편집순서 1 : 겉표지 주 의 학술연구용역사업최종결과보고서 이보고서는질병관리본부에서시행한학술연구용역사업의최종결 과보고서입니다 과 국문과제명 제 명 영문과제명 이보고서내용을발표할때에는반드시질병관리본부에서시행한 학술연구용역사업의연구결과임을밝혀야합니다 주 의 ( 주의내용기재

편집순서 1 : 겉표지 주 의 학술연구용역사업최종결과보고서 이보고서는질병관리본부에서시행한학술연구용역사업의최종결 과보고서입니다 과 국문과제명 제 명 영문과제명 이보고서내용을발표할때에는반드시질병관리본부에서시행한 학술연구용역사업의연구결과임을밝혀야합니다 주 의 ( 주의내용기재 ) 2 0 주관연구기관 : 국가과학기술기밀유지에필요한내용은대외적으로발표또는공개 하여서는아니됩니다 ( 글 14 point 고딕체 ) 질병관리본부 질병관리본부 1 2

과제번호 학술연구용역사업연구결과점검보고서 2012E4400400 목 차 과제명주관연구기관 국문 영문 Antimicrobial resistance and molecular epidemiology of major pathogens isolated from patients with bacteremia and urinary tract infection 기관명소재지대표 서울송재훈 Ⅰ. 연구개발결과요약문 ( 한글 ) 성명소속및부서전공 ( 영문 ) 주관연구 정두련 감염내과 책임자 연락처 이메일 Ⅱ. 학술연구용역사업연구결과 연구비 109,000천원연구기간 2012.03.16-2012.12.15 총참여연구원비고 31명 ( 책임연구원 : 명, 연구원 : 21명, 연구보조원 : 10명보조원 : 명 ) 보안성유 ( ) 무 (O) 2012년도학술연구용역사업에의하여수행중인학술연구용역과제의최종결과보고서를붙임과같이제출합니다. 제1장최종연구개발목표제2장최종연구개발내용및방법제3장최종연구개발결과제4장연구결과고찰및결론제5장연구성과및활용계획제6장기타중요변경사항제7장연구비사용내역제8장첨부서류 2012 년 12 월 11 일 주관연구책임자정두련 ( 인또는서명 ) 주관연구기관장송재훈 ( 직인 ) 질병관리본부장귀하 1 2

과제명 중심단어 항생제내성, 임상진단, 균혈증, 요로감염 주관연구기관아시아태평양감염재단주관연구책임자정두련 연구기간 2012.03.16-2012.12.15. 2006 2007.,,. 16 2012 MC,. ESBL ESBL MRSA.. E. coli (34.5%), K. pneumoniae (17.5%), S. aureus (12.9%), P. aeruginosa (6.5%), E. faecium (4.9%), Enterobacter spp. (4.3%), coagulase-negative staphylococci (4.1%), Acinetobacter spp. (3.7%), E. faecalis (2.6%), Streptococcus spp. (2.0%), S. pneumoniae (1.2%). E. coli (61.9%), K. pneumoniae (9.7%), E. faecalis (7.2%), P. aeruginosa (6.0%), Enterobacter spp. (2.9%), E. faecium (2.9%), Proteus spp. (1.9%), Acinetobacter spp. (1.7%), Citrobacter spp. (1.2%), S. aureus (1.0%), K. oxytoca (1.0%). 2006 2007 K. pneumoniae, coagulase-negative staphylococci. 2006 2007 P. aeruginosa ceftazidime, cefepime, piperacillin/tazobactam, imipenem, meropenem, amikacin, ciprofloxacin, E. coli ciprofloxacin, cefotaxime, piperacillin/tazobactam, carbapenem. E. faecium vancomycin. (31.5% vs. 13.6%, P<0.001) 30 (18.5% vs. 11.1%, P=0.004). ESBL ESBL ESBL E. coli ESBL CTX-M-14 CTX-M-15, K. pneumoniae CTX-M-15. MRSA 24% SCCmec type V ST72 CA-MRSA PFGE., P. aeruginosa, E. coli, E. faecium.. Title of Project Key Words Antimicrobial resistance and molecular epidemiology of major pathogens isolated from patients with bacteremia and urinary tract infection Antimicrobial resistance, Clinical diagnosis, Bacteremia, Urinary tract infection nstitute Asia Pacific Foundation for nfectious Diseases Project Leader Doo Ryeon Chung Project Period 2012.03.16-2012.12.15 ncreased emergence and rapid spread of antibiotic-resistant pathogens have caused big concerns in treatment of infections, and selection of appropriate antimicrobial agents for empirical treatment of infections and effective infection control policies have become essential. n this study, we updated the etiologies of bacteremia and urinary tract infection and antimicrobial resistance in major pathogens using the bacterial strains and the clinical database from a Korean nationwide collection in 2012, and compared our results with those of previous study in 2006 2007. We also determined the clinical impact of antimicrobial resistance in bacteremia and urinary tract infection. The mechanisms of antimicrobial resistance and regional transmission were investigated in some bacterial species. Bacterial isolates and clinical record forms collected from 16 hospitals were transported to a reference center, and MCs were tested by broth microdilution method and antimicrobial susceptibility were determined according to the CLS criteria. For ESBL-producing E. coli or K. pneumoniae, ESBL genes were tested using the PCR. Community-associated MRSA strains were molecularly characterized. The most frequent etiology of bacteremia was E. coli (34.5%), followed by K. pneumoniae (17.5%), S. aureus (12.9%), P. aeruginosa (6.5%), E. faecium (4.9%), Enterobacter spp. (4.3%), coagulase-negative staphylococci (4.1%), Acinetobacter spp. (3.7%), E. faecalis (2.6%), Streptococcus spp. (2.0%), and S. pneumoniae (1.2%). E. coli (61.9%) was the most frequent etiology of urinary tract infection, followed by K. pneumoniae (9.7%), E. faecalis (7.2%), P. aeruginosa (6.0%), Enterobacter spp. (2.9%), E. faecium (2.9%), Proteus spp. (1.9%), Acinetobacter spp. (1.7%), Citrobacter spp. (1.2%), S. aureus (1.0%), and K. oxytoca (1.0%). Our results on bacterial etiologies of bacteremia and urinary tract infection are generally similar to those of previous study in 2006 2007 except that the frequency of K. pneumoniaeis higher compared to a previous study. The frequency of coagulase-negative staphylococci in bacteremia become much lower and it probably resulted from that we excluded the culture results suggestive of contamination with no definite evidence of true bacteremia. Comparison of antimicrobial resistance of major pathogens of bacteremia and urinary tract infection to those of study in 2006 2007 showed that resistance rates of P. aeruginosa to ceftazidime, cefepime, piperacillin/tazobactam, imipenem, meropenem, amikacin, and ciprofloxacin increased during the five years. Resistance rates of E. coli to ciprofloxacin, cefotaxime, piperacillin/tazobactam, and carbapenem also increased. Among Gram-positive bacteria, vancomycin resistance of E. faecium showed increased rates (20.9% from 15.6% in bacteremia). n bacteremia, the rates of initial treatment failure (31.5% vs. 13.6%, P<0.001) and overall 30-day mortality rates (18.5% vs. 11.1%, P=0.004) were higher in the patients receiving inappropriate intial empirical antimicrobial therapy compared to those receiving appropriate therapy. ESBL genotyping revealed that CTX-M-14 and CTX-M-15 were the most frequent types of ESBL-producing E. coli, and CTX-M-15 was the most frequent type of ESBL-producing K. pneumoniae. Twenty-four percent of MRSA isolates carried SCCmec type V, and all those isolates except one belonged to ST72, which were closely related in PFGE patterns. Our results suggest that antimicrobial resistance of major pathogens of bacteremia and urinary tract infection is serious, and especially antimicrobial resistance rates of P. aeruginosa, E. coli, and E. faecium have significantly increased during the past 5 years. Continued surveillance of changing antimicrobial resistance of major pathogens is necessary, and more active strategies against antimicrobial resistance are required through researches on resistance mechanisms and determination of transmission of resistant pathogens. 3 4

(2) 학술연구용역사업연구결과제 1 장최종연구개발목표 (1) l 1940 l l (World Health Organization, WHO. 2008) 2 (24%) l l, 2-13 (Roberts RR, et al. Clin nfect Dis 2009;49:1175-84) l (Boucher HW, et al. Clin nfect Dis 2009;48:1-12) l l 2000 " " l 10 2010 10 (Bull World Health Organ 2010;88:805806) l., l l (Maragakis LL, et al. Expert Rev Anti nfect Ther 2008;6:751-63) l 200 350 (Roberts RR, et al. Clin nfect Dis 2009;49:1175-84) l, (Owens RC Jr. Diag Microb nfect Dis 2008;61:110-28) l l l 연구목적 - -, - Streptococcus pneumoniae, Staphylococcus aureus, Enterococcus, Escherichia coli, Klebsiella pneumoniae, Enterobacter, Pseudomonas aeruginosa, Acinetobacter - () 5 6

- 1.2 1.3 (1) - Korean Nationwide Surveillance of Antimicrobial Resistance (KONSAR) - - - 2006-2007 5 - (2) - - - (ANSORP) 1996,, 14 (3) - (APFD) 1999 12, " (Asian Network for Surveillance of Resistant Pathogens, ANSORP)" - ANSORP,, 2012 14 120 230-1996,, - 1997 " (SAAR)" 2, -, 2003 "KONSD (Korean Network for Study of nfectious Diseases)". 7 8

20 ( 11, 9) - " ",, - know-how 제 2 장최종연구개발내용및방법 2.1 () l l l l () l () () l l l l () l () () l l 2.2, (RB), 2006-2007 9 10

. (ii) transport (central lab ) (), CLS (Clinical and Laboratory Standards nstitute) broth microdilution method (MC) 2011 CLS / Streptococcus pneumoniae, Staphylococcus aureus, Enterococcus, Escherichia coli, Klebsiella pneumoniae, Enterobacter, Pseudomonas aeruginosa, Acinetobacter (2006-2007 S. pneumoniae 30-40, S. aureus 200-300, Enterococcus 100-150, E. coli 400, K. pneumoniae 200, Enterobacter 50, Pseudomonas aeruginosa 100, Acinetobacter 50 ) E. coli, Klebsiella ESBL, CLS double-disk synergy. A. (2 ) Central lab, 2 70 (Deep freezer). ) -70 (central lab ) 1) Tryptic soy broth (TSB) brain heart infusion (BH) 2) Glycerol 50%. 3) 1)2) (glycerol 25%). 4) Cryo vial 1ml 4. (heavy inoculum). B. (2 ) (i) blood agar plate parafilm (),, 10 5 CFU/ml ( 10 4 CFU/ml ), (,,, ) (,,,, ) :,,, 1, CLS (Clinical and Laboratory Standards nstitute) broth microdilution method (MC) 2011 CLS / Enterococcus, Escherichia coli, Klebsiella pneumoniae, Enterobacter, Pseudomonas aeruginosa, Acinetobacter (2006-2007 Enterococcus 200, E. coli 1,000, 11 12

Klebsiella 200, Enterobacter 50, Pseudomonas aeruginosa 100-150, Acinetobacter 50 ) E. coli, Klebsiella ESBL, CLS double-disk synergy () ESBL PCR ESBL., bla CTX-M, bla SHV, bla TEM PCR PCR primers, subtyping GenBank nucleotide S. aureus SCCmec typing MRSA SCCmec type V MLST, PVL toxin SCCmec methicillin mec genetic element SCCmec type,,, V, V. type pattern MRSA. SCCmec typing Oliveira de Lencastre (2002) multiplex PCR. CA-MRSA SCCmec type V primer subtype. mecva F: 5 -TTT GAA TGC CCT CCA TGA ATA AAA T-3 R: 5 -AGA AAA GAT AGA AGT TCG AAA GA-3 mecvb F: 5 -AGT ACA TTT TAT CTT TGC GTA-3 R: 5 -AGT CAT CTT CAA TAT CGA GAA AGT A-3 mecvc F: 5 -TGG GGT ATT TTT ATC TTC AAC TC-3 R: 5 -TGG GAT TTT AAA GCA GAA TAT CA-3 mecvd F: 5 -ACG GGA GAT TAG GAG ATG TTA T-3 R: 5 -CAG CCA TCA ATT TTG TTT CAC C-3 MRSA(CA-MRSA) pulsed-field gel electrophoresis (PFGE) multilocus sequence typing (MLST) PFGE Pfaller (1995). 1 MBL 18 tryptic soy broth 8. 2PV buffer(10 mm Tris, 1 M NaCl) 5 ml 4 108 CFU/ml. 3 1.3% ncert agarose (low-melting agarose: FMC no. 50121) 1 ml plug mold 4 20. 4 Lysozyme (BM no.107255) 1 mg/ml RNase lysis buffer (6 mm Tris, 1 M NaCl, 100 mm EDTA, 0.5% Brij-58, 0.2% sodium deoxycholate, 0.5% sodium lauroyl sarcosine) 10 ml plug 37 1-2. 5 ESP (0.5 M EDTA, 10% sodium lauroyl sarcosine, proteinase K (Sigma no.p-4914) 100 μg/ml) 50 3 16-24. 6 1X TE (10 mm Tris, 1m M EDTA) 10 ml 37 2 2 TE. 7 plug buffer Sma 10 U 37 24 1X TE (10 mm Tris, 1 mm EDTA) 1ml 50 2. 8 CHEF-DR system (Bio-Rad), 200 Volt, 5-15, Run-time 10 1, 15-45, Run-time 10 2. 9 ethidium bromide. PFGE pattern Bionumerics software (Applied Maths, Austin, TX), UPGMA dendrogram. PFGE type PFGE band 3 group. MLST 2-3 colony boiling-lysis DNA. DNA MLST 7 housekeeping gene primer premixe mixture PCR. EtBR agarose gel, DNA purification kit. automated DNA sequencer, allele sequence type (ST) (www.mlst.net), eburst program ST clonality. S. aureus MLST housekeeping gene primer (Enright et al., 2000). arcc (Carbamate kinase) arc up - 5' TTG ATT CAC CAG CGC GTA TTG TC -3' arc dn - 5' AGG TAT CTG CTT CAA TCA GCG -3' aroe (Shikimate dehydrogenase) aro up - 5' ATC GGA AAT CCT ATT TCA CAT TC -3' aro dn - 5' GGT GTT GTA TTA ATA ACG ATA TC -3' glpf (Glycerol kinase) glp up - 5' CTA GGA ACT GCA ATC TTA ATC C -3' glp dn - 5' TGG TAA AAT CGC ATG TCC AAT TC -3 13 14

gmk (Guanylate kinase) gmk up - 5' ATC GTT TTA TCG GGA CCA TC -3' gmk dn - 5' TCA TTA ACT ACA ACG TAA TCG TA -3' pta (Phosphate acetyltransferase) pta up - 5' GTT AAA ATC GTA TTA CCT GAA GG -3' pta dn - 5' GAC CCT TTT GTT GAA AAG CTT AA -3' tpi (Triosephosphate isomerase) tpi up - 5' TCG TTC ATT CTG AAC GTC GTG AA -3' tpi dn - 5' TTT GCA CCT TCT AAC AAT TGT AC -3' yqil (Acetyle coenzyme A acetyltransferase) yqi up- 5' CAG CAT ACA GGA CAC CTA TTG GC -3' yqi dn- 5' CGT TGA GGA ATC GAT ACT GGA AC 3' () < > Case Report Form (CRF)-bacteremia. Demographic data Center code : ( ) Code of patient: ( ) Age: year Gender: Male Female Date of admission (YY/MM/DD): / / / Date of discharge (YY/MM/DD): / / / Acquisition site : ER or OPD Hospital Date of bacteremia (YY/MM/DD): / / / Date of clear up (YY/MM/DD): / / / Category of infection Community-acquired Healthcare-associated Hospital-acquired Criteria for healthcare-associated infection (multiple choice) - Hospitalization for 2 or more days in the 90 days before infection No Yes - Residence in nursing home or long-term care facility No Yes - Hemodialysis in the30 days No Yes - V therapy or chemotherapy in outpatients clinic or V infusion therapy at home No Yes - Home wound care in the 30 days No Yes. Underlying disease and severity of illness Underlying disease: None Solid tumor Hematologic malignancy Chronic liver disease Cardiovascular disease Neurologic disease Chronic renal disease Diabetes Mellitus Chronic lung disease solid organ transplantation Hematopoietic stem cell transplantation Others ( ) Severity of underlying illness (McCabe and Jackson classification) rapidly fatal ultimately fatal non-fatal 1) rapidly fatal disease : acute leukemia or blastic relapse of chronic leukemia 2) ultimately fatal disease: estimated to become fatal within 4 years 즉 4년안에사망할것같은환자. aplastic anemia, chronic leukemia, myeloma, lymphomas, metastatic carcinomas (metastasis가 있는 cancer 환자 ), polyarteritis, nephritis caused by lupus erythematus (SLE with nephritis) cirrhosis with hepatic coma or bleeding varices (LC환자에서이런합병증이있었던환자 ) chronic renal disease with urea nitrogen retention in excess of 70 mg % ( 곧투석이필요한 CRF 환자나투석중인 ESRD 환자 ) - 추가적으로 severe HF 환자 (dyspnea로입퇴원을반복하고있는환자 ), severe COPD, Tb destroyed lung으로입퇴원을지속적으로반복하고있는환자. 평소 severe pulmonary hypertension이있는호흡기환자도포함될수있음. 3) nonfatal underlying disease diabetes or genitourinary, gastrointestinal, or obstetric conditions... V. Comorbid condition Neutropenia No Yes Corticosteroid use (> 10 mg/d prednisolone for > 3 weeks) No Yes mmunosuppressant use No Yes ndwelling urinary catheter No Yes Central venous catheterization No Yes Percutaneous tube No Yes L-tube insertion No Yes nvasive procedure within 7 days No Yes Recent operation within 3 months No Yes Prior antibiotics use within 1 month No Yes ( ) Prior antibiotics use within 3 month No Yes ( ) Prior colonization of same organism No Yes 15 16

f yes Urine Stool or Rectal swab Pus Nasal swab Others : (described) V. Microbiologic evaluation V. Severity of nfection No SRS SRS Severe sepsis Septic shock Date of culture performed : (YY/MM/DD) / / Pitt bacteremia Score ( ) dentified pathogen from specimens : Streptococcus pneumoniae Staphylococcus aureus Enterococcus faecalis Enterococcus faecium E. coli K. pneumoniae Enterobacter spp. Pseudomonas aeruginosa Acinetobacter baumannii Other isolates, specify ( ) Types of Automated system Microscan Vitek Others, specify ( ) Antimicrobial susceptibility: ( 해당항균제에 S,, R 중에서선택 ) Penicillin ( ) Oxacillin ( ) Vancomycin ( ) Linezolid ( ) Clindamycin ( ) Cefotaxime ( ) Ceftazidime ( ) Cefepime ( ) Tazocin ( ) mipenem ( ) Meropenem ( ) Ertapenem ( ) Ciprofloxacin ( ) Levofloxacin ( ) Gentamicin ( ) Amikacin ( ) Trimethoprim/Sulfamethoxazole ( ) Colistin ( ) Minocycline ( ) Tigecycline ( ) Gram negative : ESBL : No Yes V. Site of nfection Primary bacteremia Catheter related infection Urinary tract infection Pancreaticobiliary infection ntra-abdominal infection Respiratory track infection Skin and soft tissue infection Bone and Joint infection CNS infection Others : V. Antimicrobial therapy nitial empirical antimicrobial therapy (multiple choices): Ampicillin or amoxicillin or those w/ b-lactamase inhibitors (specify: ) Piperacillin/tazobactam (specify: ) Ceftriaxone or cefotaxime 4 th generation cephalosporins (specify: ) 1 st or 2 nd G cephalosporins (specify: ) Aminoglycosides Fluoroquinolones (specify: ) mipenem or meropenem Ertapenem 17 18

Vancomycin or teicoplanin Linezolid TMP/SMX Others (specify: ) Concordance of initial empirical antimicrobial therapy No Yes ( 두가지이상의원인균이확인된경우에는모두에 concordant한항생제가사용된경우에만 Yes ) (increase in serum creatinine of > 2 mg/dl or dialysis after a bacteremic episode) Mechanical ventilator Hospital length of stay after bacteremia (Day): F no admission, 0 30-day mortality: Survival Death nfection-related 30-day mortality: No Yes Time-to-death (days): days after diagnosis nitial empirical regimen 이 discordant 했다면 culture 결과토대로 concordant 한항생제로 modification 되었 는가? No Yes è 이경우 concordant한항생제로변경될때까지의경과된시간은? ( 초기경험적항생제투여시 점으로부터 ) < 24h 24 48h 48 72h 72 96h > 96h 배양결과를토대로변경된항생제는? (multiple choices) Ampicillin or amoxicillin or those w/ b-lactamase inhibitors (specify: ) Piperacillin/tazobactam (specify: ) Ceftriaxone or cefotaxime 4 th generation cephalosporins (specify: ) 1 st or 2 nd G cephalosporins (specify: ) Aminoglycosides Fluoroquinolones (specify: ) mipenem or meropenem Ertapenem Vancomycin or teicoplanin Linezolid TMP/SMX Others (specify: ) X. Outcome evaluation Early outcome at 72h of initial antimicrobial therapy Complete response (resolved all symptoms and improved of laboratory finding) Partial response Failure (progression of infection or death) During treatment : CU care Acute Kidney injury < > Case Report Form (CRF) Urinary tract infection. Demographic data Center Code ( ) Code of patient: ( ) Age: year Gender: Male Female Date of admission (YY/MM/DD): / / / Date of discharge (YY/MM/DD): / / /. nclusion Criteria 1+ 2+3 1. Any of fever, urinary frequency, voiding difficulty, suprapubic pain, CVA tenderness 2. One or more of followings A. Positive dipstick for leukocyte esterase and/or nitrite B. Pyuria ( 10 WBC/uL or 3 WBC /HPF ) C. Organisms seen on Gram stain 3. Bacteria isolated from the culture Urine culture : 10 5 CFU/uL in voided urine or 10 3 CFU/uL in catheterized urine Or Blood culture +. Category of nfection According to site of infection Acute pyelonephritis Cystitis Renal abscess Acute prostatitis Prostatic abscess 19 20

Others, specify ( ) Other isolates, specify ( ) According to onset of infection Community-acquired Healthcare-associated Hospital-acquired Criteria for healthcare-associated infection (multiple choices): Hospitalization for 2 or more days in the 90 days before infection Attend a hospital in the 30 days Hemodialysis in the 30 days ntravenous therapy in the 30 days Home wound care in the 30 days Nursing home or long-term care facility Uncomplicated vs. complicated Uncomplicated Complicated Definition of complicated UT ndwelling urinary catheter Percutaneous nephrostomy Anatomical or functional abnormality of urinary tract History of urinary intervention within a month before onset of infection UT developing in male (f yes, answer the followings) Prostatitis Benign prostatic hypertrophy Prostate cancer [Organism 1] Antimicrobial susceptibility: ( 해당항균제에 S,, R 중에서선택 ) Penicillin ( ) Oxacillin ( ) Vancomycin ( ) Linezolid ( ) Clindamycin ( ) Cefotaxime ( ) Ceftazidime ( ) Cefepime ( ) Tazocin ( ) mipenem ( ) Meropenem ( ) Ertapenem ( ) Ciprofloxacin ( ) Levofloxacin ( ) Gentamicin ( ) Amikacin ( ) Trimethoprim/Sulfamethoxazole ( ) Colistin ( ) Minocycline ( ) Tigecycline ( ) Gram negative : ESBL : No Yes [Organism 2] E. coli K. pneumoniae Enterobacter spp. Proteus Enterococcus faecalis Enterococcus faecium Staphylococcus aureus Pseudomonas aeruginosa Acinetobacter baumannii Other isolates, specify ( ) [Organism 2] Antimicrobial susceptibility: ( 해당항균제에 S,, R 중에서선택 ) Penicillin ( ) Oxacillin ( ) Vancomycin ( ) Linezolid ( ) Clindamycin ( ) Cefotaxime ( ) Ceftazidime ( ) Cefepime ( ) Tazocin ( ) mipenem ( ) Meropenem ( ) Ertapenem ( ) Ciprofloxacin ( ) Levofloxacin ( ) Gentamicin ( ) Amikacin ( ) Trimethoprim/Sulfamethoxazole ( ) Colistin ( ) Minocycline ( ) Tigecycline ( ) V. Microbiologic data Type of Automated system for D and susceptibility test Microscan Vitek Others, specify ( ) Culture specimen of collected isolate: Blood Urine Date of culture performed : (YY/MM/DD) / / Monomicrobial vs. Polymicrobial [Organism 1] E. coli K. pneumoniae Enterobacter spp. Proteus Enterococcus faecalis Enterococcus faecium Staphylococcus aureus Pseudomonas aeruginosa Acinetobacter baumannii Gram negative : ESBL : No Yes [Organism 3] E. coli K. pneumoniae Enterobacter spp. Proteus Enterococcus faecalis Enterococcus faecium Staphylococcus aureus Pseudomonas aeruginosa Acinetobacter baumannii Other isolates, specify ( ) [Organism 3] Antimicrobial susceptibility: ( 해당항균제에 S,, R 중에서선택 ) Penicillin ( ) Oxacillin ( ) Vancomycin ( ) Linezolid ( ) Clindamycin ( ) Cefotaxime ( ) Ceftazidime ( ) Cefepime ( ) Tazocin ( ) mipenem ( ) Meropenem ( ) Ertapenem ( ) Ciprofloxacin ( ) Levofloxacin ( ) Gentamicin ( ) Amikacin ( ) Trimethoprim/Sulfamethoxazole ( ) Colistin ( ) Minocycline ( ) Tigecycline ( ) 21 22

Gram negative : ESBL : No Yes V. Underlying diseases None Solid tumor Hematologic malignancy Chronic liver disease Cardiovascular disease Neurologic disease Chronic renal disease Diabetes Mellitus Solid organ transplantation ( Kidney transplantation Other solid organ transplantation) Hematopoietic stem cell transplantation or BMT Others ( ) Severity of underlying illness (McCabe and Jackson classification) rapidly fatal ultimately fatal non-fatal 1) rapidly fatal disease : acute leukemia or blastic relapse of chronic leukemia 2) ultimately fatal disease: estimated to become fatal within 4 years 즉 4년안에사망할것같은환자. aplastic anemia, chronic leukemia, myeloma, lymphomas, metastatic carcinomas (metastasis가 있는 cancer 환자 ), polyarteritis, nephritis caused by lupus erythematus (SLE with nephritis) cirrhosis with hepatic coma or bleeding varices (LC환자에서이런합병증이있었던환자 ) chronic renal disease with urea nitrogen retention in excess of 70 mg % ( 곧투석이필요한 CRF 환자나투석중인 ESRD 환자 ) - 추가적으로 severe HF 환자 (dyspnea로입퇴원을반복하고있는환자 ), severe COPD, Tb destroyed lung으로입퇴원을지속적으로반복하고있는환자. 평소 severe pulmonary hypertension이있는호흡기환자도포함될수있음. 3) nonfatal underlying disease diabetes or genitourinary, gastrointestinal, or obstetric conditions... V. Comorbid conditions Pregnancy No Yes Neurogenic bladder No Yes Neutropenia No Yes Previous genitourinary surgery or procedure within 72hr No Yes Recurrent UT ( 2 episodes/6 months or 3 episodes/ 1year ) No Yes Presence of urologic devices No Yes (DJ catheter, supurapubic cather, PCN) Patients with intermittent catheterization No Yes Patients with indwelling urethral catheters No Yes Prior use of antibiotics within 3 months No Yes f YES : Specific antibiotics: V. Clinical Data Hydronephrosis No Yes Stone disease of urinary tract No Yes Concomitant Bacteremia No Yes Severity of infection No SRS Sepsis (SRS) Sever sepsis Septic shock V. Antimicrobial therapy nitial empirical antimicrobial therapy (multiple choices): Ampicillin or amoxicillin or those w/ b-lactamase inhibitors (specify: ) Piperacillin/tazobactam (specify: ) Ceftriaxone or cefotaxime 4 th generation cephalosporins(specify: ) 1 st or 2 nd G cephalosporins(specify: ) Aminoglycosides Fluoroquinolones (specify: ) mipenem or meropenem Ertapenem Vancomycin or teicoplanin Linezolid TMP/SMX Others (specify: ) Concordance of initial empirical antimicrobial therapy No Yes ( 두가지이상의원인균이확인된경우에는모두에 concordant한항생제가사용된경우에만 Yes ) nitial empirical regimen이 discordant 했다면 culture 결과토대로 concordant한항생제로 modification 되었 는가? No Yes è 이경우 concordant한항생제로변경될때까지의경과된시간은? ( 초기경험적항생제투여시 점으로부터 ) < 24h 24 48h 48 72h 72 96h > 96h 배양결과를토대로변경된항생제는? (multiple choices) Ampicillin or amoxicillin or those w/ b-lactamase inhibitors (specify: ) Piperacillin/tazobactam (specify: ) 23 24

Ceftriaxone or cefotaxime 4 th generation cephalosporins (specify: ) 1 st or 2 nd G cephalosporins (specify: ) Aminoglycosides Fluoroquinolones (specify: ) mipenem or meropenem Ertapenem Vancomycin or teicoplanin Linezolid TMP/SMX Others (specify: ) 제 3장최종연구개발결과 3.1-36%, 25%, 39%( 1). 640(56.5%), 492 (43.5%). 47.7%, 52.3%. X. Outcome evaluation Clinical Outcome Time to defervescence (24시간이상지속적으로 37.8도미만유지 ): ( ) hours after starting antimicrobial treatment < 24h 24 48h 48 72h 72 96h > 96h During treatment Acute Kidney njury No Yes nvasive procedure or surgical procedure No Yes f Yes, specify: ( ) Hospital stay after Dx. of UT (Days) days (f no admission: 0 ) 30-day all-cause mortality: Survival Death nfection-related 30-day mortality: No Yes Time to Death (Days): days after diagnosis 1. (N=1118) - (community-onset healthcare-associated infection) 90 (70.5%), (17.1%), (12.8%), 30 (5.3%), (2.5%). 3.1.1-1191 E. coli 435(36.5%), K. pneumoniae 239(20.1%), S. aureus 188(15.8%), E. faecium 87(7.3%), P. aeruginosa 75(6.3%), E. faecalis 56(4.7%), Enterobacter spp. 50(4.2%), Acinetobacter spp. 35(2.9%), S. pneumoniae 14 (1.2%), S. maltophilia 12(1.0%) ( 2). 25 26

2. (N=1,191) - E. coli (34.5%), K. pneumoniae (17.5%), S. aureus (12.9%), P. aeruginosa (6.5%), E. faecium (4.9%), Enterobacter spp. (4.3%), coagulase-negative staphylococci (4.1%), Acinetobacter spp. (3.7%), E. faecalis (2.6%), Streptococcus spp. (2.0%), S. matlophilia (1.7%), S. pneumoniae (0.8%) ( 3). 3. (N=1132) 3.1.2-2006 2007 Coagulase-negative staphylococci. K. pneumoniae S. aureus.. - S. aureus penicillin 94.4%, oxacillin 64.0%. Ciprofloxacin, clindamycin, erythromycin, tetracycline, gentamicin 49.1%, 49.1%, 57.8%, 46.6%, 43.5% rifampicin 8.1%, cotrimoxazole 5.0%. Linezolid. - E. faecium E. faecalis ampicillin 88.1%, vancomycin 20.9% gentamicin 56.7%, streptomycin 32.8%. Linezolid. Vancomycin 2006 2007 15.6%. - E. faecalis ampicillin vancomycin 1(2.4%). 27 28

11.3%. mipenem 2 (4.6%), ertapenem 13.6%. Tigecycline 45.5%. Ertapenem tigecycline. - P. aeruginosa ceftazidime, piperacillin/tazobactam, cefepime 50.0%, 39.3%, 35.7%, amikacin, ciprofloxacin 21.4%, 32.1%. mipenem meropenem 42.9%, 35.7% colistin 10.7%. 2006 2007 amikacin, ciprofloxacin. - Acinetobacter spp., 7 2 imipenem meropenem, 1 colistin.. - E. coli ampicillin 68.7%, gentamicin 28.0%, cotrimoxazole 40.4%, ciprofloxacin 37.0%, cefotaxime 28.9%, ampicillin/sulbactam 53.2%, piperacillin/tazobactam 11.2%. ESBL 26.2%. mipenem, ertapenem 1.8%. Tigecycline 2.1%. E. coli 2006 2007. - K. pneumoniae ampicillin 93.0% gentamicin 13.0%, cotrimoxazole 13.0%, ciprofloxacin 16.0%, cefotaxime 20.5%, ampicillin/sulbactam 21.5%, piperacillin/tazobactam 8.5%. ESBL 22.0%. mipenem 3 (1.5%), ertapenem 1.0%. Tigecycline 20.0%. 2006 2007 cefotaxime ( 14.5%). - Enterobacter spp. ampicillin (88.6%) ampicillin/sulbactam (61.4%), gentamicin 9.1%, cotrimoxazole 25.0%, ciprofloxacin 13.6%, cefotaxime 31.8%, piperacillin/tazobactam 29 30

-,,. - E. coli TMP/SMX 23.2%, 50.7% ciprofloxacin 25.4%, 50.0%. E. coli. - S. aureus oxacillin 17.9%, 71.4%. 52.1%, 50.0%.. 3.1.3 -, E. coli 52.1%, 33.1%, 18.6% (). K. pneumoniae (17.7%), S. aureus (16.8%) P. aeruginosa (9.8%), E. faecium (8.6%), A. baumannii (6.5%), S. pneumoniae. ( 4). - (40.5%), (22.9%) (10.3%), (19.6%), (25.6%) (17.7%), (15.4%), (17%), (11.7%) (10%). - S. aureus, S. pneumoniae, E. faecium, A. baumannii, CoNS (). Variables Gender Overall (N=1132) Communityassociated (N=407) Community-onset Healthcare-assoc iated (N=281) Hospital-onset (N=430) Female 527 (46.6) 215 (52.8) 124 (44.1) 182 (42.2) Age, mean (SD) 60.1 (19.7) 62.2 (20.3) 62.1 (18.0) 57.7 (20.0) Culture Acqusition site N=354 N=274 N=411 ER or OPD 544 (52.3) 315 (88.9) 219 (79.9) 9 (2.2) Hospital 497 (47.7) 39 (11.1) 55 (20.1) 402 (97.8) Etiology E. coli 391 (34.5) 212 (52.1) 93 (33.1) 80 (18.6) K. pneumoniae 198 (17.5) 70 (17.2) 51 (18.1) 76 (17.7) S. aureus 146 (12.9) 33 (8.1) 39 (13.9) 72 (16.8) P. aeruginosa 74 (6.5) 11 (2.7) 21 (7.5) 42 (9,8) E. faecium 55 (4.9) 4 (1.0) 14 (5) 37 (8.6) Enterobacter 49 (4.3) 13 (3.2) 16 (5.7) 20 (4.7) CoNS 46 (4.1) 15 (3.7) 9 (3.2) 23 (5.3) A. baumannii 42 (3.7) 3 (0.7) 11 (3.9) 28 (6.5) E. faecalis 29 (2.6) 5 (1.2) 9 (3.2) 15 (3.5) Streptococcus 23 (2.0) 11 (2.7) 5 (1.8) 5 (1.2) S. maltophilia 19 (1.7) 3 (0.7) 6 (2.1) 10 (2.3) S. pneumoniae 9 (0.8) 6 (1.5) 2 (0.7) 1 (0.2) Candida 27 (2.4) 4 (1.4) 21 (4.9) Polymicrobial 53 (4.7) 13 (3.2) 11 (3.9) 29 (6.8) Primary source Primary bacteremia 196 (17.3) 34 (8.4) 52 (18.5) 110 (25.6) CR 96 (8.5) 0 19 (6.8) 76 (17.7) UT 290 (25.6) 165 (40.5) 58 (20.6) 66 (15.4) Hepatobiliary 204 (18) 92 (22.9) 61 (21.7) 50 (11.7) ntra-abdominal 131 (11.6) 42 (10.3) 45 (16) 43 (10) Respiratory 146 (12.9) 43 (10.6) 30 (10.7) 73 (17) 31 32

Skin & soft tissue 47 (4.2) 14 (3.4) 9 (3.2) 22 (5.1) Bone and Joint 28 (2.5) 14 (3.4) 8 (2.8) 6 (1.4) Central nervous system 6 (0.5) 5 (1.2) 1 (0.4) 0 21 6 6 9 Others No. (%) E:13 Graft infection: 2 Chorioamnionitis:1 PD: 2 Perianal infection: 2 Necrotizing gingivitis: 1 E: 4 Graft infection: 1 Necrotizing gingivitis: 1 E: 4 Chorioamnionitis: 1 PD: 1 Graft infection: 1 Perianal infection: 2 4B. (N=281) 4A. (N=407) 4C. (N=430) 33 34

. 종합병원 상급종합병원 (N=452) (N=680) (N=1132) S. pneumoniae 0 9 (1.3) 9 (1.3) S. aureus 36 (8) 110 (16.2) 146 (12.9) E. faecalis 8 (2.1) 21(3.1) 29 (2.8) E. faecium 10 (2.7) 45 (6.6) 55 (5.2) E. coli 136 (30.1) 255 (37.5) 391(34.5) K. pneumoniae 67 (14.8) 131 (19.3) 198 (17.5) Enterobacter 14 (3.1) 35 (5.1) 49 (4.3) P. aeurginosa 28 (6.2) 46 (6.8) 74 (6.5) A. baumannii 22 (4.9) 20 (2.9) 42 (3.7) Acinetobacter spp. 3 4 7 CNS 34 (7.5) 12 (1.8) 46 (4.1) S. maltophilia 10 (2.2) 9 (1.3) 19 (1.7) Streptococcus spp. 10 (2.2) 13 (1.9) 23 (2.0) Others 74 15 89 Polymicrobial 12 (2.7) 41 (6.6) 53 (4.9) 3.1.4 E. coli No. Resistance CO (N=168) 1 HCA (N=76) 2 HO (N=67) 3 Ampicillin S 41 23 14 1 1 R 79 47 47 Amp/sulbactam S 106 32 17 6 5 7 R 7 34 35 Gentamicin S 87 44 41 4 3 2 R 28 25 18 Amikacin S 140 71 59 7 2 3 R 21 3 3 Ciprofloxacin 전체 S 125 44 33 1 2 1 R 43 26 34 TMX/SMZ S 128 49 33 1 R 39 28 34 Cefotaxime S 131 58 33 5 1 R 33 17 34 Piperacillin/tazobactam S 152 71 53 9 6 1 R 7 5 13 Aztreonam S 102 57 36 1 5 R 17 13 20 Ertapenem S 117 75 61 2 3 R 1 3 mipenem S 168 76 66 R 1 Tigecycline S 114 70 58 R 5 1 3 1: Clinical microbiology laboratory results were used for 49 isolates. 2: Clinical microbiology laboratory results were used for 5 isolates. 3: Clinical microbiology laboratory results were used for 6 isolates. K. pneumoniae No. Resistance CO (N=58) 1 HCA (N=49) 2 HO (N=67) 3 Ampicillin S 5 6 6 1 R 42 39 52 Amp/sulbactam S 30 26 36 6 6 6 R 10 12 15 Gentamicin S 43 36 45 35 36

1 R 3 9 12 Amikacin S 55 45 61 1 1 2 R 2 3 3 Ciprofloxacin S 50 37 49 1 2 1 R 8 10 17 TMX/SMZ S 54 40 50 R 4 9 14 Cefotaxime S 51 31 47 1 1 R 7 17 18 Piperacillin/tazobactam S 54 46 52 3 1 3 R 1 2 11 Aztreonam S 43 32 43 1 1 R 4 12 13 Ertapenem S 58 47 65 R 2 1 mipenem S 55 48 64 2 R 1 1 2 Tigecycline S 42 37 48 R 5 8 9 1: Clinical microbiology laboratory results were used for 11 isolates. 2: Clinical microbiology laboratory results were used for 4 isolates. 3: Clinical microbiology laboratory results were used for 9 isolates. S. aureus No. Resistance CO (N=28) 1 HCA (N=29) 2 HO (N=63) 3 Penicillin S 6 19 5 R 22 9 58 Oxacillin S 23 16 18 R 5 12 45 Ciprofloxacin S 26 20 27 1 R 2 8 36 Clindamycin S 25 20 26 R 3 8 37 Erythromycin S 13 10 17 2 1 R 3 8 32 Vancomycin S 27 27 60 R 1 Tetracycline S 17 14 23 R 1 5 26 TMP/SMX S 18 21 50 R 1 Gentamicin S 16 12 28 R 2 7 21 Rifampicin S 15 19 44 1 1 R 2 5 Linezolid S 27 27 60 R 1 1: Clinical microbiology laboratory results were used for 10 isolates. 2: Clinical microbiology laboratory results were used for 9 isolates. 3: Clinical microbiology laboratory results were used for 14 isolates. 37 38

E. faecium HCA HO No. Resistance CO (N= ) 1 (N= ) 2 (N= ) 3 Vancomycin S 3 10 17 R 1 9 Teicoplanin S 2 10 17 2 R 5 Ampicillin S 2 3 1 R 23 Tetracycline S 2 6 20 1 R 3 4 Erythromycin S 1 2 2 R 1 8 22 Ciprofloxacin S 3 3 3 R 9 23 Rifampicin S 2 4 2 5 R 8 15 Linezolid S 1 7 20 1 4 6 R Streptomycin_1000 S P. aeruginosa HCA HO No. Resistance CO (N= ) 1 (N= ) 2 (N= ) 3 mipenem S 4 9 12 1 R 2 12 Meropenem S 4 8 13 2 1 R 6 9 Colistin S 4 6 16 1 R 4 6 Ciprofloxacin S 4 9 15 R 3 10 Cefepime S 4 8 10 5 R 2 8 Ceftazidime S 4 8 11 2 R 3 12 Amikacin S 4 7 20 1 R 4 4 Piperacillin/tazobactam S 4 10 14 R 1 11 R Gemtamicin_500 S R 39 40

S. aureus Resistance 종합 상급종합 전체 Penicillin S 3 12 15 R 21 84 105 Oxacillin S 12 46 68 R 12 50 62 Ciprofloxacin S 12 52 74 R 8 28 36 Clindamycin S 12 60 72 R 12 36 48 Vancomycin S 23 92 115 R 1 1 TMP/SMX S 11 79 90 R 1 1 Rifampicin S 10 69 79 1 1 R 2 6 8 Linezolid S 33 92 115 R 1 1 E. faecium Resistance 종합 상급종합 전체 Vancomycin S 1 29 30 R 1 9 10 Teicoplanin S 29 29 2 2 R 5 5 Ampicillin S 6 6 R 30 30 Ciprofloxacin S 2 7 9 R 32 32 Rifampicin S 6 6 7 7 R 23 23 Linezolid S 2 25 27 12 12 R P. aeruginosa Resistance 종합 상급종합 전체 mipenem S 7 18 25 1 1 R 1 13 14 Meropenem S 6 19 25 1 1 2 R 10 10 Colistin S 26 26 1 R 7 3 10 Ciprofloxacin S 7 21 28 R 1 12 13 Cefepime S 7 15 22 10 10 R 5 5 Ceftazidime S 8 15 23 2 2 R 15 15 Amikacin S 7 24 31 1 1 R 7 7 Piperacillin/tazobactam S 8 20 28 R 12 12 41 42

K. pneumoniae Resistance 종합 상급종합 전체 Ampicillin S 10 7 17 1 1 R 35 98 133 Amp/sulbactam S 30 62 92 3 15 18 R 11 26 51 Gentamicin S 36 88 124 1 1 R 10 14 24 Amikacin S 52 100 161 4 4 R 2 3 8 Ciprofloxacin S 41 95 136 3 1 4 R 13 22 35 TMX/SMZ S 53 91 144 R 4 23 27 Cefotaxime S 45 84 129 1 1 2 R 11 31 42 Piperacillin/tazobactam S 52 100 152 2 5 7 R 3 11 14 Aztreonam S 37 79 118 1 1 2 R 6 23 29 Ertapenem S 56 114 170 R 1 2 3 mipenem S 55 112 167 2 2 R 4 4 Tigecycline S 41 86 127 R 5 17 22 E. coli Resistance 종합 상급종합 전체 Ampicillin S 17 61 78 1 1 2 R 48 126 174 Amp/sulbactam S 29 72 101 1 23 24 R 29 90 119 Gentamicin S 48 125 173 9 9 R 18 53 71 Amikacin S 80 186 266 0 15 15 R 13 16 29 Ciprofloxacin S 69 137 206 1 3 4 R 23 82 105 TMX/SMZ S 76 135 211 1 0 1 R 16 85 101 Cefotaxime S 65 157 222 2 4 6 R 25 58 84 Piperacillin/tazobactam S 73 198 271 10 4 14 R 10 17 27 Aztreonam S 49 146 195 7 7 R 17 33 50 Ertapenem S 91 211 302 2 3 5 R 0 5 5 mipenem S 93 218 311 1 R 1 Tigecycline S 59 184 243 R 7 2 9 43 44

요로감염 - 982, 748 MC. - 865 48.4%, 26.6%, 25%( 5). 42.4%, 57.6%. 864 E. coli (61.9%), K. pneumoniae (9.7%), E. faecalis (7.2%), P. aeruginosa (6.0%), Enterobacter spp. (2.9%), E. faecium (2.9%), Proteus spp. (1.9%), Acinetobacter spp. (1.7%), Citrobacter spp. (1.2%), S. aureus (1.0%), K. oxytoca (1.0%) ( 7). - 2006 2007 K. pneumoniae.. 5. (N=865) 6. (N=982) - (community-onset healthcare-associated infection) 90 (60.4%), (33.5%), (20.9%), (1.7%), 30 (1.3%). 69.4%, 30.6% 57( 23). 344 (39.7%) (53.1%), (48.4%), (32.2%), (9.1%), percutaneous nephrostomy (7.5%), (3.4%), (1.6%). 811 436(53.8%), 35(4.3), 11(1.4%), 9(1.1%), 3(0.4%). 3.2.1-982 E. coli 655(66.7%), K. pneumoniae 90(9.2%), E. faecalis 64(6.5%), P. aeruginosa 58(5.9%), Enterobacter spp. 29 (3.0%), E. faecium 26(2.7%), Proteus spp. 20(2.0%), S. aureus 16(1.6%), Acinetobacter spp. 13 (1.3%), Citrobacter spp. 11(1.1%) ( 6). - 7. (N=864) 45 46

3.2.2 - E. coli cotrimoxazole ciprofloxacin 42.7% 40.5%. Ampicillin, ampicillin/sulbactam, cefotaxime, piperacillin/tazobactam, gentamicin, amikacin 70.5%, 59.5%, 29.1%, 14.0%, 33.5%, 8.8% imipenem ertapenem 1.8% 2.8%. ESBL 29.3%. Tigecycline 0.2%. - K. pneumoniae ampicillin 87.8% gentamicin 18.9%, cotrimoxazole 35.1%, ciprofloxacin 28.4%, cefotaxime 32.4%, ampicillin/sulbactam 40.5%, piperacillin/tazobactam 23.0%. ESBL 38.6%. mipenem 5 (6.8%), ertapenem 10.8%. Tigecycline 17.6%. 2006 2007. - P. aeruginosa ceftazidime, piperacillin/tazobactam, cefepime 70.0%, 67.5%, 65.0%, amikacin, ciprofloxacin 62.5%, 67.5%. mipenem meropenem 55.0%, 65.0% colistin 30.0%. 2006 2007 amikacin, ciprofloxacin. - E. faecalis ampicillin vancomycin, E. faecium ampicillin vancomycin 100% 12.5%. linezolid. 47 48

3.2.3 3.2.4. Community-onset Communityassociated Overall Healthcare-associ Hospital-onset (N=864) ated (N=216) (N=419) (N=230) Gender Female 601 (69.4) 328 (78.3) 131 (57) 141 (65.3) Age, mean (SD) 57.6 (22.9) 55.0 (23.6) 57.1 (25.4) 62.9 (17.3) Complicated UT N=344 N=100 N=118 N=126 Urinary catheter 155 52 41 94 Percutaneous nephrostomy 24 46 13 8 Functional or anatomical urinary tract 103 52 37 14 abnormality Male 170 46 70 54 Prostatitis 11 7 3 1 BPH 29 16 11 2 Prostatic cancer 5 3 1 1 Site of nfection Acute pyelonephritis 436 (50.3) 207 (49.4) 128 (55.7) 101 (46.8) Cystitis 35 (40.6) 185 (44.2) 78 (34.5) 89 (41.2) Renal abscess 9 8 1 0 Prostatitis 11 9 2 0 Prostatic abscess 3 0 3 0 Etiology E. coli 535 (61.8) 325 (77.6) 123 (53.5) 86 (39.8) K. pneumoniae 84 (9.7) 21 (5) 28 (12.2) 35 (16.2) E. faecailis 62 (7.2) 17 (4.1) 23 (10) 22 (10.2) P. aeurginosa 52 (6) 4 18 (7.8) 30 (13.9) Enterobacter 25 (2.9) 11 (2.6) 8 (3.5) 6 (2.8) E. faecium 25 (2.9) 5 (1.2) 5 (2.2) 15 (6.9) Proteus 16 (1.8) 2 (0.5) 11 (4.8) 3 (1.4) A. baumannii 15 (1.7) 2 (0.5) 4 (1.7) 9 (4.2) S. aureus 9 (1.0) 6 (1.4) 1 (0.4) 2 (0.9) Others 53 (6.1) 27 (6.4) 12 (5.2) 14 (6.5) Polymicrobial 12 (1.4) 1 (0.2) 3 (1.3) 8 (3.7) No. (%) E. coli No. Resistance CO (N=188) 1 HCA (N=52) 2 HO (N=53) 3 Ampicillin S 46 12 8 8 5 R 125 34 35 Amp/sulbactam S 61 15 10 15 4 3 R 100 29 30 Gentamicin S 129 31 31 5 1 1 R 54 20 17 Amikacin S 172 43 50 4 1 2 R 12 8 1 Ciprofloxacin S 130 23 21 2 R 56 29 32 TMX/SMZ S 112 25 25 R 67 26 18 Cefotaxime S 143 34 36 R 36 18 17 Piperacillin/tazobactam S 156 39 45 11 7 1 R 21 6 7 Aztreonam S 147 31 35 1 3 1 R 31 17 17 Ertapenem S 180 50 53 3 1 R 5 1 mipenem S 185 50 53 2 R 1 2 49 50

Tigecycline S 174 48 41 R 5 3 2 1: Clinical microbiology laboratory results were used for 9 isolates. 2: Clinical microbiology laboratory results were used for 1 isolates. 3: Clinical microbiology laboratory results were used for 10 isolates. K. pneumoniae No. Resistance CO (N=15) 1 HCA (N=19) 2 HO (N=23) 3 Ampicillin S 1 3 3 1 R 8 16 13 Amp/sulbactam S 7 11 4 1 1 R 6 12 Gentamicin S 14 17 17 R 1 2 6 Amikacin S 15 13 17 6 1 R 5 Ciprofloxacin S 12 13 16 1 R 2 6 8 TMX/SMZ S 9 12 9 R 7 7 Cefotaxime S 8 13 14 R 1 6 9 Piperacillin/tazobactam S 13 14 13 1 4 R 1 5 6 Aztreonam S 8 13 16 1 R 6 8 Ertapenem S 9 18 14 R 1 mipenem 2 S 7 16 21 1 2 1 R 1 1 1 Tigecycline S 6 8 6 R 4 11 10 1: Clinical microbiology laboratory results were used for 6 isolates. 2: Clinical microbiology laboratory results were used for 0 isolates. 3: Clinical microbiology laboratory results were used for 7 isolates. P. aeruginosa HCA No. Resistance CO HO (N= ) 1 (N= ) 2 (N= ) 3 Ceftazidime S 1 4 8 2 R 2 6 14 Cefepime S 1 6 9 R 2 6 13 Ciprofloxacin S 1 6 7 1 R 1 6 15 mipenem S 1 8 9 3 R 2 4 10 Meropenem S 1 6 8 1 1 R 1 6 13 Colistin S 2 8 R 3 2 Amikacin S 1 6 9 1 1 R 1 6 12 51 52

Piperacillin/tazobactam S 2 6 8 R 2 6 14 E. faecalis HCA HO No. Resistance CO (N= ) 1 (N= ) 2 (N= ) 3 Ampicillin S 7 16 11 R 1 1 1 Vancomycin S 7 16 11 R Teicoplanin S 1 11 8 R Tetracycline S 2 R 7 14 Erythromycin S 1 2 2 1 R 5 14 9 Ciprofloxacin S 3 9 6 2 3 2 R 3 6 4 Rifampin S 4 8 7 2 1 R 3 6 3 Streptomycin, high level S 6 10 7 R 1 6 3 3.3. (2006-2007 ) - S. aureus oxacillin (64%) ciprofloxacin, clindamycin, erythromycin, tetracycline 5 TMP/SMX. gentamcin, rifampicin, linezolid ( 8). 8. S. aureus - E. faecium vancomycin (20.9%) 5 ampicillin ciprofloxacin 5 ( 9). Gentamicin, high level S 4 8 5 R 3 8 Linezolid S 6 16 11 1 R 9. E. faecium 53 54

- E. faecalis ciprofloxacin 5 ( 10). - K. pneumoniae cefotaxime 5 ESBL ( 12). 10. E. faecalis - E. coli piperacillin/tazobactam, cefotaxime, ceftazidime beta-lactam ciprofloxacin, gentamicin 5 ESBL ( 11). 12. K. pneumoniae - P. aeruginosa piperacillin/tazobactam, ceftazidime, cefepime, ciprofloxacin, amikacin 5, imipenem, meropenem ( 13). Colistin. 11. E. coli 13. P. aeruginosa 55 56

-... 3.5.1. ESBL - ESBL E. coli K. pneumoniae PCR ESBL., bla CTX-M, bla SHV, bla TEM PCR PCR primers, subtyping GenBank nucleotide. - ESBL E. coli 98 K. pneumoniae 47 beta-lactamase. - 835 238(28.5%)... No. (%) nappropriate initial empirical antimicrobial therapy (N=238) Appropriate initial empirical antimicrobial therapy (N=597) P value nitial treatment failure 75 (31.5) 81 (13.6) <0.001 30-day mortality 44 (18.5) 66 (11.1) 0.004 - ESBL E. coli 182 K. pneumoniae 34 beta-lactamase. - 389 162(41.6%)... Defervescence within 24h of treatment No. (%) nappropriate initial empirical antimicrobial therapy (N=162) Appropriate initial empirical antimicrobial therapy (N=227) P value 93 (57.4) 149 (65.6) 0.099 30-day mortality 6 (3.7) 4 (1.8) 0.233 57 58

- E. coli ESBL CTX-M-14 CTX-M-15, K. pneumoniae CTX-M-15. 3.5.2. MRSA - SCCmec typing MRSA 103 SCCmec type 75(72.8%), SCCmec type V 25 (24.3%). SCCmec type V MLST ST770 ST72. ST770 ST72 DLV (double locus variant) Panton-Valentine leukocidin encoding ST72 ST770. - ST72 CA-MRSA 20 PFGE ( 14). ( 79.4%) 80%. 제 4 장연구결과고찰및결론 - 2006 2007 E. coli, K. pneumoniae, P. aeruginosa. - E. coli, K. pneumoniae, S. aureus, E. faecium, P. aeruginosa, Enterobacter spp., E. faecalis, Acinetobacter spp., S. pneumoniae, Streptococcus spp., coagulase-negative staphylococci, 2006 2007 coagulase-negative staphylococci coagulase-negative staphylococci,. -, E. coli 52.1%, 33.1%, 18.6%. K. pneumoniae, S. aureus P. aeruginosa, E. faecium, A. baumannii, S. pneumoniae.. - K. pneumoniae S. aureus. -,,,,,,. 14. ST72 CA-MRSA PFGE - E. coli, K. pneumoniae, E. faecalis, P. aeruginosa, Enterobacter spp., Acinetobacter spp., E. faecium 2006 2007 K. pneumoniae. -,,. - 2006 2007. - P. aeruginosa, 59 60

. (%) 2006 2007 2012 2006 2007 2012 Ceftazidime 23.5 51.7 43.1 68.9 Piperacillin/tazobactam 28.4 41.4 43.1 64.4 Cefepime 20.6 37.9 46.6 62.2 Amikacin 5.9 20.7 38.8 57.8 Ciprofloxacin 11.8 34.5 47.4 66.7 mipenem 12.8 41.4 33.6 53.3 Meropenem 11.8 34.5 28.5 62.2 Colistin MC90=4 10.3 MC90=2 33.3 제 5장연구성과및활용계획 5.1 과제명 과제책임자 / ( ) / SC 2 Journal of Antimicrobial Chemotherapy, Antimicrobial Agents and Chemotherapy, Journal of Clinical M icrobiology. - E. coli ciprofloxacin, cefotaxime, piperacillin/tazobactam 2006 2007. (%) 2006 2007 2012 2006 2007 2012 Ampicillin 59.5 68.9 70.6 69.4 Ampicillin/sulbactam - 51.8-59.0 Piperacillin/tazobactam 4.9 10.7 5.5 10.6 Gentamicin 22.5 27.2 26.9 31.9 Cotrimoxazole 36.4 40.8 41.4 42.0 Ciprofloxacin 23.9 36.9 30.3 40.3 Cefotaxime 9.4 29.1 10.1 26.4 mipenem 0.2 0.3 0.3 1.2 Ertapenem - 2.3-2.0 - E. coli ciprofloxacin 30.0% 2006 2007 29.0%, TMP/SMX 37.4% 41.1%. 2006-2007, 5 - S. aureus oxacillin 17.9%, 71.4% 2006 2007 17.8%, 69.4%. - E. faecium vancomycin vancomycin 2006 2007 15.6% 20.9%. - P. aeruginosa, E. coli, E. faecium.. 5.2 () () 61 62

제 7 장연구비사용내역및연구원분담표 () () () 63 64

7.2 연구분담표 65 66

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