치료전정상신기능이었던환자의 27% 에서신부전이발생하였고 25, 또다른최근의한연구에서신독성발생률은 14.3% 이며 colistin 누적용량과혈청크레아티닌농도간에유의한연관관계가있음을보고하였다 26,27. 일부연구에서는효과적인살균작용을기대할수있는항생제의농도는최저억제농도의 25배, 최소한 10배이상 이되어야한다고제안하였으며 28, 또다른연구에서는항생제정주시객담내항생제농도가혈청최고농도의약 12% 에불과하다고보고하였다 29. 또한 polymyxin 항균제의낮은폐내분포가다제내성그람음성균에의한폐렴을치료할때실패의원인이될수있다는보고도있었다 30. 이런내용들을종합해보면약물의체내흡수를최소화하여약물독성의부작용에대한부담을줄이면서기도내항생제농도를높일수있다는점이분무투여를시도하는이론적배경이될수있겠다 31. Colistin 분무치료시적절한용량과투여간격에대해서는그근거가충분치않지만최근한연구에서낭성섬유증환자 30명을대상으로 colistin 2백만단위분무치료후객담, 혈청및소변내농도를측정한결과, 분무 1시간후객담내농도가최고에도달하였고최소 8시간이상높은농도가유지된다고보고하였다 32. 다제내성그람음성균에의한병원획득폐렴에서의 colistin 분무치료에대한문헌조사결과총 5개의논문이확인되었다 년 Hamer는다제내성 P. aeruginosa에의한병원획득폐렴 3예에서처음으로 colistin 분무치료를보조적으로사용하였고 20, 2004 년 Michalopoulos 등은다제내성 A. baumannii와 P. aeruginosa에의한병원획득폐렴환자 8명에서역시정주용항생제에대한보조치료로 colistin 분무치료를시행하였으며 7명에서효과적인반응 105

5 CH Kim et al: Aerosolized colistin for the treatment of MDR A. baumannii pneumonia 을나타냈다 년 Berlana 등의보고에서는다제내성 A. baumannii 폐렴환자 33명의환자에서 colistin 분무치료를단독또는보조요법으로사용해모든환자에서세균학적반응을확인하여정주치료에비해분무치료시높은 A. baumannii 박멸률을보여주었다 18,25, 년 Kwa 등도주로다제내성 A. baumannii에감염된 21명의환자에서보조적인 colistin 분무치료를통해 85.7% 에서효과적인반응을확인하였으나 1명에서기관지연축의부작용이관찰되었다 17. Pereira 등은주로 P. aeruginosa에의해폐렴이발생한 19명의환자를대상으로 polymyxin B를이용해단독또는보조요법으로분무치료를시행하였으며, 95% 에서완치또는호전을보였다 16. 본연구의결과와마찬가지로문헌고찰에서도 colistin 분무치료시의부작용은소수의환자에서기관지연축이나타났던것외에는특별한것이없었다. Colistin 분무치료시의기관지연축에관한연구는모두낭성섬유증환자를대상으로주로소아에서이루어져본연구의대상환자에적용하기는어렵겠지만, 대부분의경우에서 15분이내에 10% 미만의 1초간노력성호기량의감소를가져오나드물게 30분간지속되기도하였으며 24, 천식이동반된환자에서기관지연축이보다잘유발될수있음을시사하는결과도찾아볼수있었다 33. 분무용액의삼투압에따른 1 초간노력성호기량의감소에는차이가없었으나고장액일수록보다빠르게 1초간노력성호기량의감소를보이는것으로나타났으며, 분무치료전기관지확장제흡입을통한예방을시행하는것이권고되기도하였다 34. 본연구의결과와문헌고찰결과를종합해보면, 다제내성 A. baumannii에의한병원획득폐렴의치료에있어서 colistin 1 2백만단위를 8 12시간간격으로분무투여하는것은매우효과적일가능성이있으며, 치료를중단할만한부작용은드물다고하겠다. 향후전향적인방법의환자대조군연구를통하여다제내성그람음성균에의한병원획득폐렴에서의 colistin 분무치료의효과를평가하는것이필요하다고판단되며, 보조치료가아닌단독치료로서의가능성도평가대상으로함께고려해야할것이다. 요약연구배경 : 최근다제내성 A. baumannii에의한폐렴이중환자실환자에서매우빈번하게발생하고있으며, 이탈지연, 중환자실재원기간및사망률의증가가초래되기도한다. 수년전부터 colistin 이치료제로다시주목받고있 으나병원획득폐렴에대한치료경험은많지않으며, 분무치료의효과에대해서는근거가매우부족하다. 이에저자들은한대학병원중환자실에서발생한다제내성 A. baumannii에의한병원획득폐렴에서 colistin 분무치료의적용가능성을평가해보고자하였다. 방법 : 다제내성 A. baumannii에의한병원획득폐렴의발생이확인되어 colistin 분무치료를시행한환자 10명을대상으로후향적분석을시행하였다. 결과 : Colistin 분무치료기간은평균 12.7±2.4일이었다. 10명의대상환자중 9명 (90.0%) 의환자에서효과적인치료반응을나타내었다. 치료종료후추적한객담배양검사에서다제내성 A. baumannii는단한명도분리되지않았다. 1명의환자에서기관지연축이발생하였으나기관지확장제치료후호전되었다. 결론 : 다제내성 A. baumannii에의한병원획득폐렴에서 colistin 분무치료는매우효과적일가능성이있으며, 향후전향적인연구를진행할가치가있을것으로판단된다. 참고문헌 1. American Thoracic Society; Infectious Diseases Society of America. Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171: Gales AC, Jones RN, Forward KR, Linares J, Sader HS, Verhoef J. Emerging importance of multidrug-resistant Acinetobacter species and Stenotrophomonas maltophilia as pathogens in seriously ill patients: geographic patterns, epidemiological features, and trends in the SENTRY Antimicrobial Surveillance Program ( ). Clin Infect Dis 2001;32 Suppl 2:S Cisneros JM, Rodriguez-Bano J. Nosocomial bacteremia due to Acinetobacter baumannii: epidemiology, clinical features and treatment. Clin Microbiol Infect 2002;8: Corbella X, Montero A, Pujol M, Dominguez MA, Ayats J, Argerich MJ, et al. Emergence and rapid spread of carbapenem resistance during a large and sustained hospital outbreak of multiresistant Acinetobacter baumannii. J Clin Microbiol 2000;38: Garcia-Garmendia JL, Ortiz-Leyba C, Garnacho-Montero J, Jimenez-Jimenez FJ, Monterrubio-Villar J, Gili-Miner M. Mortality and the increase in length of stay attributable to the acquisition of Acinetobacter in critically ill patients. Crit Care Med 1999;27:

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untitled 다약제내성 Acinetobacter baumannii 에의한폐렴에서 Colistin 분무치료의효과 경희대학교의과대학호흡기내과학교실최혜숙, 황연희, 박명재, 강홍모 Effects of Aerosol Colistin Treatment of Pneumonia Caused by Multi-drug Resistant Acinetobacter baumannii Hye