4. 지침갱신.., 4-5. II. 진료지침개발과정 1. 진료지침위원회구성 Guidelines, The Cochrane Library, KoreaMed cellulitis, erysipelas, skin abscess, soft tissue infection, bite

Transcription

1 Supplementary Infection & Chemotherapy 피부 연조직감염항생제사용지침 곽이경 1,2 *, 최성호 3,4 *, 김탁 1,5 *, 박성연 3,6 *, 서수홍 7,8, 김민범 9,10, 최상호 2,11 1 대한감염학회 ; 2 인제의대내과 ; 3 대한화학요법학회 ; 4 중앙의대내과 ; 5 순천향의대내과 ; 6 동국의대내과 ; 7 대한피부과학회 ; 8 고려의대피부과, 9 대한정형외과학회 ; 10 서울의대정형외과 ; 11 울산의대내과 Skin and soft tissue infection (SSTI) is common and important infectious disease. This work represents an update to 2012 Korean guideline for SSTI. The present guideline was developed by the adaptation method. This clinical guideline provides recommendations for the diagnosis and management of SSTI, including impetigo/ecthyma, purulent skin and soft tissue infection, erysipelas and cellulitis, necrotizing fasciitis, pyomyositis, clostridial myonecrosis, and human/animal bite. This guideline targets community-acquired skin and soft tissue infection occurring among adult patients aged 16 years and older. Diabetic foot infection, surgery-related infection, and infections in immunocompromised patients were not included in this guideline. Key Words: Impetigo; Erysipelas; Cellulitis; Fasciitis; Pyomyositis I. 서론 1. 지침작성의배경.,,,..,,,.., 지침대상집단및제외질환 16.,,,,. 3. 지침활용을권장하는대상,,,,.. Received: September 27, 2017 Published online: December 21, 2017 교신저자 : 최상호 서울특별시송파구올림픽로 43 길 88, 울산대학교의과대학서울아산병원감염내과 Tel: , Fax : sangho@amc.seoul.kr * 공동제 1 저자

2 4. 지침갱신.., 4-5. II. 진료지침개발과정 1. 진료지침위원회구성 Guidelines, The Cochrane Library, KoreaMed cellulitis, erysipelas, skin abscess, soft tissue infection, bites, pyomyositis, fasciitis, clinical guideline, practice guideline, consensus, recommendation 6 (Fig. 1). 6, Surgical Infection Society Guideline [1], Italian Society of Infectious Diseases and International Society of Chemotherapy Consensus Statement [2], [3], Infectious Diseases Society of America Guideline [4], World Society of Emergency Surgery Guideline [5], Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases Guideline [6]. 1 ( ) 4 (,,, ), 1 ( ), 1 ( ). 2. 진료지침개발방법및과정 (adaptation process)..,,,. 2011,. 3) 진료지침의평가및선택 6 AGREE II 5. 6 (,,,,, ), 4 (Surgical Infection Society Guideline,, Infectious Diseases Society of America Guideline, World Society of Emergency Surgery Guideline). 4) 권고안도출과정, 권고의강도및근거수준 1) 핵심질문 (key question) 도출 Population, Intervention, Comparison, Outcome (PICO). Population, Intervention, Comparison, Outcome ) 진료지침검색 PubMed, National Guideline Clearing House, Guideline International Network, National Library of Figure 1. 평가대상진료지침의선택.

3 Table 1. 근거수준정의 [7] High quality quality quality Very low quality 향후연구가추정된결론의신뢰도에영향을줄가능성이거의없음향후연구가추정된결론의신뢰도에영향을주고중요한변화를일으킬가능성이있음향후연구가추정된결론의신뢰도에영향을주고중요한변화를일으킬가능성이높음추정된결론을확신할수없음.. Grading of Recommendations Assessment, Development and Evaluation (GRADE) [7]. ( ), High quality, quality, quality, Very low quality (Table 1).. 7, 18. 5) 권고안채택을위한전문가합의와의견수렴 , 4-6, 1-3, 75%. 2 1,2 100% , 2 (1 ) 2 50.,, , Ⅲ. 질환별임상진료지침 1. 농가진 (impetigo) 과농창 (ecthyma) Key Question (KQ) 1.? 1-1. 병변의농이나삼출물로그람염색과세균배양검사를추천한다. 하지만, 전형적인경우는검사없이치료할수있다 농가진은경구항생제또는항생제연고로치료할수있다. 병변수가많거나특정 Streptococcus pyogenes 전파로사구체신염이유행하는경우경구항생제사용이추천된다. 농창은경구항생제로치료한다 경구항생제는 amoxicillin/clavulanate, 1 세대 cephalosporin, 또는 clindamycin 을사용하고, 항생제연고는 mupirocin, fusidic acid, retapamulin 을사용한다 Methicillin-resistant Staphylococcus aureus (MRSA) 가의심되거나확인된경우 doxycycline, clindamycin, trimethoprim/sulfamethoxazole 을사용한다 경구항생제는 7 일간사용하며, 항생제연고는 5 일동안하루 2 회사용한다. High High (epidermis) (nonbullous impetigo), (bullous impetigo) [4]. (vesicle) (pustule) [3, 8]. (bullae) [8]. (dermis),. [3, 4, 8]. streptococci, S. aureus, S. aureus [3, 4, 8]. streptococci, S. aureus, [4] S. aureus MRSA [9].,. streptococci S. aureus [10], amoxicillin/clavulanate, 1 cephalosporin, clindmaycin, mupirocin, fusidic acid, retapamulin [10-12]. [12].,, (poststreptococcal glomerulonephritis) (nephritogenic strains of S. pyogenes). [13].

4 [14, 15] MRSA, MRSA doxycycline, trimethoprim/sulfamethoxazole, clindamycin. MRSA (community-associated MRSA, CA-MRSA) USA300 oxacillin [4]., CA-MRSA,,,. 2. 화농성피부 연조직감염 (purulent skin and soft tissue infections) KQ 2.? 2-1. 화농성피부 연조직감염병변의농검체로그람염색과세균배양검사를추천한다. 하지만, 전형적인경우는검사없이치료할수있다. (cutaneous abscess), (furuncle), (carbuncle).,, [3, 4, 8]. (polymicrobial infection) S. aureus [8]. S. aureus [3, 4, 8]., [8]. [1, 3-5, 8]., (cellulitis),, [1, 3-5, 8]. KQ 4.? 4-1. 화농성피부 연조직감염의경험적항생제로 1 세대 cephalosporin, amoxicillin/clavulanate, clindamycin 을추천한다. 과거 MRSA 감염, 기존에 MRSA 집락화 (colonization) 가있었던경우, 1 차치료에실패한경우에는 MRSA 에항균력이있는항생제사용을고려할수있다. S. aureus 1 cephalosporin, amoxicillin/clavulanate, clindamycin, MRSA, MRSA. 50% MRSA [16],. KQ 5. (recurrent skin abscess)? 5-1. 같은부위에재발할경우이물질 (foreign material) 의존재, 화농땀샘염 (hidradenitis suppurativa), 모발둥지낭 (pilonidal cyst) 등국소요인을찾아교정하고, 절개와배농과함께세균배양검사를조기에시행해야한다 분리된원인세균에대해 5-10 일간항생제를사용한다 S. aureus 에의한재발성피부농양환자에서비강내 mupirocin 연고도포 ( 매달 5 일간하루 2 회 ), chlorhexidine 목욕, 개인물품 ( 수건, 시트, 옷등 ) 세탁등의방법을고려할수있다. KQ 3.? 3-1. 화농성피부 연조직감염은절개와배농으로치료한다 화농성병변주위에광범위한연조직염이동반되거나, 화농성피부 연조직감염환자가발열등전신증상이있거나, 면역저하환자일경우는항생제사용을추천한다. High, (hidradenitis suppurativa), (pilonidal cyst) [4].,, / 5-10 [3, 4]., mupirocin, chlorhexidine

5 ,,,, [17-21]. 3. 단독 (erysipelas) 과연조직염 (cellulitis) KQ 6.? 6-1. 단독과연조직염의원인균을알기위한일률적인혈액배양, 병변흡인배양또는생검배양검사는권장되지않는다. 그러나, 면역저하자, 항암치료중인암환자, 호중구감소증환자, 물에빠진후생긴상처 (immersion injury), 동물교상에의한감염의경우에는혈액배양검사, 병변흡인배양또는생검배양검사를고려할수있다 단독과연조직염의진단에영상검사는대부분필요하지않다. 골수염이동반되었을가능성이있을경우, 괴사성근막염과구분하기어려운경우에는영상검사가필요할수있다. (diffuse), (superficial), (warmth) (erythema) (spreading). [22].,. 5% [23]. 5% 40% [24, 25], (punch biopsy) 20%-30% [24, 26]. β-hemolytic streptococci S. aureus.,,.,,,, (immersion injury), β-hemolytic streptococci S. aureus,, [25].., (magnetic resonance imaging, MRI) [3]. KQ 7.? 7-1. 단독치료에권장하는으뜸항생제는 penicillin, amoxicillin 이다 연조직염치료를위해 1 세대 cephalosporin, nafcillin, ampicillin/ sulbactam, amoxicillin/clavulanate 투여를권장한다. 그외 clindamycin 도고려할수있다 과거 MRSA 감염, 기존에 MRSA 집락화 (colonization) 가있었던경우, 1 차치료에실패한경우에는 MRSA 에항균력이있는항생제사용을고려할수있다 중증면역저하자에서발생한중증연조직염감염의경험적치료로 vancomycin + piperacillin/tazobactam, 또는 vancomycin + imipenem or meropenem 병합요법이추천된다 합병증이없는단독및연조직염의적절한치료기간은 5 일이다. 이기간동안호전이없거나합병증이있을경우치료기간을연장할수있다 병변부위를높이올리는것은연조직염경과를단축시키는데도움이된다. 연조직염을유발하는부종이나피부질환이있는경우이를치료한다. Very low High group A β-hemolytic streptococci (S. pyogenes), group C group G β-hemolytic streptococci [27] % 3 2 S. pyogenes, 1 group G β-hemolytic streptococci [28]. S. pyogenes β-hemolytic streptococci penicillin [3, 29]. penicillin V, penicillin amoxicillin [3]. streptococci S. aureus [30] %(57 ), S. aureus (44.0%, 26/57), streptococci(27.1%, 16/57) [28]. 13 2, %(355 ), S. aureus (45%, 162/355) streptococci(24%, 85/355) [31]., S. aureus streptococci cefazolin 1 cephalosporin nafcillin penicillinase-resistant penicillin [3, 4]. ampicillin/sulbactam cefazolin [32].

6 Table 2. MRSA. MRSA, cefazolin oxacillin β-lactam 95.8%, β-hemolytic streptococci (73%)., MRSA MRSA [33]., MRSA 2, %(39 ), 1.5%(29/1,977) [31]. MRSA 2%., MRSA, MRSA,, MRSA [34]. 5 5, [4].. [35, 36].,,, (Tinea pedis)... [4]. KQ 8.? 8-1. 재발성연조직염환자에서연조직염의유발요인 ( 부종, 미만, 습진, 정맥부전, 발샅 [toe web abnormality]) 이있는지확인하고교정가능한유발요인은교정한다 년에 3-4 회이상재발하는연조직염환자에게는예방목적의항생제를투여할수있다. 예방적항생제는경구 amoxicillin, 근주 benzathine penicillin G 를고려할수있다. Table 2. 단독또는연조직염의항생제치료 원인균항생제성인용량 Streptococcus Penicillin 2 4 million units q4 6 h IV Methicillin-susceptible Staphylococcus aureus Methicillin-resistant Staphylococcus aureus IV, intravenous; PO, per os. Nafcillin Ampicillin/sulbactam Amoxicillin Cefazolin Cephalexin Cephradine Cefadroxil Clindamycin Nafcillin Cefazolin Cephalexin Cephradine Cefadroxil Clindamycin Doxycycline Trimethoprim/sulfamethoxazole Vancomycin Linezolid Clindamycin Doxycycline Trimethoprim/sulfamethoxazole 1 2 g q4 6 h IV g q6 h IV 500 mg q 12 h PO or 250 mg q8 h PO 1 2 g q8 h IV 500 mg q6 h PO 500 mg q6 h PO 500 1,000 mg q12 24 h mg q8 h IV or mg qid PO 1 2 g q4 h IV 1 2 g q8 h IV 500 mg q6 h PO 500 mg q6 h PO mg q12 24 h mg q8 h IV or mg qid PO 100 mg bid PO 1 2 double-strength tablets bid PO 15 mg/kg q12 h IV 600 mg every 12 h IV or 600 mg bid PO 600 mg every 8 h IV or mg qid PO 100 mg bid PO 1 2 double-strength tablets bid PO

7 8%-20% [37-39]..,, [37-41]., [4]., [3] penicillin erythromycin 2 [42-44] penicillin 250 mg (22% vs. 38%), [45]. Benzathine penicillin 1.2 million unit, [46]., amoxicillin benzathine penicillin.. [4]. 4. 괴사성근막염 KQ 9.? 9-1. 다음과같은임상증상이나징후가있는피부연조직감염에서는괴사성근막염을의심해야한다 : (1) 진찰소견에비해극심한통증, (2) 긴장성부종 (tense edema), (3) 물집, (4) 반상출혈 (ecchymoses) 이나피부괴사, (5) 촉진시마찰음 (crepitus), (6) 국소적피부감각저하, (7) 전신독성을보이면서급격히악화 9-2. CT 나 MRI 가괴사성근막염진단에도움이될수있다. 하지만, 영상의학적검사이후로괴사성근막염의진단과치료결정을미뤄서는안된다 원인균확인을위해조직또는농양을이용한미생물검사를시행해야한다 원인균진단에혈액배양검사가도움이될수있다.., %(21/99) [47] %(39/168) [48].,..,,,,,, [3, 49]. CT MRI. CT,,,,. MRI T1 T2 [50]., CT 80% [51], MRI % [52].,.,,.,. 64.1%(66/103), (48.5%, 32/66) (43.9%, 29/66) [47]. [48]. KQ 10.? 괴사성근막염을진단함과동시에최대한빨리적절한외과적치료를고려해야한다 경험적항생제는그람양성균, 그람음성균과혐기성균을대상으로하는광범위항생제를사용하며, MRSA 에항균력이있는항생제사용을고려한다 간경변증이나알코올중독으로간기능저하가있으면서최근해산물섭취나바닷물접촉병력이있는경우에는 Vibrio vulnificus 감염을고려하여 cefotaxime 또는 ceftriaxone 과같은 3 세대 cephalosporin 과 doxycycline 또는 tetracycline 의병합요법을사용한다.

8 10-4. 원인균이확인되면감수성결과에따라항균범위가좁은효과적인항생제로변경한다 사슬알균독성쇼크증후군 (streptococcal toxic shock syndrome) 이의심되는경우 intravenous immunoglobulin (IVIG) 을보조치료로고려할수있다. Very low.. 66 streptococci, staphylococci 63.6%(42/66), 42.4%(28/66). 5%, [47]., 19.2% [48].,,. MRSA [4]. MRSA, 35% MRSA [53] MRSA 3.9%(4/103) [47], %(10/165) [48]. MRSA, MRSA. cefepime metronidazole, piperacillin/tazobactam, carbapenem (Table 3) [4]. Vibrio vulnificus., cefotaxime ceftriaxone 3 cephalosporin doxycycline tetracycline [3]. (Table 3). Methicillin-susceptible S. aureus cefazolin nafcillin. Group A β-hemolytic streptococci penicillin clindamycin. clindamycin penicillin [54, 55], clindamycin clindamycin [56].. [57-59]. Wong 24 [57].,. Intravenous immunoglobulin (IVIG) IgG T- (superantigen-elicited T-cell activation), (opsonization) [60]. (streptococcal toxic shock syndrome) IVIG [61, 62], IVIG [63]. IVIG,. 5. 화농성근육염 KQ 11.? 원인균확인을위해농배양검사와혈액배양검사를시행한다 영상학적진단검사로는 MRI 가추천되고, CT 도유용할수있다..,.,,. 5-30%, [4]. 70.7%, 39.2% (55/140) 24.4% (34/140) [64]. MRI. T2, [65]. MRI. CT,, [66]. CT MRI,.

9 Table 3. 괴사성근막염의항생제치료 질병분류항생제성인용량 Empirical therapy Teicoplanin or 6 12 mg/kg q24 h IV vancomycin or 15 mg/kg q12 h IV linezolid 600 mg q12 h IV plus piperacillin/tazobactam or g q8 h IV ertapenem or 1 g q24 h IV meropenem or 1 g q8 h IV imipenem or 500 mg q6 h IV cefepime 2 g q8 h IV plus metronidazole 500 mg q8 h IV Streptococcus Penicillin 2-4 million units q4 6 h IV plus clindamycin mg q8 h IV Methicillin-susceptible Staphylococcus aureus Nafcillin or 1 2 g q4 h IV cefazolin 1 2 g q8 h IV Methicillin-resistant Staphylococcus aureus Vancomycin or 15 mg/kg q12 hr IV teicoplanin or 6-12 mg/kg q24 h IV linezolid 600 mg q12 h IV Aeromonas hydrophilia Ciprofloxacin or 400 mg q12 h IV cefotaxime or 2 g q8 h IV ceftriaxone 2 g q24 h IV plus doxycycline 100 mg bid PO Vibrio vulnificus Cefotaxime or 2 g q8 h IV ceftriaxone 2 g q24 h IV plus doxycycline 100 mg bid PO IV, intravenous; PO, per os. KQ 12.? 경험적항생제는그람양성균, 그람음성균에항균력을가지는항생제를사용한다 원인균이확인되면감수성결과에따라항균범위가좁은효과적인항생제로변경한다 과거 MRSA 감염, 기존에 MRSA 집락화 (colonization) 가된경우, 1 차치료에실패한경우경험적으로 MRSA 에항균력이있는항생제사용을고려할수있다 화농성물질은조기에배액또는제거한다 치료에반응이없는경우 MRI/ CT 등의영상의학적검사를재시행하여화농성물질의배액또는제거가적절하게되었는지평가한다. Very low S. aureus [67]. S. aureus 50%., 30% [64]. S. aureus (Table 4). MRSA MRSA [4, 68]., MRSA 2.9%(4/140) [64]., MRSA, MRSA, 1 MRSA. (Table 4). Methicillin S. aureus cefazolin nafcillin. S. pyogenes

10 penicillin clindamycin [34]. [4]. MRI CT [4]. KQ 13. Clostridium? 조기에감염부위의수술적제거와배농을하고, 반복적인육안적평가와감염부위의제거가시행되어야한다 확정적항생제로는 penicilin 과 clindamycin 병합요법이추천된다. Clostridial gas gangrene Clostridium species, C. perfringens.,. 2-3.,,,.,,. Clostridial [4, 69, 70].. Clostridial penicillin 2-4 million units q 4-6 h IV clindamycin mg q 8 h IV. clindamycin + penicillin [71], C. perfringens clindamycin [72]. 6. 동물이나사람교상 KQ 14. (animal or human bite)? 선제적항생제투여 (preemptive antimicrobial therapy) 는감염위험이낮은경도 (mild) 의교상에는추천되지않는다 면역저하, 무비증 (asplenism), 중증간질환, 물린부위에부종이있는경우, 중등도 - 중증의손상 ( 특히손과얼굴 ), 골막이나관절낭까지손상을입은환자들에게는선제적으로 3-5 일간항생제를투여하는것이권장된다.,, [73, 74]. (8 ), 85%.,.,,., 2%., 50% [1]. (deep puncture), (crush injury), (devitalized tissue), (heavy contamination) [74]. Table 4. 화농성근육염의항생제사용질병분류 항생제 성인용량 Empirical therapy Ampicillin/sulbactam or 3 g q6 h IV cefepime or 2 g q8 h IV piperacillin/tazobactam or g q6 8 h IV ertapenem 1 g q24 h IV Streptococcus Penicillin 2 4 million units q4 6 h IV Plus clindamycin mg q8 h IV Methicillin-susceptible Staphylococcus aureus Nafcillin or 1 2 g q4 h IV cefazolin 1 2 g q8 h IV Methicillin-resistance Staphylococcus aureus Vancomycin or 15 mg/kg q12 h IV teicoplanin or 6 12 mg/kg q24 h IV linezolid 600 mg q12 h IV IV, intravenous; PO, per os.

11 [74].. (inoculation). (tendon sheath). [1].,,,,. [74].,., 48 1 [75] [73]. 8 16% [76]. 9 amoxicillin/ clavulanate., 8,., (,,,, ) [77-80]. 24 -,,,, 3-5. KQ 15. (animal or human bite)? Amoxicillin/clavulanate 와같이호기균과혐기균모두에항균력이있는항생제를사용한다 세대 cephalosporin, penicillinase-resistant penicillin, macrolide, clindamycin 은단독으로사용해서는안된다 정맥주사용항생제로는 β -lactam/β-lactamase inhibitor (ampicillin/sulbactam, piperacillin/tazobactam) 나 cefotixin 과같은 2 세대 cephalosporin, ertapenem 같은 carbapenem 등을사용할수있다. Very low [1]. 5. Staphylococci streptococci Bacteroides spp., peptostreptococci, Fusobacterium spp., Prevotella heparinolytica. Pasteurella spp. Capnocytophaga canimorsus. Pasteurella spp. (50%) (75%). coccobacilli. Haemophius spp. Eikenella corrodens (Table 5). staphylococci streptococci [81, 82]. Pasteurella spp. [82]. amoxicillin/clavulanate (Table 6)., 2 /3 cephalosporin metronidazole clindamycin. Ertapenem carbapenem, moxifloxacin, doxycycline. Trimethoprim/sulfamethoxazole levofloxacin metronidazole clindamycin. macrolide Pasteurella multocida, Fusobacterium. tetracycline fluoroquinolone trimethoprim/sulfamethoxazole Table 5. 교상에의한상처감염의원인균순위 [73] 순위 원인균 원인동물 1 Pasteurella multocida 개, 고양이 2 Capnocytophaga canimorsus 개 3 Eikenella corrodens 사람 4 Streptococcus 모든종 5 Staphylococcus aureus 모든종 6 Staphylococcus intermedius 개 7 Anaerobes 대부분

12 3 [81-86]. Fusobacterium, Peptostreptococcus, Prevotella, Porphyromonas spp. streptococci, S. aureus, Eikenella corrodens. Eikenella corrodens 1 cephalosporin, macrolide, clindamycin, aminoglycoside amoxicillin/clavulanate, ampicillin/sulbactam, ertapenem. ciprofloxacin levofloxacin + metronidazole moxifloxacin., B C, (HIV) [3]. KQ 16. (animal or human bite)? 상처상태에따라 5 년혹은 10 년이내에파상풍예방접종을하지않은환자에게는파상풍백신을투여해야한다. 과거에 Tdap 을맞지않은환자라면 Td 보다 Tdap 이추천된다. ( 3 10 ). [87, 88]. DTaP Td (Table 7). (dirty wound) 5, (clean wound) 10. Tdap Td Tdap [89]. KQ 17. (animal bite)? 야생동물에의한교상이나광견병유행지역에서는광견병에대한노출후예방이필요할수있다. 예방접종을시작해야할지결정하기위해감염내과전문의와협의하는것이권장된다.. (0, 3, 7, 14, ± 28 ) [90, 91]. Table 6. 교상상처감염의경험적치료항생제분류 항생제 성인용량 Drug of choice Amoxicillin/clavulanate 875/125 mg bid PO Ampicillin/sulbactam g q6 8 h IV Piperacillin/tazobactam g q6-8 h IV Ceftriaxone or 2 g q24 h IV Cefotaxime 1 2 g q6 8 h IV plus Metronidazole or 500 mg q8 h IV or mg tid PO Clindamycin 600 mg q6 8 h IV or 300 mg tid PO Alternatives Cefoxitin 1 g q6 8 h IV Ertapenem 1 g q24 h IV Moxifloxacin 400 mg q24 h IV or PO Doxycycline 100 mg bid PO Ciprofloxacin or 400 mg q12 h IV or mg bid PO Levofloxacin or 750 mg q24 h IV or PO Trimethoprim-sulfamethoxazole or TMP 5 10 mg/kg/day IV or mg bid Cefuroxime 1 g q12 h IV or 500 mg bid PO plus Metronidazole or 500 mg q8 h IV or mg tid PO Clindamycin 600 mg q6 8 h IV or 300 mg tid PO PO, per os; IV, intravenous.

13 Table 7. 파상풍백신접종력과상처의상태에따른파상풍예방조치 백신접종력 깨끗하고작은상처기타다른상처 Td TIG Td TIG 미상또는 3회미만 필요 불필요 필요 필요 3회이상마지막접종후 >10년 필요 불필요 필요 불필요 마지막접종후 5-9년 불필요 불필요 필요 불필요 마지막접종후 <5년 불필요 불필요 불필요 불필요 Td, tetanus-diphtheria toxoid; TIG, tetanus immunoglobulin. [90]., [4]. [3].,. KQ 18.? 충분한상처부위세척과죽은조직제거술후에지연일차봉합혹은이차봉합을하는것이권고된다 얼굴의상처는예외적으로일차봉합을시도하나이때에는세심한상처관리, 많은양의세척, 선제적항생제투여가필요하다 주먹구타상처에대해서는수부전문의에게힘줄, 활막, 관절낭, 뼈손상여부에대해진찰을의뢰한다 ml 19- [3].. (debridement).. (laceration), (perforation) 1% [92]. [93]. 345 (puncture wound) [94, 95].. [3]... References 1. May AK, Stafford RE, Bulger EM, Heffernan D, Guillamondegui O, Bochicchio G, Eachempati SR; Surgical Infection Society. Treatment of complicated skin and soft tissue infections. Surg Infect (Larchmt) 2009;10: Esposito S, Bassetti M, Borre S, Bouza E, Dryden M, Fantoni M, Gould IM, Leoncini F, Leone S, Milkovich G, Nathwani D, Segreti J, Sganga G, Unal S, Venditti M; Italian Society of Infectious Tropical Diseases; International Society of Chemotherapy. Diagnosis and management of skin and soft-tissue infections (SSTI): a literature review and consensus statement on behalf of the Italian Society of Infectious Diseases and International Society of Chemotherapy. J Chemother 2011;23: The Korean Society of Infectious Diseases, The Korean Society for Chemotherapy, The Korean Orthopaedic Association, The Korean Society of Clinical Microbiology, The Korean Dermatologic Association. Clinical practice guidelines for soft tissue infections. Infect Chemother 2012;44: Stevens DL, Bisno AL, Chambers HF, Dellinger EP, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan SL, Montoya JG, Wade JC; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 2014;59:e Sartelli M, Malangoni MA, May AK, Viale P, Kao LS, Catena F, Ansaloni L, Moore EE, Moore FA, Peitzman AB, Coimbra R, Leppaniemi A, Kluger Y, Biffl W, Koike K, Girardis M,

14 Ordonez CA, Tavola M, Cainzos M, Di Saverio S, Fraga GP, Gerych I, Kelly MD, Taviloglu K, Wani I, Marwah S, Bala M, Ghnnam W, Shaikh N, Chiara O, Faro MP Jr, Pereira GA Jr, Gomes CA, Coccolini F, Tran? C, Corbella D, Brambillasca P, Cui Y, Segovia Lohse HA, Khokha V, Kok KY, Hong SK, Yuan KC. World Society of Emergency Surgery (WSES) guidelines for management of skin and soft tissue infections. World J Emerg Surg 2014;9: Japanese Society of Chemotherapy Committee on guidelines for treatment of anaerobic infections; Japanese Association of Anaerobic Infections Research. Chapter 2-5-3a. Anaerobic infections (individual fields): skin and soft tissue infections. J Infect Chemother 2011;17 (Suppl 1): Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schünemann HJ; GRADE Working Group. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336: Pasternack MS, Swartz MN. Cellulitis, necrotizing fasciitis, and subcutaneous tissue infections. In: Bennett JE, Dolin R, Blaser MJ, eds. Mandell, Douglas, and Bennett s Principles and Practice of Infectious Diseases, 8th ed. Philadelphia, PA: Churchill Livingstone; 2015; Durupt F, Mayor L, Bes M, Reverdy ME, Vandenesch F, Thomas L, Etienne J. Prevalence of Staphylococcus aureus toxins and nasal carriage in furuncles and impetigo. Br J Dermatol 2007;157: Hirschmann JV. Impetigo: etiology and therapy. Curr Clin Top Infect Dis 2002: Koning S, van der Wouden JC, Chosidow O, Twynholm M, Singh KP, Scangarella N, Oranje AP. Efficacy and safety of retapamulin ointment as treatment of impetigo: randomized double blind multicentre placebo controlled trial. Br J Dermatol 2008;158: Koning S, van der Sande R, Verhagen AP, van Suijlekom-Smit LW, Morris AD, Butler CC, Berger M, van der Wouden JC. Interventions for impetigo. Cochrane Database Syst Rev 2012;1:CD Wasserzug O, Valinsky L, Klement E, Bar-Zeev Y, Davidovitch N, Orr N, Korenman Z, Kayouf R, Sela T, Ambar R, Derazne E, Dagan R, Zarka S. A cluster of ecthyma outbreaks caused by a single clone of invasive and highly infective Streptococcus pyogenes. Clin Infect Dis 2009;48: Bae EY, Lee JD, Cho SH. Isolation of causative microorganism and antimicrobial susceptibility in impetigo. Korean J Dermatol 2003;41: Kim WJ, Lee KR, Lee SE, Lee HJ, Yoon MS. Isolation of the causative microorganism and antimicrobial susceptibility of impetigo. Korean J Dermatol 2012;50: Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, Mc- Dougal LK, Carey RB, Talan DA; EMERGEncy ID Net Study Group. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006;355: Rahimian J, Khan R, LaScalea KA. Does nasal colonization or mupirocin treatment affect recurrence of methicillin-resistant Staphylococcus aureus skin and skin structure infections? Infect Control Hosp Epidemiol 2007;28: Ellis MW, Griffith ME, Dooley DP, McLean JC, Jorgensen JH, Patterson JE, Davis KA, Hawley JS, Regules JA, Rivard RG, Gray PJ, Ceremuga JM, Dejoseph MA, Hospenthal DR. Targeted intranasal mupirocin to prevent colonization and infection by community-associated methicillin-resistant Staphylococcus aureus strains in soldiers: a cluster randomized controlled trial. Antimicrob Agents Chemother 2007;51: Whitman TJ, Herlihy RK, Schlett CD, Murray PR, Grandits GA, Ganesan A, Brown M, Mancuso JD, Adams WB, Tribble DR. Chlorhexidine-impregnated cloths to prevent skin and soft-tissue infection in Marine recruits: a cluster-randomized, double-blind, controlled effectiveness trial. Infect Control Hosp Epidemiol 2010;31: Wiese-Posselt M, Heuck D, Draeger A, Mielke M, Witte W, Ammon A, Hamouda O. Successful termination of a furunculosis outbreak due to luks-lukf?positive, methicillin-susceptible Staphylococcus aureus in a German village by stringent decolonization, Clin Infect Dis 2007;44:e Fritz SA, Hogan PG, Hayek G, Eisenstein KA, Rodriguez M, Epplin EK, Garbutt J, Fraser VJ. Household versus individual approaches to eradication of community-associated Staphylococcus aureus in children: a randomized trial. Clin Infect Dis 2011;54: Bisno AL, Stevens DL. Streptococcal infections of skin and soft tissues. N Engl J Med 1996;334: Perl B, Gottehrer NP, Raveh D, Schlesinger Y, Rudensky B, Yinnon AM. Cost-effectiveness of blood cultures for adult patients with cellulitis. Clin Infect Dis 1999;29: Hook EW 3rd, Hooton TM, Horton CA, Coyle MB, Ramsey PG, Turck M. Microbiologic evaluation of cutaneous cellulitis in adults. Arch Intern Med 1986;146: Kielhofner MA, Brown B, Dall L. Influence of underlying disease process on the utility of cellulitis needle aspirates. Arch Intern Med 1988;148: Duvanel T, Auckenthaler R, Rohner P, Harms M, Saurat JH.

15 Quantitative cultures of biopsy specimens from cutaneous cellulitis. Arch Intern Med 1989;149: Eriksson B, Jorup-Rönström C, Karkkonen K, Sjöblom AC, Holm SE. Erysipelas: clinical and bacteriologic spectrum and serological aspects. Clin Infect Dis 1996;23: Kwak YG, Kim NJ, Choi SH, Choi SH, Chung JW, Choo EJ, Kim KH, Yun NR, Lee S, Kwon KT, Cho JH. Clinical characteristics and organisms causing erysipelas and cellulitis. Infect Chemother 2012;44: Stevens DL, Bisno AL, Chambers HF, Everett ED, Dellinger P, Goldstein EJ, Gorbach SL, Hirschmann JV, Kaplan EL, Montoya JG, Wade JC; Infectious Diseases Society of America. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 2005;41: Bernard P, Bedane C, Mounier M, Denis F, Catanzano G, Bonnetblanc JM. Streptococcal cause of erysipelas and cellulitis in adults. A microbiologic study using a direct immunofluorescence technique. Arch Dermatol 1989;125: Park SY, Kim T, Choi SH, Jung J, Yu SN, Hong H-L, Kim YK, Park SY, Song EH, Park KH, Cho OH, Choi SH, Kwak YG, and the Korean SSTI (Skin and Soft Tissue Infection) Study Group. A multicenter study of clinical features and organisms causing community-onset cellulitis in Korea [abstract]. Int J Antimicrob Agents 2017;50 (Suppl 1):S Chan JC. Ampicillin/sulbactam versus cefazolin or cefoxitin in the treatment of skin and skin-structure infections of bacterial etiology. Adv Ther 1995;12: Jeng A, Beheshti M, Li J, Nathan R. The role of beta-hemolytic streptococci in causing diffuse, nonculturable cellulitis: a prospective investigation. Medicine (Baltimore) 2010;89: Hepburn MJ, Dooley DP, Skidmore PJ, Ellis MW, Starnes WF, Hasewinkle WC. Comparison of short-course (5 days) and standard (10 days) treatment for uncomplicated cellulitis. Arch Intern Med 2004;164: Dupuy A, Benchikhi H, Roujeau JC, Bernard P, Vaillant L, Chosidow O, Sassolas B, Guillaume JC, Grob JJ, Bastuji-Garin S. Risk factors for erysipelas of the leg (cellulitis): case-control study. BMJ 1999;318: Björnsdóttir S, Gottfredsson M, Thórisdóttir AS, Gunnarsson GB, Ríkardsdóttir H, Kristjánsson M, Hilmarsdóttir I. Risk factors for acute cellulitis of the lower limb: a prospective case-control study. Clin Infect Dis 2005;41: Jorup-Rönström C, Britton S. Recurrent erysipelas: predisposing factors and costs of prophylaxis. Infection 1987;15: McNamara DR, Tleyjeh IM, Berbari EF, Lahr BD, Martinez J, Mirzoyev SA, Baddour LM. A predictive model of recurrent lower extremity cellulitis in a population-based cohort. Arch Intern Med 2007;167: Lewis SD, Peter GS, Gómez-Marín O, Bisno AL. Risk factors for recurrent lower extremity cellulitis in a U.S. Veterans Medical Center population. Am J Med Sci 2006;332: Karppelin M, Siljander T, Vuopio-Varkila J, Kere J, Huhtala H, Vuento R, Jussila T, Syrjänen J. Factors predisposing to acute and recurrent bacterial non-necrotizing cellulitis in hospitalized patients: a prospective case-control study. Clin Microbiol Infect 2010;16: Pavlotsky F, Amrani S, Trau H. Recurrent erysipelas: risk factors. J Dtsch Dermatol Ges 2004;2: Sjöblom AC, Eriksson B, Jorup-Rönström C, Karkkonen K, Lindqvist M. Antibiotic prophylaxis in recurrent erysipelas. Infection 1993;21: Kremer M, Zuckerman R, Avraham Z, Raz R. Long-term antimicrobial therapy in the prevention of recurrent soft-tissue infections. J Infect 1991;22: UK Dermatology Clinical Trials Network s PATCH Trial Team, Thomas K, Crook A, Foster K, Mason J, Chalmers J, Bourke J, Ferguson A, Level N, Nunn A, Williams H. Prophylactic antibiotics for the prevention of cellulitis (erysipelas) of the leg: results of the UK Dermatology Clinical Trials Network s PATCH II trial. Br J Dermatol 2012;166: Thomas KS, Crook AM, Nunn AJ, Foster KA, Mason JM, Chalmers JR, Nasr IS, Brindle RJ, English J, Meredith SK, Reynolds NJ, de Berker D, Mortimer PS, Williams HC; U.K. Dermatology Clinical Trials Network s PATCH I Trial Team. Penicillin to prevent recurrent leg cellulitis. N Engl J Med 2013;368: Wang JH, Liu YC, Cheng DL, Yen MY, Chen YS, Wang JH, Wann SR, Lin HH. Role of benzathine penicillin G in prophylaxis for recurrent streptococcal cellulitis of the lower legs. Clin Infect Dis 1997;25: Choi SH, Choi SH, Kwak YG, Chung JW, Choo EJ, Kim KH, Yun NR, Lee S, Kwon KT, Cho JH, Kim NJ. Clinical characteristics and causative organisms of community-acquired necrotizing fasciitis. Infect Chemother 2012;44: Kim T, Park SY, Gwak YG, Choi SH, Jung J, You SN, Hong H-L, Kim YK, Park SY, Song EH, Park K-H, Cho OH, Choi SH, and the Korean SSTI (Skin and Soft Tissue Infection) Study Group. A multicenter study of clinical characteristics and microbial etiology in commmunity-onset necrotizing fasciitis in Korea [abstract]. Int J Antimicrob Agents 2017;50

16 (Suppl 1):S Wang YS, Wong CH, Tay YK. Staging of necrotizing fasciitis based on the evolving cutaneous features. Int J Dermatol 2007;46: Schmid MR, Kossmann T, Duewell S. Differentiation of necrotizing fasciitis and cellulitis using MR imaging. AJR Am J Roentgenol 1998;170: Becker M, Zbären P, Hermans R, Becker CD, Marchal F, Kurt AM, Marré S, Rüfenacht DA, Terrier F. Necrotizing fasciitis of the head and neck: role of CT in diagnosis and management. Radiology 1997;202: Arslan A, Pierre-Jerome C, Borthne A. Necrotizing fasciitis: unreliable MRI findings in the preoperative diagnosis. Eur J Radiol 2000;36: Kao LS, Lew DF, Arab SN, Todd SR, Awad SS, Carrick MM, Corneille MG, Lally KP. Local variations in the epidemiology, microbiology, and outcome of necrotizing soft-tissue infections: a multicenter study. Am J Surg 2011;202: Zimbelman J, Palmer A, Todd J. Improved outcome of clindamycin compared with beta-lactam antibiotic treatment for invasive Streptococcus pyogenes infection. Pediatr Infect Dis J 1999;18: Mulla ZD, Leaverton PE, Wiersma ST. Invasive group A streptococcal infections in Florida. South Med J 2003;96: Ardanuy C, Domenech A, Rolo D, Calatayud L, Tubau F, Ayats J, Martín R, Liñares J. Molecular characterization of macrolide- and multidrug-resistant Streptococcus pyogenes isolated from adult patients in Barcelona, Spain ( ). J Antimicrob Chemother 2010;65: Wong CH, Chang HC, Pasupathy S, Khin LW, Tan JL, CO. Necrotizing fasciitis: clinical presentation, microbiology, and determinants of mortality. J Bone Joint Surg Am 2003;85-A: Elliott DC, Kufera JA, Myers RA. Necrotizing soft tissue infections. Risk factors for mortality and strategies for management. Ann Surg 1996;224: Voros D, Pissiotis C, Georgantas D, Katsaragakis S, Antoniou S, Papadimitriou J. Role of early and extensive surgery in the treatment of severe necrotizing soft tissue infection. Br J Surg 1993;80: Darabi K, Abdel-Wahab O, Dzik WH. Current usage of intravenous immune globulin and the rationale behind it: the Massachusetts General Hospital data and a review of the literature. Transfusion 2006;46: Kaul R, McGeer A, Norrby-Teglund A, Kotb M, Schwartz B, O Rourke K, Talbot J, DE. Intravenous immunoglobulin therapy for streptococcal toxic shock syndrome--a comparative observational study. The Canadian Streptococcal Study Group. Clin Infect Dis 1999;28: Norrby-Teglund A, Ihendyane N, Darenberg J. Intravenous immunoglobulin adjunctive therapy in sepsis, with special emphasis on severe invasive group A streptococcal infections. Scand J Infect Dis 2003;35: Darenberg J, Ihendyane N, Sjölin J, Aufwerber E, Haidl S, Follin P, Andersson J, Norrby-Teglund A; StreptIg Study Group. Intravenous immunoglobulin G therapy in streptococcal toxic shock syndrome: a European randomized, double-blind, placebo-controlled trial. Clin Infect Dis 2003;37: Kim T, Park SY, Gwak YG, Choi SH, Jung J, You SN, Hong H-L, Kim YK, Park SY, Song EH, Park K-H, Cho OH, Choi SH, and the Korean SSTI (Skin and Soft Tissue Infection) Study Group. A multicenter study of clinical characteristics and microbial etiology in community-onset pyomyositis in Korea [abstract]. Int J Antimicrob Agents 2017;50 (Suppl 1):S Yu JS, Habib P. MR imaging of urgent inflammatory and infectious conditions affecting the soft tissues of the musculoskeletal system. Emerg Radiol 2009;16: Turecki MB, Taljanovic MS, Stubbs AY, Graham AR, Holden DA, Hunter TB, Rogers LF. Imaging of musculoskeletal soft tissue infections. Skeletal Radiol 2010;39: Crum NF. Bacterial pyomyositis in the United States. Am J Med 2004;117: Chiu SK, Lin JC, Wang NC, Peng MY, Chang FY. Impact of underlying diseases on the clinical characteristics and outcome of primary pyomyositis. J Microbiol Immunol Infect 2008;41: Faraklas I, Stoddard GJ, Neumayer LA, Cochran A. Development and validation of a necrotizing soft-tissue infection mortality risk calculator using NSQIP. J Am Coll Surg 2013;217: e3; discussion Bryant AE, Stevens DL. Clostridial myonecrosis: new insights in pathogenesis and management. Curr Infect Dis Rep 2010;12: Stevens DL, Maier KA, Laine BM, Mitten JE. Comparison of clindamycin, rifampin, tetracycline, metronidazole, and penicillin for efficacy in prevention of experimental gas gangrene due to Clostridium perfringens. J Infect Dis 1987;155: Stevens DL, Laine BM, Mitten JE. Comparison of single and combination antimicrobial agents for prevention of experimental gas gangrene caused by Clostridium perfringens.

17 Antimicrob Agents Chemother 1987;31: Broder J, Jerrard D, Olshaker J, Witting M. risk of infection in selected human bites treated without antibiotics. Am J Emerg Med 2004;22: Medeiros I, Saconato H. Antibiotic prophylaxis for mammalian bites. Cochrane Database Syst Rev 2001:CD Zubowicz VN, Gravier M. Management of early human bites of the hand: a prospective randomized study. Plast Reconstr Surg 1991;88: Cummings P. Antibiotics to prevent infection in patients with dog bite wounds: a meta-analysis of randomized trials. Ann Emerg Med 1994;23: Callaham M. Prophylactic antibiotics in common dog bite wounds: a controlled study. Ann Emerg Med 1980;9: Dire DJ. Emergency management of dog and cat bite wounds. Emerg Med Clin North Am 1992;10: Elenbaas RM, McNabney WK, Robinson WA. Prophylactic oxacillin in dog bite wounds. Ann Emerg Med 1982;11: Dire DJ, Hogan DE, Walker JS. Prophylactic oral antibiotics for low-risk dog bite wounds. Pediatr Emerg Care 1992;8: Abrahamian FM, Goldstein EJ. Microbiology of animal bite wound infections. Clin Microbiol Rev 2011;24: Goldstein EJ, Citron DM, Wield B, Blachman U, Sutter VL, Miller TA, Finegold SM. Bacteriology of human and animal bite wounds. J Clin Microbiol 1978;8: Goldstein EJ, Citron DM. Comparative activities of cefuroxime, amoxicillin-clavulanic acid, ciprofloxacin, enoxacin, and ofloxacin against aerobic and anaerobic bacteria isolated from bite wounds. Antimicrob Agents Chemother 1988;32: Goldstein EJ, Citron DM, Finegold SM. Dog bite wounds and infection: a prospective clinical study. Ann Emerg Med 1980;9: Goldstein EJ, Citron DM, Richwald GA. Lack of in vitro efficacy of oral forms of certain cephalosporins, erythromycin, and oxacillin against Pasteurella multocida. Antimicrob Agents Chemother 1988;32: Stevens DL, Higbee JW, Oberhofer TR, Everett ED. Antibiotic susceptibilities of human isolates of Pasteurella multocida. Antimicrob Agents Chemother 1979;16: Muguti GI, Dixon MS. Tetanus following human bite. Br J Plast Surg 1992;45: Talan DA, Citron DM, Abrahamian FM, Moran GJ, Goldstein EJ. Bacteriologic analysis of infected dog and cat bites. Emergency Medicine Animal Bite Infection Study Group. N Engl J Med 1999;340: Kroger AT, Atkinson WL, Marcuse EK, Pickering LK; Advisory Committee on Immunization Practices (ACIP) Centers for Disease Control and Prevention (CDC). General recommendations on immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2006;55: Korean Centers for Disease Control and Prevention (KCDC). Guideline for rabies control Available at: jsp?menuids=home001-mnu1154-u0005- MNU0088&cid= Accessed 22 December, Rupprecht CE, Briggs D, Brown CM, Franka R, Katz SL, Kerr HD, Lett SM, Levis R, Meltzer MI, Schaffner W, Cieslak PR; Centers for Disease Control and Prevention (CDC). Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the advisory committee on immunization practices. MMWR Recomm Rep 2010;59: Zook EG, Miller M, Van Beek AL, Wavak P. Successful treatment protocol for canine fang injuries. J Trauma 1980;20: Schultz RC, McMaster WC. The treatment of dog bite injuries, especially those of the face. Plast Reconstr Surg 1972;49: Chen E, Hornig S, Shepherd SM, Hollander JE. Primary closure of mammalian bites. Acad Emerg Med 2000;7: Maimaris C, Quinton DN. Dog-bite lacerations: a controlled trial of primary wound closure. Arch Emerg Med 1988;5:

18 부록 피부 연조직감염진단과치료요약 질환배양검사영상검사치료항생제 농가진 (impetigo) 추천. 전형적인경우는생략필요없음항생제연고 (5 일 ) 또는 경구항생제 (7 일 ) Amoxicillin/clavulante, 1 세대 cephalosporin, clindamycin 농창 (ecthyma) 추천. 전형적인경우는생략 필요없음 경구항생제 (7일) Amoxicillin/clavulante, 1 세대 cephalosporin, clindamycin 피부농양 (cutaneous abscess), 종기 (furuncle), 큰종기 (carbuncle) 단독 (erysipelas) 과 연조직염 (cellulitis) 괴사성근막염 (necrotizing fasciitis) 추천. 전형적인경우는생략필요없음절개와배농 ± 경구항 면역저하자, 호중구감소증, 물에빠진후발생 (immersion injury), 동물교 상의경우 골수염동반가능성이있 거나괴사성근막염과 구분이 어려울때 생제 (5 일 ; 주위연조 직염, 전신증상, 면 역저하환자 ) 항생제치료 (5 일 ). 병 변부위높게유지 추천 ( 혈액배양포함 ) MRI > CT 조기에외과적치료. 광범위항생제 화농성근육염 (pyomyositis) 추천 ( 혈액배양포함 ) MRI > CT 광범위항생제. 농양 Clostridium 근육괴사 (clostridial myonecrosis) 동물이나사람교상 (animal or human bite) 배액 추천 ( 혈액배양포함 ) MRI > CT 조기에외과적치료. 추천 ( 감염징후가있는 경우만 ) 뼈 힘줄손상이나농양형 성이의심될때 항생제 충분한세척과죽은 조직제거. 지연봉 합. 항생제 Amoxicillin/clavulante, 1 세대 cephalosporin, clindamycin 단독 : penicillin, amoxicillin. 연조직염 : 1 세대 cephalosporin, nafcillin, ampicillin/sulbactam, amoxicillin/clavulanate, clindamycin Vancomyin + piperacillin/ tazobactam, cefotaxime + doxycyline (Vibrio 의심시 ) 1 세대 cephalosporin, ampicillin/sulbactam, cefepime Penicillin + clindamycin Amoxicillin/clavulanate, ampicillin/sulbactam