한국정맥경장영양학회지제 1 권제 1 호 2007 JKSPEN Vol. 1, No. 1, 2007 원저 Enterococcus faecium 함유프로바이오틱스복용자에서발생한 Enterococcus faecium 유발원내감염증의항생제내성양상 중앙대학교의과대학내과학교실 김정욱 The Antimicrobial Resistance of Nosocomial Enterococcus faecium Infection in Patients Received Probiotics Containing Enterococcus faecium Jeong Wook Kim, M.D. Department of Internal Medicine, Chung-Ang University College of Medicine, Seoul, Korea Purpose: Probiotics are live microorganisms that confer a health benefit to the host when administered in adequate amounts. The bacteria used as probiotics in Korea are Lactobacillus, Bifidobacterum, Enterococcus, Bacillus and Clostridium. Enterococci form part of the lactic acid bacteria of importance in foods and are used as human probiotics. However, they are also important nosocomial pathogens e.g. vancomycin-resistant enterococcus in a nosocomial infection. Therefore, this study examined the antimicrobial resistance of Enterococcus faecium (E. faecium) related nosocomial infections in patients who received probiotics containing E. faecium. Methods: This study analyzed 234 patients with an E. faecium infection, who were hospitalized between 2003 and 2005. Results: An infection developed in 171 patients during hospitalization and 22 (12.6%) of these had received probiotics E. faecium prior to the infection. Seventy-one (41.5%) of the 171 patients had an urinary tract infection, 44 (25.7%) had a biliary tract infection, 19 (11.1%) had an infection of the blood, 15 (8.8%) had a wound infection and bedsores, 11 (6.4%) had a hemo-bag infection, 6 (3.5%) had an intravenous hyperalimentation infection, and 3 (1.8%) each had pneumonia, vaginal discharge and spontaneous bacterial peritonitis. There were no differences in the source of infection between the group given probiotics and group without probiotics. The frequency of 책임저자 : 김정욱, 중앙대학교용산병원내과 140-757, 서울시용산구한강로 3 가 65-207 Tel: 02-748-9941, Fax: 02-3785-0160 E-mail: ekg001@chol.com 접수일 :2007 년 10 월 31 일, 게재승인일 :2007 년 11 월 28 일이논문은 2007 년 8 월 31 일한국정맥경장영양학회제 6 회학술대회에서포스터발표되었음. antimicrobial resistance to ampicillin, chloramphenicol, ciprofloxacin, gentamycin, streptomycin, vancomycin and teicoplanin, and the use of these antibiotics were similar in both groups. Conclusion: Probiotics containing E. faecium do not increase the antimicrobial resistance of nosocomial infections by E. faecium. (JKSPEN 2007;1(1):13-18) Key Words: Probiotics, Enterococcus faecium, Nosocomial infection, Bacterial drug resistance 중심단어 : 프로바이오틱스, Enterococcus faecium, 원내감염, 세균약제내성 서 프로바이오틱스 (probiotics) 란경구로복용하였을때인체에도움을주는미생물이다. 1965년에 Lilly와 Stillwell이다른미생물의성장을유도하는미생물의생성물질을프로바이오틱스라고최초로명명하였다. 1 현재에는건강에도움을주는병원성이없거나매우낮은농도로살아있는미생물을포함한음식이나약제로정의되고있으며 2001년세계보건기구 (World Health Organization, WHO) 와국제식량기구 (Food and Agriculture Organization of the United Nations, FAO) 의합동전문가위원회는프로바이오틱스를 살아있는미생물로, 적당한양을섭취하면건강에유익한세균 ' 이라고정의했다. 2 프로바이오틱스는체내에서다양한기전에의하여정상세균무리와균형을이루어장내에서병원성세균의증식을억제하고장상피세포에서면역능력을조절할수있는물질을생성하게하여체내의면역능력을증가시키고장관의염증을줄이기도한다. 1 그러나프로바이오틱스는복용하였을때항상안전한것은아니며프로바이오틱스균에의한인체감염이발생하기도한다. 2 현재국내에서사용되고있는프로바이오틱스에는주로소장에존재하는젖산균 (Lactobacillus) 과대장에존재하는 론 13
14 한국정맥경장영양학회지제 1 권제 1 호 2007 비피도박테리아 (Bifidobacterum) 가많이사용되고있으며, 이외에장내구균 (Enterococcus), 막대균 (Bacillus), 클로스트리듐 (Clostridium) 같은세균과효모균 (Saccharomyces) 과같은진균류가있다. 이중장내구균은국내에서약품형태로가장많이사용되고있으나세계보건기구와국제연합식량농업기구의연구자들은 2001년장내구균의항생제내성위험성을문제삼아이를사람이복용하는프로바이오틱스로는사용하지말것을권유하였다. 2 그러나아직국내에서장내구균을포함한프로바이오틱스의복용이장내구균감염에미치는영향에대해서는보고된것이없다. 본연구자들은후향적조사를통하여장내구균인 Enterococcus faecium (E. faecium) 이포함된프로바이오틱스를복용한환자에서발생한 E. faecium 감염증의특성을알아보았다. 대상및방법 2003년 1월부터 2005년 12월까지중앙대학교부속용산병원에입원한환자중복수, 담즙, 혈액, 중심정맥도관, 복강내유치도관, 복강내농양, 소변, 욕창과상처부위, 질내분비물에서 E. faecium이배양된환자 234명을대상으로후향적으로조사하였다. E. faecium 감염환자와감염균의특성을알아보기위해성별, 연령, 입원부터감염까지기간, 외래와입원중에사용한항생제를조사하였다. E. faecium이배양된검체의종 류와 E. faecium의항생제내성양상도조사하였다. 입원 72 시간후에발생한감염을원내감염 (nosocomial infection) 으로정의하였으며, 입원부터 72시간이내에발생한감염을입원시감염으로정의하였다. 3 E. faecium이함유프로바이오틱스복용자는배양검사시행때까지 E. faecium이함유된프로바이오틱스인메디락디에스장용캡슐 (Medilac-DS Enteric Capsule; Hanmi Pharm. Co. Ltd., Seoul, Korea) 를 10일이상복용한군으로하여, 4 원내감염군 171명중 22명이복용군 147명이비복용군으로하였으며 2명은감염발생일주일전에 2일미만으로프로바이오틱스를복용하였기에단기간의복용으로는프로 Table 1. Characteristics of patients with Enterococcus faecium infection Variable Number of cases (% of total) INF-AD (n=63) (n=171) Sex Male (n=109) 26 (41.3%) 83 (48.5%) NS Female (n=125) 37 (58.7%) 88 (51.5%) Age (yrs old; means±sd) 59.7±20.7 62.8±16.6 NS Analyses were performed using the Chi-square test and independent t-test. NS = not significant; INF-AD = patients with infection at time of admission; = patient with infection 72 hours after admission. Infection site Table 2. Site of infection in cases who developed an Enterococcus faecium infection INF-AD (n=63) Probiotics (+) (n=22) Probiotics ( ) (n=149) Total (n=171) Ascites 1 (1.6%) 0 (0%) 1 (0.7%) 1 (0.6%) Bile 40 (63.5%) 1 (4.5%) 43 (28.9%) 44 (25.7%) Blood 8 (12.7%) 4 (18.2%) 15 (10.1%) 19 (11.1%) Central catheter 0 (0%) 1 (4.5%) 5 (3.4%) 6 (3.5%) Hemobag 2 (3.2%) 2 (9.1%) 9 (6.0%) 11 (6.4%) Intraperitoneal abscess 1 (1.6%) 1 (4.5%) 1 (0.7%) 2 (1.2%) Respiratory 0 (0%) 0 (0%) 1 (0.7%) 1 (0.6%) Urine 11 (17.5%) 10 (45.5%) 61 (40.9%) 71 (41.5%) Vaginal discharge 0 (0%) 0 (0%) 1 (0.7%) 1 (0.6%) Wound and Bedsore 0 (0%) 3 (13.6%) 12 (8.1%) 15 (8.8%) INF-AD = patients with infection at time of admission; = patient with infection 72 hours after admission; Probiotics (+) = patients with consumption of probiotics containing Enterococcus faecium; Probiotics ( ) = patients without consumption of probiotics containing Enterococcus faecium.
김정욱 :E. faecium 함유프로바이오틱스의 E. faecium 원내감염에대한영향 15 Table 3. Characteristics of used antibiotics before infection in patients with Enterococcus faecium infection INF-AD (n=63) (n=171) Ampicillin (n=1) 0 (0%) 1 (0.6%) NS Chroamphenicol (n=0) 0 (0%) 0 (0%) Ciprofloxacin (n=25) 3 (4.8%) 22 (12.9%) NS Gentamycin (n=1) 0 (0%) 1 (0.6%) NS Imipenem (n=16) 0 (0%) 16 (9.4%) NS Streptomycin (n=0) 0 (0%) 0 (0%) Tetracycline (n=0) 0 (0%) 0 (0%) Vancomycin (n=4) 0 (0%) 4 (2.3%) NS Teicoplanin (n=0) 0 (0%) 0 (0%) 1st generation cephalosporin (n=14) 5 (7.9%) 9 (5.3%) NS 2nd generation cephalosporin (n=35) 5 (7.9%) 30 (17.5%) NS 3rd generation cephalosporin (n=90) 6 (9.5%) 84 (49.1%) <0.001 Fluoroquinolone (n=36) 5 (7.9%) 31 (18.1%) NS Metronidazole and ornidazole (n=41) 5 (7.9%) 36 (21.1%) <0.05 Aminoglycoside (n=83) 7 (11.1%) 76 (44.4%) <0.001 INF-AD = patients with infection at time of admission; = patient with infection 72 hours after admission. 바이오틱스의효과를발생하기어려우므로비복용군으로분류하였다. 4 모든수치는평균 ± 표준편차로표시하고각군간의차이는 SPSS 11.5 프로그램 (SPSS Inc, Chicago, IL, USA) 을이용하여 chi-square test, independent t-test에서 P값이 0.05 이하인경우를유의성이있는것으로판정하였다. 결 E. faecium이배양된환자 234명중 63명은입원시감염군이었으며 171명은원내감염군이었다. 두군사이에성별과연령에서는차이가없었다 (Table 1). 입원시감염군에서배양검체는담즙, 소변, 혈액순이었으며원내감염군에서는소변이가장많았으며담즙, 혈액순이었다 (Table 2). 원내감염군에서입원시감염군보다감염발생전 3세대세팔로스포린, 메트로니다졸, 아미노글리코사이드계통항생제의사용빈도가높았다. 암피실린 (ampicillin), 시프로플록사신 (ciprofloxacin), 겐타마이신 (gentamycin), 이미페넴 (imipenem), 스트렙토마이신 (streptomycin) 의사용빈도는양군 과 Table 4. Characteristics of antibiotic resistance in patients with Enterococcus faecium infection INF-AD (n=63) (n=171) Ampicillin (n=148) 20 (31.7%) 128 (74.9%) <0.001 Chroamphenicol (n=35) 8 (12.7%) 27 (15.8%) NS Ciprofloxacin (n=178) 33 (52.4%) 145 (84.8%) <0.001 Gentamycin (n=134) 15 (23.8%) 119 (69.6%) <0.001 Imipenem (n=142) 14 (22.2%) 128 (74.9%) <0.001 Streptomycin (n=92) 13 (20.6%) 79 (46.2%) <0.001 Tetracycline (n=37) 13 (20.6%) 25 (14.6%) NS Vacomycin (n=23) 4 (6.3%) 19 (11.1%) NS Teicoplanin (n=21) 3 (4.8%) 18 (10.5%) NS INF-AD = patients with infection at time of admission; = patient with infection 72 hours after admission. Table 5. Characteristics of patients with Enterococcus faecium infection developed 72 hours after admission regarding to consumption of probiotics containing Enterococcus faecium Probiotics (+) (n=22) Probiotics ( ) (n=149) Sex Male (n=83) 10 (45.5%) 73 (49.0%) NS Female (n=88) 12 (54.5%) 76 (51.0%) Age (yrs old; means±sd) 58.7±18.7 63.4±16.3 NS Duration from admission to infection (days; means±sd) 29.6±22.5 d20.6±22.2 NS treatment before infection Yes (n=145) 17 (72.3%) 128 (85.9%) NS No (n=26) 5 (27.3%) 21 (14.1%) Analyses were performed using the Chi-square test and independent t-test. NS = not significant; Probiotics (+) = patients with consumption of probiotics containing Enterococcus faecium; Probiotics ( ) = patients without consumption of probiotics containing Enterococcus faecium. 간차이가없었으나, 원내감염군에서입원시감염군보다상기항생제에대한내성균비율이높았다. 클로람페니콜 (chroamphenicol), 테트라시클린 (tetracycline), 반코마이신 (vancomycin), 테이코플라닌 (teicoplanin) 은사용빈도와항생제내성균의비율에서양군간차이를보이지않았다 (Table 3, 4). 원내감염군 171 명중 22 명이감염발생전 E. faecium 이
16 한국정맥경장영양학회지제 1 권제 1 호 2007 Table 6. Characteristics of used antibiotics before infection in patients with Enterococcus faecium infection developed 72 hours after admission regarding to consumption of probiotics containing Enterococcus faecium Probiotics (+) (n=22) Probiotics ( ) (n=149) Ampicillin (n=1) 1 (4.5%) 0 (0%) NS Chroamphenicol (n=0) 0 (0%) 0 (0%) Ciprofloxacin (n=22) 0 (0%) 22 (14.8%) NS Gentamycin (n=1) 0 (0%) 1 (0.7%) NS Imipenem (n=16) 1 (4.5%) 15 (10.1%) NS Streptomycin (n=0) 0 (0%) 0 (0%) NS Tetracycline (n=0) 0 (0%) 0 (0%) NS Vancomycin (n=8) 4 (18.2%) 4 (2.7%) 0.01 Teicoplanin (n=0) 0 (0%) 0 (0%) NS 1st generation cephalosporin (n=9) 0 (0%) 9 (6.0%) NS 2nd generation cephalosporin (n=30) 3 (13.6%) 27 (18.1%) NS 3rd generation cephalosporin (n=84) 13 (59.1%) 71 (47.7%) NS Fluoroquinolone (n=31) 1 (4.5%) 30 (20.1%) NS Aminoglycoside (n=36) 3 (13.4%) 33 (22.1%) NS Metronidazole and ornidazole (n=76) 13 (59.1%) 63 (42.3%) NS Probiotics (+) = patients with consumption of probiotics containing Enterococcus faecium; Probiotics ( ) = patients without consumption of probiotics containing Enterococcus faecium. 함유된프로바이오틱스를 10일이상지속복용하였으며 147명이복용하지않았다. 2명은감염발생일주일전에 2일미만으로프로바이오틱스를복용하였으며단기간의복용으로는프로바이오틱스의효과를발생하기어려우므로비복용군으로분류하였다. 4 프로바이오틱스복용군과비복용군사이에성별, 연령, 입원부터감염발생까지기간, 항생제사용빈도에서는차이가없었다 (Table 5). 배양검체는양군모두소변, 담즙, 혈액순이었다 (Table 2). 프로바이오틱스비복용군에서복용군보다반코마이신의사용비율이높았으나다른항생제사용빈도는차이가없었다. 반코마이신을포함한모든항생제에서내성균의비율이양군간차이가없었다 (Table 6, 7). 고 장내구균은젖산균을생성하는세균으로지중해지역에서생산되는치즈와소세지등의각종발효음식의생성과 찰 Table 7. Characteristics of antibiotic resistance in patients with Enterococcus faecium infection developed 72 hours after admission regarding to consumption of probiotics containing Enterococcus faecium Probiotics (+) (n=22) Probiotics ( ) (n=149) Ampicillin (n=128) 20 (90.9%) 108 (72.5%) NS Chroamphenicol (n=27) 3 (13.6%) 24 (16.1%) NS Ciprofloxacin (n=145) 20 (90.9%) 125 (83.9%) NS Gentamycin (n=119) 19 (86.4%) 100 (67.1%) NS Imipenem (n=128) 20 (90.9%) 108 (72.5%) NS Streptomycin (n=79) 13 (59.1%) 66 (44.3%) NS Tetracycline (n=24) 1 (4.5%) 24 (16.1%) NS Vacomycin (n=19) 4 (18.2%) 15 (10.1%) NS Teicoplanin (n=18) 4 (18.2%) 14 (9.4%) NS Probiotics (+) = patients with consumption of probiotics containing Enterococcus faecium; Probiotics ( ) = patients without consumption of probiotics containing Enterococcus faecium. 정에중요한역할을한다. 하지만육류등의음식부패에도관여하며사람에서질병을유발하기도한다. 특히중요질환을앓고있는환자에서병원감염을유발한다. 5 이러한점으로장내구균의프로바이오틱스사용에있어안정성에대한의문점이있다. 그러나장내구균이함유된프로바이오틱스는인체에서여러가지효과를보인다. E. faecium은과거에 Streptococcus faecium으로명칭되었으며현재국내에서약제로가장많이처방되고있는프로바이오틱스이다. 그러나일반적으로프로바이오틱스에사용되는균주로는젖산균과비피도박테리아가주로사용되고있다. 국내에서도식품으로는두가지균주가주로사용되고있으며장내구균을이용한식품은판매되지않고있다. 또한국내외에서도판매되고있는 E. faecium 함유프로바이오틱스제품일부에서균주이름을 Streptococcus faecium으로잘못표기하여의료진과환자에게혼돈을주고있다. 6 장내구균중 E. faecium SF68는프로바이오틱스로사용시에소아와성인설사환자에서증상을줄여주고배변양상의정상화에도움이된다. 5,7 그러나항생제유발설사에는도움이되지못한다. 8 또한단기간사용으로혈중콜레스테롤을감소시킨다. 9 하지만장기간의사용으로저밀도지질단백콜레스테롤을감소시키지는못한다. 5 또한장내구균은면역결핍환자나중환자의병원내감염의중요균주로원내감염원인균주의 10% 이상을차지하며균혈증, 심내막염, 요로감염을유발한다. 10
김정욱 :E. faecium 함유프로바이오틱스의 E. faecium 원내감염에대한영향 17 원내감염을유발하는장내구균은 E. faecalis가 80% 를차지하고있으나반코마이신저항성균주의증가에따라 E. faecium이차지하는비율이증가하고있다. 11 특히반코마시신내성균주는기존에사용되는항생제중치료할수있는적절한약제가없으므로매우중요한문제이다. 하지만프로바이오틱스로장내구균을복용하였을때항생제저항유전자나균독성인자와연관된유전자가프로바이오틱스로전달될위험성이있으나아직장내구균을함유한프로바이오틱스의안정성은규명되지않았다. 5 장내구균의항생제내성은염색체의유전자와연관된고유내성이있으며이에는세팔로스포린, 베타락탐, 설폰아마이드에대한내성과클린다마이신과아미노글리코사이드에대한내성이있다. 플라스미드와전위유전단위의유전자와연관된획득내성에는클로람페니콜, 에리트로마이신, 플루오로퀴롤론, 당펩티드에대한내성과클린다마이신, 베타락탐과아미노글리코사이드에대한고도내성이있다. 12 이번연구에서는내원시감염군과원내감염군사이에 3세대세팔로스포린, 메트로니다졸, 아미노글리코사이드계통항생제의사용빈도가높았으나, E. faecium의획득내성과연관성있는항생제인암피실린, 클로람페니콜, 시프로플록사신, 겐타마이신, 스트렙토마이신, 반코마이신, 테이코플라닌과연관성이없는이미페넴, 테트라시클린의사용빈도는차이가없었다. 하지만암피실린, 시프로플록사신, 겐타마이신, 스트렙토마이신과이미페넴에대한내성균주의비율이내원시감염군보다원내감염군에서높았다. 이는두군간에항생제사용기간을고려하더라도원내감염을유발하는항생제내성 E. faecium이해당환자에서항생제사용에의하여발생할수도있지만, 이미항생제내성을획득한병원내병원체에의한감염의가능성도높다는것을의미한다. 입원환자의항생제내성 E. faecium 감염을예방하거나치료하기위해서는장관내에정상적으로존재하는세균이라는상기균주의특성을고려해야한다. 장내세균무리로존재하고있는 E. faecium은항생제의부적절한사용에의하여약제내성을획득하거나이미내성을보유한 E. faecium이환자의소화관으로유입되어다른장기로장내세균전위에의하여전파될수있다. 13 이때외부로부터의 E. faecium의추가적인유입은획득내성에의한장관내의약제내성균주의수를증가시킬수있으며장내세균전위와같은이차적인타장기의감염증을유발할수있다. 또한균주의발병력 (virulence) 도전이될수있으므로균의장기침투를촉진할수있다. 5 이와같은 E. faecium의특성으로 E. faecium을함유한프로바이오틱스의안전성에대하여문제점이제시되어왔다. 이에대한연구로건강한피험자를대상으로한연구에서반코마이신과 E. faecium을함유한프로바이오틱스를병합투여하였을때반코마이신단독투여군과비교해서반코마이신내성균주발생비율이차이가없다는보고가있다. 4 하지만상기균주에의한원내감염은상당수가면역력이감소된환자에서발생한다. 이에본연구자들은후향적조사를통하여 E. faecium에의한원내감염환자에서 E. faecium 함유프로바이오틱스복용이항생제내성에미치는영향을알아보았다. 프로바이오틱스복용군과비복용군사이에성별, 연령, 입원부터감염발생까지기간, 항생제사용빈도, 배양검체에서는차이가없었다, 각종항생제사용양상도차이가없었으며단비복용군에서반코마이신사용이많았다. 항생제내성률은양군간반코마이신을포함하여 E. faecium의획득내성과연관된항생제뿐만아니라연관성이없는약제에서도차이가없었다. 현재 E. faecium을함유한프로바이오틱스는당펩티드항생제내성장내구균의원내감염증가와약제내성과발병력전파의가능성으로그사용의안전성에대한문제점이계속제시되고있다. 2,14 그러나이번연구에서는 E. faecium을함유한프로바이오틱스의복용이 E. faecium에의한원내감염에서항생제내성률에는영향을주지않았다. 하지만후향적조사이며프로바이오틱스복용군의수가적고, 대상군에서최근장내구균의원내감염에서항생제획득내성으로문제가되고있는반코마이신이나테이코플라닌과같은당펩티드의사용빈도가적다는제한점이있다. 또한장내구균감염발생에서발병력도중요한역할을하나이에대한연구도이루어지지않았다. 이와같이이번연구는제한점이있으므로더많은대상군을대상으로균의발병력에대한사항도포함하여지속적인연구가필요하다. 비록의미있는차이는발견하지못하였지만세계보건기구와국제연합식량농업기구의권고와같이장내구균의항생제내성위험성을고려하여사람이복용하는경우, 특히면역력이감소되어있거나장관장벽손상으로장내세균전위등의감염성합병증의위험성이높은환자와당펩티드항생제사용환자등에서는 E. faecium 함유프로바이오틱스사용에세심한주의를요한다. 또한가능하면젖산균이나비피도박테리아와같은비교적안전한프로바이오틱스의사용을고려해야할것으로생각한다. REFERENCES 1. Fioramonti J, Theodorou V, Bueno L. Probiotics: what are they? What are their effects on gut physiology? Best Pract Res
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