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1 ORIGINAL ARTICLE pissn: eissn: Korean J Clin Geri 2015;16(2): 요양병원과연관된균혈증의임상양상및항균제내성현황 김영주, 안성영, 지종현, 김창오 연세대학교의과대학내과학교실 Clinical Finding and Antimicrobial Resistance in Bacteremia Associated Geriatric Hospital Young-Joo Kim, Sung-Young Ahn, Jong-Hyun Jhee, Chang-Oh Kim Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea Background: The risk of healthcare-associated infections (HCAI) is increasing, due to the increase in geriatric hospitals. However there has been a lack of studies on HCAI in patients of geriatric hospitals. Hence, we aimed to investigate the epidemiological and microbiological characteristics of geriatric hospital patients who developed bloodstream infections (BSI). Method: Among patients who visited emergency department of a single university hospital between January 2007 and December 2011 and showed BSI, we selected patients transferred from geriatric hospitals by reviewing the medical records. Results: Among a total of 921 patients who visited the emergency department with BSI during the study period, 63 patients (6.84%) were residents at geriatric hospitals. Of these, 53.7% were male, the mean age was 69.8 years, and 73.0% were elderly patients of 65 years or over. Malignant tumor was the most common underlying disease. Urinary tract infection (30.1%) was the most common cause of BSI, and in terms of causative pathogen, there were 34.8% of gram-positive bacteria, 31.3% of gram-negative bacteria, and 17.3% of multiple infection with two or more types of bacteria. Multidrug resistant bacteria were reported in 13.0%, including 8.7% of MRSA infection. In patients with less than the mean length of stay (LOS) (20 days), there was a significant association between appropriate early antibiotics use and mean LOS. Conclusion: Treating BSI in geriatric hospital patients requires appropriate antibiotics treatment taking into account multi-factors, including the pathogen of BSI, antibiotics resistance, the patient s age. Use of appropriate early antibiotics reduces the mean LOS. Key Words: Geriatric hospital, Healthcare-associated infection, Bloodstream infection, Multidrug resistant Received: November 27, 2015 Revised: December 4, 2015 Accepted: December 6, Corresponding author: Chang-Oh Kim Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea Tel: , Fax: , 본연구는연세대학교의과대학 2011년도연구비에의하여이루어졌음 ( ). Copyright C 2015 The Korean Academy of Clinical Geriatrics This is an open access article distributed under the term s of the C reative Com m ons Attribution N on-c om m ercial License ( licenses/by-nc/4.0) which perm its unrestricted non-comm ercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 64 Korean J Clin Geri 2015;16(2):63-68 서론 균혈증은혈액배양검사에서균이동정된상태로 1) 적절한항생제및보존적치료에도불구하고사망률이 22% 40% 에달하는질병이다. 2,3) 균혈증이의심되는환자에서는원인균이진단되기전에경험적항생제치료를시작하는것이중요하며이를위해서는주요원인균의분포와항생제감수성양상을알고있어야한다. 하지만병원균의분포와항생제감수성양상은균획득장소, 기간및환자의특성에따라서크게영향을받게되어 4-6) 경험적항생제선택시이에대한고려가필요하다. 또한전통적으로감염질환의원인장소에따라병원획득감염 (hospital-acquired infection, HAI) 과지역사회획득감염 (community-acquired infection, CAI) 으로구분하였고, 노인및만성질환자의증가로정맥주사치료, 혈액투석등을통한감염위험성및요양병원, 요양원등의장기요양시설에의입원이증가하여의료관련감염 (health careassociated bloodstream infection, HCAI) 이라는새로운개념이도입되었으며, 7) 이경우위험인자가전혀없는환자의경우에서와는다른역학적, 미생물학적특징을보였음이알려져있다. 8-10) 국내에서도요양병원등요양시설의증가로 11) 의료관련감염 (HCAI) 의위험이증가하고있으나아직이에대한연구가부족한실정이다. 따라서본연구에서는요양병원과관련된균혈증의임상양상및내성균현황을파악함으로써국내의료관련감염의특성을규명하고자하였다. 대상및방법 1. 연구대상및방법 2007년 1월부터 2011년 12월까지일개대학병원응급실에내원하여시행한혈액배양검사에서균혈증을보인 921명의의무기록을검토하여요양병원에서전원된총 65명을선별하였으며대상자에서균혈증의원인질환, 원인균및원인균의항생제내성발생률, 적절한항생제치료여부, 임상경과에대하여조사하였다. 본연구는대학병원임상시험심사위원회승인을받았다 ( ). 2. 정의균혈증은응급실내원 48시간이내에시행한혈액배 양검사에서한번이상균이동정된경우로정의하였고, 감염부위는환자의증상과기저질환및영상검사를포함한검사소견, 체내장치보유유무등을바탕으로담당의가판단한결과를근거로하였다. 다제내성그람음성균 (multi drug resistant Gram negative bacteria, MDRGNB) 은다음중 3가지종류이상의항생제군에내성으로보이는그람음성세균으로 (1) ampicillin-sulbactam/piperacillin-tazobactam (2) carbapenem (3) ceftazidime or ceftriaxone (4) quinolone (5) gentamicin or amikacin로정의하였고, 다제내성그람양성균은 methicillin-resistant Staphylococcus aureus (MRSA) 와 Vancomycin-Resistant Enterococcus (VRE) 에국한하여조사하였다. 원인균주에대한항생제감수성시험결과를바탕으로 적절한항생제투여 는균동정 24시간이내에적절한항생제의사용및정확한용량과용법으로투여, 약제관련이상반응이없는경우로정의하였으며, 투여된항생제에내성이있거나항생제의항균범위가일치하지않는경우, 균동정 24시간이내에적절한항생제투여가이루어지지않은경우 부적절한초기항생제투여 로평가하였다. 12) 3. 미생물학적분석 1) 혈액배양및미생물동정연구기간중혈액배양및미생물동정방법에변화가있었으며기간별검사방법은다음과같다. 2007년 1월부터 2008년 1월까지혈액배양은혈액 10 ml를무균적으로채혈하여 0.025% 의 sodium polyanethol sulfonate가들어있는 Tryptic soy broth (TSB, BBL, Becton Dickinson Co., Cockeysville, MD, USA) 와 Thioglycollate medium (Thio, BBL) 50 ml가들어있는병에나누어각각접종하고 35 o C에배양하였다. TSB에서의증식검출은 BACTEC 9240 (Becton Dickinson, Canada Inc., Mississauga, Ontario, Canada) 과 BacT/Alert 3D (Organon Teknika, Scarborough, Ontario, Canada) 로병용하였고 Thio 병은매일육안으로혼탁, 용혈, 변색, 가스발생등을관찰하고세균의증식이없는경우 7일까지배양하였고맹계대배양은시행하지않았다. 2008년 2월부터의혈액배양은 BacT/ Alert 3D (Organon Teknika, Scarborough, Ontario, Canada) 로혐기성과호기성균을배양하였다. 혈액배양용배지에서균이증식한경우생화학적방

3 김영주외 : 요양병원관련균혈증 65 법혹은 VITEK system (biomerieux Vitek Inc., Marcyl Etoile, France) 으로동정하였다. 2) 항균제감수성시험연구기간중항균제감수성시험검사방법에변화가있었으며기간별검사방법은다음과같다. 분리세균의항균제감수성시험은 2007년 1월부터 2009년 10월까지 National Committee for Clinical Laboratory Standards (NCCLS) 디스크확산법을이용하였으며, 2009년 11월이후의항균제감수성시험은 VITEK 2 system (biomerieux Vitek Inc., Marcy-l Etoile, France) 을이용하였다. 4. 통계및검정연구대상의임상적특성및미생물학적특성을분석하였으며, 적절한항생제치료와사망률, 재원기간간의상관관계를분석하였다. 명목변수의비교는카이제곱검정, 연속변수의비교에서정규분포를따르는변수들은독립 t-검정, 정규분포를따르지않는경우에는 Mann- Whitney U-검정방법을이용하였다. P 값의유의성검증은 0.05 미만일때통계적으로유의한것으로평가하였다. 통계프로그램은한글판 SPSS ver (SPSS Inc., Chicago, IL, USA) 을사용하였다. 결과 1. 일반적및임상적특성 연구기간동안응급실에내원한환자중균혈증을보인환자는총 921명이었으며, 그중요양병원에서전원되어온것이확실한경우는 63명 (6.84%) 이었다. 남성이 53.7%, 평균연령은 69.8세였으며그중 46명 (73.0%) 이 65세이상의노인이었다. 기저질환으로는악성종양 24명 (26.7%), 뇌졸중 19명 (21.1%) 순이었다. 침습적장치보유빈도는도뇨관유치 (45.5%), 비위관또는위루관삽입 (25.5%) 순이었으며기타침습적장치로는중심정맥관삽입상태 2예및뇌실-복강단락술상태, 담관내스텐트삽입상태, 골절로인한내고정상태가각각 1예에서있었다 (Table 1). 2. 균혈증의원인및원인균균혈증의원인으로는요로감염 22예 (30.1%), 소화기계 Table 1. Clinical characteristics of geriatric hospital associated bacteremia Characteristics n=63 Age (yr) 69.8±12.3 Female 31 (46.3) Hospital stay (day) 20.6±32.3 Do not resuscitate order at admission 27 (40.3) Underlying disease Malignancy 24 (26.7) Stroke 19 (21.1) Diabetes 14 (15.6) Dementia 9 (10.0) Coronary artery disease 8 (8.9) Pressure ulcer 7 (7.8) End-stage renal disease/hemolysis 4 (4.4) Liver cirrhosis 2 (2.2) Chronic obstructive pulmonary disease 2 (2.2) Hypothyroidism 1 (1.1) Presence of invasive device Indwelling urinary catheter 25 (45.5) Feeding tube 14 (25.5) PTBD 4 (7.3) Pigtail 2 (3.6) Hemocatheter 2 (3.6) Trachotube 3 (5.5) Other 5 (9.1) Values are presented as mean±sd, ratio, or number (%). PTBD: percutaneous transhepatic bile drainage. 감염 17예 (23.3%), 폐렴 17예 (23.3%) 순이었고원발부위를모르는경우가 11예 (15.1%) 였다. 가장높은빈도를나타낸요로감염 22예중도뇨관유치상태는 12예 (54.4%), 65세이상의노인은 18명 (81.8%) 이었다. 원인균으로는그람양성균이 40예 (34.8%), 그람음성균이 33예 (31.3%) 였고다제내성균은 15예 (13.0%) 에서보고되었으며 MRSA가 10예 (8.7%) 로가장많았다 (Table 2). 3. 적절한항생제투여상태및임상경과균혈증의원인별적절한항생제투여는원인미상의감염, 소화기계감염, 요로감염순으로나타났으며평균재원기간은요로감염 (29.8±53.6일) 에서가장길었고균혈증을보인환자 63명중 37명 (58.7%) 이사망하였다 (Table 3). 부적절한초기항생제치료, 침습적장치의보유상태, 다제내성균의감염이사망률에미치는영향은통계적으로의미가없었다. 요양병원관련균혈증환자에서사망및재원기간과관련된독립인자를확인하기위한다변량분석결과통계적으로유의미한인자는없

4 66 Korean J Clin Geri 2015;16(2):63-68 Table 2. Sources of organisms causing geriatric hospital associated bacteremia Causative organism Source, No. of episodes (No. of resistant organism) UTI GI/GB Pneumonia Wound/skin Others Unknown Total Escherichia coli (ESBL(+) E.coli) 7 (1) 2 (1) (2) Pseudomonas aeruginosa Klebsiella pneumonia Proteus mirabilis Acinetobacter baumannii 1 (1) (1) CNS Staphylococcus aureus (MRSA) 3 (3) 0 3 (3) 1 (1) 3 (3) 2 (1) 12 (11) Enterococcus spp. (VRE) 2 (1) 3 (1) (2) Streptococcus pneumonia Other (MDR organism) Polymicrobial Total UTI: urinary tract infection, GI/GB: gastrointestinal/gallbladder, CNS: coagulase-negative Staphylcoccus, ESBL (+): extended spectrum beta-lactamase producing, MRSA: methicillin-resistant Staphylococcus aureus, VRE: vancomycin-resistant enterococci, MDR: multidrug resistant. Table 3. Antimicrobial susceptibility & outcome of geriatric hospital associated bacteremia Source, No. of episodes UTI GI/GB Pneumonia Wound/skin Others Unknown Total Adequate therapy 10 (45.4) 9 (50.0) 8 (40.0) 0 1 (16.7) 7 (77.8) 35 LOS (day) 29.8± ± ± ± ±11.3 Mortality Values are presented as mean±sd, ratio, or number (%). UTI: urinary tract infection, GI/GB: gastrointestinal/gallbladder, LOS: length of stay. 었으나, 평균재원기간 20.6일보다짧은재원기간을가진환자에서는초기적절한항생제의투여유무와평균재원기간간에유의한관련성을보였다 (P value=0.005) (Figure 1). 고 찰 본연구에서저자들은요양병원에입원중발생한균혈증으로 3차의료기관응급실을내원한 63명의환자를대상으로임상적, 미생물학적특성을분석하였으며, 환자의연령및기저질환, 감염의원인이될수있는침습적경로의유무에대한통합적접근을바탕으로한초기적절한항생제치료가중요함을보여주었다. 또한요양병원및요양병원을이용하는노인의수가증가함에따 라 13) 의료관련감염 (HCAI) 의위험이높아지고있는실정 이나요양병원관련균혈증에대한임상적, 미생물학적 Figure 1. Hospital stay according to antibiotics treatment in length of stay 20 days. *Significant difference from antibiotics treatment (P value=0.005). 특성에대한기존연구가많지않은국내현황을고려할때에본연구결과는의의가있다. 본연구에서혈액배양검사에서배양된 Staphylococcus

5 김영주외 : 요양병원관련균혈증 67 aureus 중 MRSA가차지하는비율은 91.6% 로이는국내중환자실병원감염에서분리되는 Staphylococcus aureus의 88.9% 가 MRSA로보고된기존의연구결과 14) 와유사한빈도를보였다. 또한 MRSA 외에 extended spectrum beta-lactamase (ESBL) producing E.coli, vancomycin-resistant enterococci (VRE) 가동정되었다. 요양병원에대한 MRSA 보균실태및감염관리실태조사결과상항균제내성률은종합병원수준으로높게나타난반면감염관리프로그램과감염예방조치는매우미흡한것으로나타났던점 15) 및병원감염감시기간중상대적으로기구관련감염률이감소하였다 14) 는기존연구결과에주목하여요양병원내감염관리및감시체계의강화, 내성균관리및확산방지가필요함을강조하고자한다. 본연구에서요로감염에의한균혈증이가장높은빈도를보였으며이경우적절한항생제치료에도불구하고평균재원일수가가장길었다. 또한전체연구대상자중 65세이상의노인은 73% 였으나요로감염환자에서노인의비율은 81.8% 로높았으며, 응급실내원시 30.1% 환자에서도뇨관유치상태였다. 도뇨관삽입의최소화가노인에서의요로감염의위험요인을개선할수있다 16) 는기존의연구결과를토대로요양병원입원중불필요한도뇨관삽입및유지를피하는것이요양병원입원환자에서의균혈증발생의감소및평균재원일수감소에중요하겠다. 마지막으로적절한초기항생제치료가요양병원에서전원온균혈증환자의사망률감소및총재원기간단축에유의한영향을미치지못하였으나이는연구대상자의기저질환 ( 악성종양, 뇌졸중, 당뇨, 심장질환 ), 연령및일상생활기능등의요인이해당결과에영향을미쳤을가능성을배제할수없다. 그러나평균재원기간 (20.6일) 보다재원기간이짧았던환자에서는적절한초기항생제치료에의한재원기간단축효과를나타내어적절한초기항생제치료가중요함을다시한번강조하고있다. 본연구의제한점으로우선의무기록검토를통한후향적관찰연구라는점과일개대학병원의응급실로전원온환자를대상으로하여연구결과를모든병원에일반화할수없다는것을들수있다. 또한상대적인자료수의부족으로사망및재원기간에영향을미치는위험요인에대한통계적분석시유의미한결과가없었다는점을들수있다. 추후더큰규모의연구대상자를토대로하여적절한초기항생제치료유무와더불어요 양시설거주자의경우기저질환, 연령, 일상생활기능, 침습적감염경로의보유유무등이환자의사망및재원기간에미치는영향을평가하기위한추가적인연구가필요하겠다. REFERENCES 1. Coburn B, Morris AM, Tomlinson G, Detsky AS. Does this adult patient with suspected bacteremia require blood cultures? JAMA 2012;308: Leibovici L, Samra Z, Konigsberger H, Drucker M, Ashkenazi S, Pitlik SD. Long-term survival following bacteremia or fungemia. JAMA 1995;274: Nielsen SL, Lassen AT, Gradel KO, Jensen TG, Kolmos HJ, Hallas J, et al. Bacteremia is associated with excess long-term mortality: a 12-year population-based cohort study. J Infect 2015;70: Kim NH, Hwang JH, Song KH, Choe PG, Park WB, Kim ES, et al. Changes in antimicrobial susceptibility of blood isolates in a university hospital in South Korea, Infect Chemother 2012;44: Biedenbach DJ, Moet GJ, Jones RN. Occurrence and antimicrobial resistance pattern comparisons among bloodstream infection isolates from the SENTRY Antimicrobial Surveillance Program ( ). Diagn Microbiol Infect Dis 2004;50: Raveh D, Rudensky B, Schlesinger Y, Benenson S, Yinnon A. Susceptibility trends in bacteraemias: analyses of 7544 patient-unique bacteraemic episodes spanning 11 years ( ). J Hosp Infect 2003;55: Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al. Health care-associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med 2002;137: Smith PW, Seip CW, Schaefer SC, Bell-Dixon C. Microbiologic survey of long-term care facilities. Am J Infect Control 2000;28: Warshawsky B, Hussain Z, Gregson DB, Alder R, Austin M, Bruckschwaiger D, et al. Hospital-and community-based surveillance of methicillin-resistant Staphylococcus aureus: previous hospitalization is the major risk factor. Infection Control 2000;21: Hidron AI, Edwards JR, Patel J, Horan TC, Sievert DM, Pollock DA, et al. Antimicrobial-resistant pathogens associated with healthcare-associated infections: annual summary of data reported to the National Healthcare Safety Network at the Centers for Disease Control and Prevention, Infect Control Hosp Epidemiol 2008;29: Current Status of Elderly Welfare Facilities [Internet]. Daejeon: Statistics Korea; c2008. [cited 2015 Apr 14]. Available from: idx_cd=2766.

6 68 Korean J Clin Geri 2015;16(2): Choi JH. The meaning and impact of appropriate use of antibiotics. Infect Chemother 2012;44: Song HJ. Long-term care hospital systems in developed countries and the implications for Korea. J Korean Geriatr Soc 2012;16: Jeon MH, Kim TH, Kim SR, Chun HK, Han SH, Bang JH, et al. Korean nosocomial infection surveillance system, intensive care unit module report: summary of data from July 2011 through June Korean J Nosocomial Infect Control 2014;19: Surveillance of infection control and prevalence of methicillin resistant Staphylococcus aureus carriers in long-term care facilities [Internet]. Cheongju: Centers for Diasese Control and Prevention; c2012. [cited 2015 Apr 16]. Available from: HOME001-MNU1132-MNU1138-MNU0037-MNU1380&ci d= Koh H. Urinary tract infection in the elderly. J Korean Geriatr Soc 2002;6: 국문요약 연구배경 : 균혈증에서적절한항생제사용의중요성은이미강조되어왔으며, 국내에서도요양시설의증가로의료관련감염 (HCAI) 에노출되는위험역시증가하고있으나요양병원등의요양시설거주자를대상으로한의료관련감염 (HCAI) 에대한연구가부족한실정이다. 따라서본연구에서는요양병원거주중균혈증이발생한환자들의역학적특성및미생물학적특성을규명하고자하였다. 방법 : 2007년 1월부터 2011년 12월까지일개대학병원응급실에내원하여시행한혈액배양검사에서균혈증을보인환자중요양시설에서전원되어온환자 63명을대상으로의무기록검토를통하여균혈증의원인, 원인균및원인균의항생제내성발현율, 적절한항생제치료여부, 임상경과에대하여조사하였다. 결과 : 해당기간중균혈증으로응급실에내원한총 921명중 63명 (6.84%) 가요양시설거주자였으며남성이 53.7%, 평균연령은 69.8세로그중 65세이상의노인은 46명 (73.0%) 이었다. 기저질환으로는악성종양이가장많았으며, 침습적장치로는도뇨관삽입이가장많았다. 균혈증의원인으로는요로감염이 22명으로가장많았으며원인균으로는그람양성균이 40예 (34.8%), 그람음성균이 33예 (31.3%) 였으며두종류이상의균이동정된중복감염도 20예 (17.3%) 였다. MRSA 감염 10예 (8.7%) 를포함한다제내성균은 15예 (13.0%) 에서보고되었다. 평균재원기간 (20.6일) 이하인환자에서는초기적절한항생제의투여유무와평균재원기간간에유의한관련성을보였다. 결론 : 요양병원관련균혈증치료시균혈증의원인및이에따른원인균주의특성, 대상자의연령및침습적장치의보유유무, 종류를포함한다각도의인자를고려한적절한항생제치료가필요하며이를통한평균재원일수의감소효과를가져올수있다. 중심단어 : 요양병원, 의료관련감염, 균혈증, 다제내성

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