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Ann Clin Microbiol Vol. 17, No. 1, March, 2014 http://dx.doi.org/10.5145/acm.2014.17.1.9 pissn 2288-0585 eissn 2288-6850 Clinical Characteristics of Streptococcus agalactiae Bacteremia in Adults Living in Jeju Island Kyutaeg Lee 1, Woo Jin Kim 1, Dong Lyul Kim 1, Hyun Mi Ko 1, Seung Hee Baik 2, Mi Na Kim 2, Moo Sang Chong 3 Departments of 1 Laboratory Medicine, 2 Infection, Cheju Halla General Hospital, 3 Department of Clinical Pathology, Cheju Halla College, Jeju, Korea Background: Streptococcus agalactiae (Group B streptococcus, GBS) is known to be the leading cause of neonatal sepsis and meningitis in the United States and Europe. In addition, GBS infection has been increasingly noted in adults, particularly in those with underlying diseases, such as diabetes mellitus, malignancy and liver disease. A few studies reported that resistances to antibiotics, such as erythromycin, clindamycin, tetracycline are increasing. We report clinical and microbiological characteristics of GBS bacteremic patients in Jeju Island. Methods: We retrospectively analyzed medical records, such as age, sex, underlying disease, mortality, skin defects, laboratory results and antibiotic resistances of GBS in hospitalized adult patients who were diagnosed with GBS bacteremia from 2008 to 2013 in Jeju Island. Results: Twenty two adult patients were diagnosed as GBS bacteremia from 2008 to 2013. The mean age of GBS bacteremic patients was 66.2 years old. Of 22 bacteremic patients, fifteen patients (68%) were older than 60. Twenty patients (91%) of bacteremic patients had underlying diseases such as diabetes mellitus, malignancy and liver disease. Ten (45%) patients had skin defects which were on the lower extremities and buttock, fifteen (68%) patients had fever at the time of admission, twenty one (95%) patients were admitted via the emergency department. Two (9%) patients died. The mean white blood cell (WBC) count, percentile of neutrophil count, and C-reactive protein (CRP) levels were 11,488/μL, 84.3 %, 13.5 mg/dl respectively. All GBS isolates from bacteremia showed sensitivities to penicillin, ampicillin, and vancomycin, and showed resistances to erythromycin (25%), clindamycin (30%), and tetracycline (55%). Conclusion: Bacteremia caused by GBS was prevalent in adult patients with underlying diseases. Most of the GBS bacteremic patients were emergency cases, with a high body temperature, WBC, CRP level, and neutrophil count. Half of them had skin defects, which are considered a source of GBS bacteremia. (Ann Clin Microbiol 2014;17:9-13) Key Words: Bacteremia, Drug resistance, Group B streptococci, Streptococcus agalactiae INTRODUCTION Streptococcus agalactiae (Group B streptococcus, GBS) 는혈액한천배지에서약한베타용혈을보이는그람양성알균으로임신부의생식기에정착하여신생아수막염과균혈증의주요원인균으로알려져있다 [1]. 최근미국이나유럽에서는 GBS에의한신생아감염은감소하는추세이지만성인에서균혈증, 요로감염등의감염증이증가하고있으며대부분고령이고당뇨, 암종, 간질환등의기저질환을동반하고있음이알려져있다 [2-6]. 일부연구에서 GBS에의한균혈증은해마다증가되고있으며 erythromycin, clindamycin, tetracycline 등항생제에대한내성률도해마다증가하고있다고보고하였고 [2] 균혈증이유발된환자는기존의기저질환등의악화로사망률이증가하므로 [4] 정확한진단과조기치료가중요하다. 그러나기저질환, 항생제내성에대한보고이외의균혈증환자의특성과균혈증이외의감염의특성의비교에대한제주지역의보고는드물다. 이에본연구자들은제주의한병원에입원하여 GBS 균혈증으로진단된환자를대상으로분리율, 기저질환및사망률등의임상특성에대해조사하였다. Received 5 August, 2013, Revised 20 January, 2014, Accepted 4 February, 2014 Correspondence: Kyutaeg Lee, Department of Laboratory Medicine, Cheju Halla General Hospital, 65 Doryeong-ro, Jeju 690-766, Korea. (Tel) 82-64-740-5256, (Fax) 82-64-740-5657, (E-mail) kyutaeg@daum.net c The Korean Society of Clinical Microbiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 9

10 Ann Clin Microbiol 2014;17(1):9-13 MATERIALS AND METHODS 1. 대상 2008년 1월부터 2013년 12월까지 6년동안제주의한병원에입원한환자중 GBS에의한균혈증이진단된환자를대상으로연령, 성별, 선행질환, 사망률, 피부병변, 혈액검사, 기타배양검사등에대하여의무기록을토대로후향적으로조사하였다. 동일환자가 2번이상, 혈액배양에서 GBS가배양될경우첫번째분리된경우만연구에포함하였다. 2. GBS 동정및항균제감수성검사혈액배양은전통적인방법으로시행하였다. 혈액배양은혈액 10 ml를무균적으로채혈하여 Tryptic soy broth (BBL, Cockeysville, MD, USA) 와 thioglycollate medium (BBL) 에나누어각각접종하고 35 o C에서 BACTEC 9240 (Becton Dickinson Diagnostic Instrument Systems, Sparks, MD, USA) 에서배양하였고세균의증식이없는경우 7일까지배양하였다. 세균의증식이있는경우혈액우무평판배지에접종하여 35 o C, CO 2 배양기에 24시간배양하여혈액우무평판배지에서완전용혈의집락에대해 VITEK 2 (biomérieux, Inc., Hazelwood, MO, USA) 를이용하여동정및항균제감수성검사를시행하였다. RESULTS 1. 연령과성별차이성인에서 GBS에의한균혈증 22예중 2008년에 1예, 2009년에 3예, 2010년에 5예, 2011년에 4예, 2012년에 4예, 2013년에 5예였다. 균혈증환자는 36세에서 92세까지다양하였으며평균나이는 66.2세였으며 60대, 70대, 80, 50대순으로많았다 (Fig. 1). 균혈증환자는남녀각각 11명으로성별차이는없었다. 2. 기저질환과임상적특성균혈증환자 22예중 20예 (91%) 가기저질환이동반되어있었으며암종 9예, 간질환 8예, 당뇨가 6예였고그외에뇌졸중, 심장질환등였다. 암환자 9예중 2예는간암환자이며간경화가동반되어있어간질환에중복계수되었다. 그외자궁경부암이 3예로가장많았고담낭암, 난소암, 췌장암및뇌암이각각 1예였다. 간질환 8예중간암이 2예였으나모두간경화가동반되어있었고그외간경화 5예, 알코올중독자 1예였다. 피부병변은균혈증환자 10예 (45%) 에서피부병변을가지고있었고이중 9예는하지의병변이고 1예는둔부의욕창였다. 하지피부병변중 7예는봉와직염, 2예는하지림프부종였다. 균혈증환자중응급실을경유하여입원한환자는 21예 (95%) 였고 15 예 (68%) 는발열을보였다. 균혈증환자 2예 (9%) 는사망하였다 (Table 1). 3. 검사결과 GBS 균혈증을보인 22예중 19예는 GBS만동정되었으나 3 예에서 Staphylococcus epidermidis 1예, Staphylococcus homonis 2예가 GBS와동시에검출되었다. 입원당시혈액배양과함께요배양이의뢰된 19예중 3예는 Escherichia coli가검출되었고 Klebsiella pneumoniae, Acinetobacter baumannii, S. agalactiae가 1예씩검출되었다. 입원치료후약 1주후에혈액배양이재의뢰된 9예중 8예는모두미생물이검출되지않았으나 1예는 Staphylococcus aureus가동정되었는데이환자는치료를따르지않은환자였다. 피부병변 10예중 4예에서배양검사를시행하여 3예에서미생물이검출되었고 S. agalactiae와 Staphylococcus xylosus가동시에검출된 1예, S. agalactiae와 S. epidermidis가동시에검출된 1예및 Proteus mirabilis가검출된 1예였다. 균혈증환자에서 CRP는 13.5 mg/dl, 백혈구수치는평균 11,488/μL, 호중구의백분율은평균 84.3% 였다 (Table 2). Table 1. Underlying conditions and clinical features in patients infected with Streptococcus agalactiae in blood (n=22) Characteristic Number (%) Fig. 1. Occurrence of Streptococcus agalactiae bacteremia according to age groups. Diabetes mellitus Liver disease Malignancy Skin defect Admitted via ED Fever Death Abbreviation: ED, emergency department. 6 (27.3) 8 (36.4) 9 (40.9) 10 (45.5) 21 (95.5) 15 (68.2) 2 (9.1)

Kyutaeg Lee, et al. : GBS Bacteremia in Adults Living in Jeju Island 11 Table 2. Laboratory results in patients infected with Streptococcus agalactiae in blood (n=21) Table 3. Antibiotic resistances of Streptococcus agalactiae isolated in blood (n=20) Results Mean (±S.D.) Antibiotics Resistance rate (%) WBC (/μl) Neutrophil (%) CRP (mg/dl) 11,488 (±8,089) 84.3 (±12.3) 13.5 (±12.5) Erythromycin Clindamycin Tetracycline 25 30 55 Abbreviations: S.D., standard deviation; CRP, C-reactive protein. 4. 항생제감수성균혈증군 20검체에서항생제감수성검사가시행되었다. 검출된 GBS는 penicillin, ampicillin, vancomycin에대해모두감수성을보였고 erythromycin, clindamycin, tetracycline에대한내성률이각각 25%, 30%, 55% 였다 (Table 3). DISCUSSION GBS는일반적으로신생아의패혈증과뇌막염의주요원인균으로알려져있으나최근에는신생아감염보다는성인에서요로감염, 피부감염과균혈증등의감염을야기하고있다. 본연구에서성인에서의 GBS에의한균혈증만을대상으로하였으나 2008년부터 2013년까지 6년동안 5예의신생아에서균혈증이진단되었는데모두생후 3개월이내의환아들였으나성인에서는 22예가진단되어 GBS에의한균혈증은신생아보다성인에서더자주발생함을알수있었다. 본연구의대상은모두 30세이상의성인이며 60대, 70대, 80대및 50대순으로많았다. Uh 등 [2] 은 GBS가균혈증을야기한성인의 82.6% 에서기저질환을가지고있었다고보고하였으나본연구에서성인 22 예중 20예 (91%) 에서기저질환을가지고있었으며기저질환은암종, 간질환, 당뇨병순였다. 이는 Takahashi 등 [4] 도 GBS에의한침습성감염환자에서기저질환으로암종, 당뇨병, 간질환의순으로보고한것과유사하였다. GBS에의한침습적발병기전은정확히알려진바가없으나면역기능의저하와기회감염, GBS의혈청형이거론된다 [7,8]. 당뇨병에서탐식작용의부전, 호중구세포내살균작용의장애가원인으로보았고간질환환자에서소화기계상재균였던 GBS가위장관출혈또는위장관점막의미란에의한일시적인균혈증, 암종의수술에의한림프액배농장애에의한국소적인감염또는내인성피부상재균의혈액내전파와노년층에서의혈액내항체농도가낮은것을고려할수있다 [7,9,10]. 본연구에서균혈증군 45% 에서피부병변이관찰되었는데이는피부상재균으로있던 GBS가피부병변으로침투하여균혈증이유발할가능성이추정되었다. Takahashi 등 [4] 은 Streptococcus dysgalactiae spp. equisimilis, Streptococcus pyogenes, GBS에의한침습성감염환자에서연조직감염이각각 22.5%, 28.0%, 9.8% 를차지하였 다고보고하였는데이는 GBS 뿐만아니라사슬알균에의한침습적감염은연조직감염으로인한세균의침입으로침습성감염이유발될수있으리라판단되었다. 본연구에서 GBS 균혈증환자중피부감염이있는환자 10예중 4예에서피부병변에대한배양검사가시행되었고 3예에서미생물이동정되었다. 이중 2예에서 S. agalactiae가 Staphylococcus와동시에검출되었고 1예에서는 P. mirabilis가검출되었다. 그러나, 피부병변이동반되었던 10예중 8예에서요배양이의뢰되었지만 2예에서만 S. epidermidis와 E. coli가검출되었으나 S. agalactiae는검출되지않았다. 본연구의결과는 Takahashi 등 [4] 이주장한바와같이 GBS에의한피부감염이균혈증을야기한다는주장을뒷받침한다고판단된다. 또한, 피부병변이동반되었던균혈증환자 10예중 9예는하지의병변이고 1예는둔부의욕창으로모두하지와골반부위의병변였고봉와직염과림프부종이대부분이며, 암종환자중 3예가자궁경부암치료중에 GBS가관찰되어저자는하지의림프배액의장애와하지의감염이 GBS에의한균혈증의한원인이라추정하었다. 그러므로, 고령환자이며간질환, 암종및당뇨등의기저질환이있는환자는하지의피부병변에대한주의를기울여 GBS 등의사슬알균에의한균혈증에주의를기울여야한다고판단된다. 그러나본연구는증례의수가적어저자의주장을객관화할수없으나 GBS 균혈증과하지의피부감염과의연관성에대한연구가필요하리라판단된다. 균혈증군은고열이동반하고백혈구수, 호중구수의백분율, CRP의증가와함께다수의환자가응급실을통해입원하며사망율이 9% 이므로더욱조기진단과치료에신중을기해야하겠다. 본연구에서검출된 GBS는모두 penicillin, ampicillin, vancomycin에대해모두감수성을보였으며 erythromycin, clindamycin, tetracycline 에대한내성률은각각 25%, 30%, 55% 였다. Uh 등 [2] 은 1990년부터 2003년까지 GBS에의한침습적감염에서 erythromycin, clindamycin, tetracycline에대한감수성이 78.3%, 78.3%, 0% 였고, Tazi 등 [3] 은 2007년에서 2010년까지의 B군사슬알균에의한침습적감염에서 penicillin, amoxicillin, cefotaxime, imipenem, rifampicin, vancomycin 에대해서모두감수성였으나 erythromycin, clindamycin은각각 35.3%, 23% 에서내성을보였으며 erythromycin에대한내성은 2007년보다 2010년에더증가하였다고보고하였다. Uh 등 [11] 도 2008

12 Ann Clin Microbiol 2014;17(1):9-13 년부터 2009년까지임신부여성의질, 요도구및항문주위에서채취된 GBS에서 erythromycin, clindamycin, tetracycline에대한내성률이각각 33.3%, 44.4%, 85.2% 이며이전의항생제내성률보다증가하였다고보고하였다. 그러나, 본연구의항생제내성률은기존의보고와비슷하거나낮았는데이는 GBS의검출된검체, 지역, 항균제의사용량과종류등의차이도있으리라생각되며 B군사슬알균의항생제내성은혈청형의차이에따라다르다는여러연구결과들 [2,11-13] 로보아제주지역의 GBS의혈청형은타지역과다를수있어임상검체에서검출되는 GBS에대한내성률뿐만아니라혈청형에대한조사및감시가필요하리라판단된다. 반면, 본연구에서 GBS의항생제에대한내성률이다른보고 [3,11] 보다낮은결과는 GBS의항생제내성률과균혈증의유발과의관련이낮을수있음을시사하며본연구에서입원치료후약 1주후에혈액배양이재의뢰된 9예중 8예는모두미생물이검출되지않고항생제치료에순응하는결과는 GBS에의한균혈증의발생은 GBS의항생제내성보다환자의임상적특성과관련이크다고생각되었다. 본연구는제주지역의한병원에서발생한 GBS에의한균혈증을대상으로분석하여지역적인제한점이있을수있다. 그러나 GBS 균혈증으로인해기저질환의악화로인한사망률이증가될수있기에 GBS에의한균혈증환자의임상적인특성에대해이해하고예방하는데도움이되기를바란다. REFERENCES 1. Kasper DL, Harrison TR. eds. Harrison's Principles of Internal Medicine. 16th ed. New York: McGraw-Hill, Medical Pub. Division; 2005:823-31. 2. Uh Y, Jang IH, Yoon KJ, Kim HY. Analysis for Group B streptococci isolated from bacteremic patients. Korean J Clin Microbiol 2004;7:43-7. 3. Tazi A, Morand PC, Réglier-Poupet H, Dmytruk N, Billoët A, Antona D, et al. Invasive group B streptococcal infections in adults, France (2007-2010). Clin Microbiol Infect 2011;17:1587-9. 4. Takahashi T, Sunaoshi K, Sunakawa K, Fujishima S, Watanabe H, Ubukata K; Invasive Streptococcal Disease Working Group. Clinical aspects of invasive infections with Streptococcus dysgalactiae ssp. equisimilis in Japan: differences with respect to Streptococcus pyogenes and Streptococcus agalactiae infections. Clin Microbiol Infect 2010;16:1097-103. 5. Wang TK, Fung AM, Woo PC, Yuen KY, Wong SS. Streptococcus agalactiae (Lancefield group B) bacteraemia in nonpregnant adults. Eur J Clin Microbiol Infect Dis 2002;21:140-2. 6. Kamaratos A, Kokkoris S, Tzanakari A, Protopsaltis J, Varytimiadis K, Lentzas J, et al. Group B streptococcus (Streptococcus agalactiae) meningitis in a diabetic adult. Acta Diabetol 2005;42:117-8. 7. Schuchat A. Epidemiology of group B streptococcal disease in the United States: shifting paradigms. Clin Microbiol Rev 1998;11: 497-513. 8. Lee K, Shin JW, Chong Y, Mikamo H. Trends in serotypes and antimicrobial susceptibility of group B streptococci isolated in Korea. J Infect Chemother 2000;6:93-7. 9. Jackson LA, Hilsdon R, Farley MM, Harrison LH, Reingold AL, Plikaytis BD, et al. Risk factors for group B streptococcal disease in adults. Ann Intern Med 1995;123:415-20. 10. Kim BN, Bae IG, Kim MN, Woo JH, Ryu J, Kim YS. Group B streptococcal bacteremia in nonpregnant adults with hepatic disease in Korea. Eur J Clin Microbiol Infect Dis 2001;20:639-42. 11. Uh Y, Choi SJ, Jang IH, Lee KS, Cho HM, Kwon O, et al. Colonization rate, serotypes, and distributions of macrolide-lincosamide-streptogramin B resistant types of group B streptococci in pregnant women. Korean J Clin Microbiol 2009;12:174-9. 12. Shin JW, Roh KH, Lee K, Chong Y. Group B streptococcus isolated from bacteremic patients: serotypes and antimicrobial susceptibilities. Korean J Clin Microbiol 1999;2:220-4. 13. Uh Y, Kim HY, Jang IH, Hwang GY, Yoon KJ. Correlation of serotypes and genotypes of macrolide-resistant Streptococcus agalactiae. Yonsei Med J 2005;46:480-3.

Kyutaeg Lee, et al. : GBS Bacteremia in Adults Living in Jeju Island 13 = 국문초록 = Streptococcus agalactiae 균혈증의임상적특성 제주한라병원진단검사의학과 1, 감염내과 2, 제주한라대학임상병리과 3 이규택 1, 김우진 1, 김동렬 1, 고현미 1, 백승희 2, 김미나 2, 정무상 3 배경 : Streptococcus agalactiae (Group B streptococcus, GBS) 는주로임신부의생식기에흔히정착하여신생아수막염과균혈증의주요원인균으로알려져있다. 최근에는 GBS에의한신생아감염은드물고성인에서균혈증, 요로감염등의감염증을유발하는데대부분고령, 당뇨, 암종, 간질환등의선행질환을동반하고있음이알려져있다. GBS에의한균혈증은최근발생건수가해마다증가되고있으며 erythromycin, clindamycin, tetracycline 항생제에대한내성률도해마다증가되고있다. 이에본연구자들은제주지역에서 GBS에의한균혈증으로입원한환자의임상적특성을조사하여보았다. 방법 : 2008년 1월부터 2013년 12월까지제주의한병원에입원한환자중에서혈액배양배양에서 GBS가동정된환자를대상으로연령, 성별, 기저질환, 사망률, 피부병변, 혈액검사, 기타배양검사등에대하여의무기록을토대로후향적으로조사하였다. 결과 : 연구기간동안 GBS 균혈증이 22명의성인이진단되었다. 균혈증군의평균나이는 66.2세이며 15명 (68%) 이 60세이상였다. 20명 (91%) 는암종, 간질환, 당뇨등의기저질환을가지고있었고 10명 (45%) 은피부병변이동반되었으며대부분하지와둔부의피부병변였다. 15명 (68%) 은입원당시에발열이있었고 21명 (95%) 은응급의학과를통해입원하였다. 2명 (9%) 은입원후기존질환의악화로사망하였다. 혈액검사에서백혈구수, 호중구백분율및 CRP는각각 11,488/μL, 84.3%, 13.5 mg/dl였다. GBS는모두 penicillin, ampicillin, vancomycin에대해모두감수성을보였으나 erythromycin, clindamycin, tetracycline에대한내성률이각각 25%, 30%, 55% 였다. 결론 : GBS에의한균혈증환자는고령이며암종, 간질환, 당뇨의기저질환자에서유발되었으며열성응급질환을유발하며백혈구수, 호중구및 CRP의증가가관찰되었다. GBS 균혈증환자의 45% 는피부병변을동반되었고 GBS 균혈증의한원인이라판단된다. [Ann Clin Microbiol 2014;17:9-13] 교신저자 : 이규택, 690-766, 제주도제주시도령로 65 제주한라병원진단검사의학과 Tel: 064-740-5256, Fax: 064-740-5657 E-mail: kyutaeg@daum.net