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1 고려대학교의과대학내과학교실감염내과송준영 Antimicrobial Therapy in Diabetic Foot Infections Joon Young Song Division of Infectious Disease, Department of Internal Medicine, Korea University College of Medicine, Seoul, Korea Abstract Treatment of diabetic foot infection remains a challenging issue to be solved. Bacterial species complicating diabetic foot ulcer differ from those of non-diabetic patients. Empirical antibiotic regimens are selected based on the severity and type of infection (acute infection versus chronic infection), which should always include coverage for aerobic Gram-positive cocci, especially Staphylococcus aureus. Narrow-spectrum antibiotic agents are considered for mild-to-moderate, recent infections, while broad-spectrum agents are usually required for severe, chronic infections, targeting both Gram-positive cocci and Gram-negative bacilli. (J Korean Diabetes 2011;12:83-87) Keywords: Diabetes, Foot infection, Antimicrobial agent, Empirical therapy 83 서론 당뇨병환자의 15% 가당뇨병성족부궤양을경험하게되며그중에반수이상은감염이진행되어항생제치료를필요로한다 [1,2]. 더욱이, 당뇨병성족부감염의대략 20% 는골수염이동반되고, 그중의일부는종국에하지절단에이르게된다 [3]. 당뇨병성족부궤양발생의주위험인자는신경병증으로인한족부의구조적변형과외상이다. 혈관병증과국소감염이이차적인요인으로작용하는데, 하지절단에이른환자의 50% 가세균감염의조절실패와연관이있다는보고가있다 [4]. 따라서, 적절한항생제사용은당뇨병성족부감염에대한다각적협력치료 (multidisciplinary therapy) 의매우중요한부분을차지한다. 이글에서는지금까지보고된자료를근거로당뇨병성족부감염의원인균분포와약물치료원칙에대해서다루고자한다. 원인균분포 호기성그람양성알균 (gram-positive cocci) 은 당뇨병성족부감염의주된원인균으로 Staphylococcus a u r e u s 가가장흔하며, c o a g u l a s e 음성 Staphylococci 와 β-hemolytic streptococci 또한자주분리가된다 [5,6]. 특히, 항생제치료력이없는급성당뇨병성족부감염은그람양성알균에의한단독감염인경우가많다. 국내연구에서도호기성그람양성균이큰비중을차지했으며 ( 서등 76.4%; 박등 63.7%; 최등 74.4%), Staphylococcus aureus ( 서등 45%; 박등 39.8%; 최등 46.3%) 가가장많이분리되었다 (Table 1)[7-9]. 그람음성막대균으로는장내세균이가장흔했고 ( %), Pseudomonas aeruginosa 는 % 를차지했다. 연구자들이보고한균분포에조금씩차이가나는이유는연구기관별로검체채취방법과환자군 ( 만성환자비율, 중증도등 ) 의구성이다르기때문으로생각된다. 과거항생제치료경험이있는만성당뇨병성족부감염은여러균감염 (polymicrobial infection) 이흔한데, 그람양성알균과호기성그람음성막대균이동시에분리되는경우가많으며, 하지의허혈, 괴사또는괴저성병변이있는경우는혐기균감염의가능성이높다 [5, 교신저자 : 송준영, 서울시구로구구로동길 97 번지. 고려대학교구로병원감염내과, infection@medimail.co.kr

2 84 10]. 만성당뇨병성족부감염에서는 3-5 개의균주가동시에분리되기도하는데, 각각의균주가감염의진행에어느정도기여하는지여부가불분명한경우가많다. 메티실린내성황색포도알균 (methicillin-resistant Staphylococcus aureus, MRSA) 감염의증가가우려되고있는데, 최근외국의보고에따르면 Staphylococcus aureus 의 30-50% 가메티실린내성이었으며 [11-13], 국내발표자료에서는 MRSA 가 % 로연구기관별로큰차이를보였다 [7-9]. MRSA 는과거에원내감염으로국한되었지만최근에는지역사회획득감염빈도가증가하고있다. 지역사회획득 MRSA 는 glycopeptide 계열항생제에만감수성을보이는원내감염균주와달리 fluoroquinolone, trimethoprim-sulfamethoxazole, clindamycin, rifampin 등의항생제에도감수성을보이는경우가많다. 1. 중증도평가 중증도평가와경험적항생제선택 당뇨병성족부감염의중증도평가는입원, 항생제선택 ( 주사용광범위항생제, 경구항생제등 ), 적극적인 수술적처치등을결정하는데있어매우중요하다 년대초반까지 25 년동안궤양과허혈의정도에따라서분류한 Wagner 의기준이사용되었으나감염의심한정도에 ( 범위, 깊이등 ) 대한구분이없는한계가있다. 미국감염학회 (Infectious Diseases Society of America, IDSA) 와당뇨병성족부국제연구그룹 (International Working Group on the Diabetic Foot) 은감염의중증도를평가하는새로운기준을확립하였다 (Table 2)[5,14]. 2. 경험적항생제선택의원칙 당뇨병성족부감염에대한항생제치료를시행할때다음의몇가지원칙을고려해야한다. 첫째, 비감염성족부궤양은비록많은수의균이집락화되어있다고하더라도항생제치료의대상이아니다. 지금까지발표된대부분의연구결과가임상적으로감염소견이없는당뇨성족부궤양에대한항생제치료가상처치유또는감염예방에도움이된다는결과를보여주지못했다 [15,16]. 오히려, 약제내성, 약제부작용등의문제를야기할수있고, 치료비부담증가의원인이된다. 그러나, 실제임상에서악취가나고흐물흐물한육아조직이관찰되는경우감염과허혈성손상을감별하기어려울수있다. 적절한궤양치료에도호전이 Table 1. Distribution of causative micro-organisms of culture-positive diabetic foot infections Micro-organisms, n (%) a Seo et al. [9] (n = 51) Park et al. [8] (n = 113) Choi et al. [7] (n = 121) Gram-positive bacteria 39 (76.4) 72 (63.7) 90 (74.4) MSSA 38 (15.6) 35 (31.0) 30 (24.8) MRSA 15 (29.4) 10 (8.8)3 26 (21.5) Other Staphylococcus spp (9.7)3 14 (11.6) Streptococcus spp. 12 (23.5) - 10 (8.3)3 Enterococcus spp. 33 (5.9)3 36 (5.3)3 10 (8.3)3 Other Gram-positive bacteria 31 (2.0)3 10 (8.8)3 - Gram-negative bacteria 17 (33.3) 41 (36.3) 77 (63.6) Enterobacteriaceae 337 (13.7)3 20 (17.6) 47 (38.8) Pseudomonas spp. 34 (7.8)3 10 (8.8)3 18 (14.9) Acinetobacter baumannii 32 (3.9)3 - - Other Gram-negaitive bacteria 33 (5.9)3 11 (9.7)3 12 (9.9)3 MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus. a Summation is over 100% because of polymicrobial infections.

3 없는경우는배양결과에따라서단기간의항생제치료를시도해볼수있다 [5]. 둘째, 항생제선택시 S t a p h y l o c o c c u s a u r e u s 를포함한호기성그람양성알균에효과적인약제를반드시포함해야한다. MRSA 에대한항균력이있는 vancomycin 또는 teicoplanin 등을사용할지여부는지역사회의 MRSA 유병률, 환자의원내감염 / 의료관련감염에대한위험인자 ( 과거 MRSA 감염력, 최근입원력, 항생제사용력, 혈액투석 ) 등을고려해서결정해야한다 (Table 3). 장알균 (enterococcus spp.) 이동정되는경우가드물지않게있는데, 단순집락이대부분으로장알 균에특이적인항생제치료가대개필요없으나 cephalosporin 에치료반응이없는환자에서장알균이분리된경우는감수성결과에맞춰서 ampicillin 또는 glycopeptide 계열항생제투여를고려해야한다 [10]. 셋째, 경증의급성감염인경우는그람양성알균에효과적인, 좁은항균범위의 1 세대 cephalosporin 또는 nafcillin 이경험적치료제로적절하지만, 이전에항생제치료를받은적이있는만성당뇨병성족부감염에서는그람음성막대균을포함한여러균감염가능성을염두에둬야한다 (Table 3)[2,5]. 특히, 상처부위에수액으로세척을반복한환자에서녹색의분비물이있으면 Table 2. Route and duration of antibiotic treatment based on the severity and bone/joint involvement of diabetic foot infections Bone/Joint IDSA PEDIS Clinical manifestations Antibiotic Duration of involvement classification grade a of infection route therapy Non-involved Uninfected 1 Wound lacking purulence or any manifestations of inflammation - - cases Mild 2 Presence of 2 manifestations of inflammation (purulence, Topical or oral 1-2 wk or erythema, pain, tenderness, warmth, or induration) - cellulitis/erythema 2 cm around the ulcer - limited to the skin or superficial subcutaneous tissues - no other local complications or systemic illness. (up to 4 wk) 85 Moderate 3 Cellulitis > 2 cm, lymphangitic streaking or spread Initial parenteral, 2-4 wk beneath the superficial fascia (deep-tissue abscess, gangrene, involvement of muscle or tendon, etc) Severe 4 Systemic toxicity or metabolic instability (fever, chills, Initial parenteral, 2-4 wk tachycardia, hypotension, confusion, vomiting, leukocytosis, acidosis, severe hyperglycemia, or azotemia) Involved Moderate/Severe 3/4 Post-amputation (no residual infected bone) Parenteral or oral 2-5 day cases Residual infected soft tissue Parenteral or oral 2-4 wk Residual infected viable bone Initial parenteral, 4-6 wk No surgery Initial parenteral, > 3 mo IDSA, Infectious Diseases Society of America. a PEDIS, perfusion, extent/size, depth/tissue loss, infection, and sensation (International Consensus on the Diabetic Foot).

4 86 Pseudomonas aeruginosa 에항균력이있는경험적항생제를선택해야한다 [17]. 넷째, 족부의허혈로인한괴사또는괴저가있고악취가나는경우는혐기균감염가능성을고려해야한다 [18]. 그러나, 혐기균의경우괴사조직의제거와공기노출만으로충분한경우가많으며, 혐기균을겨냥한항생제치료를어느정도기간동안유지해야하는지는아직불분명하다. 항생제투여경로및기간 경도의당뇨병성족부감염에대한항생제치료는국소적또는경구항생제로가능하지만, 중등도 / 중증감염과골수염이동반된경우는초기에정맥내주사용항생제치료후경구전환을고려해야한다 (Table 2). 초기에는환자의치료반응평가가매우중요하다. 입원환자의경우는매일경과를주의깊게관찰해야하며, 경구치료를선택한외래환자의경우는 2~5 일간격으로추적관찰해서병변의악화시입원치료를고려해야한다 [5]. 치료기간은골수염이동반되지않은경우대개항생제를 2 ~ 4 주간투여하고필요시배농술, 괴사조직제거술등을시행한다 [3, 5]. 골수염이동반된경우의치료기간은수술방법 ( 괴사조직제거술또는절단 ) 과감염성잔여조직의범위에따라서결정해야한다 (Table 2). 절단후잔여조직이없는경우는 2~5 일간단기간항생제투여로충분하다. 괴사조직 제거술후에는잔여골조직의감염없이연부조직감염만남아있다면수술후 2~4 주간항생제치료를유지하며, 잔여골조직감염이있는경우는 4~6 주간추가적으로항생제를투여해야한다. 수술을시행하지못한경우는 3 개월이상장기간항생제투여를필요로한다. 결론 당뇨병성족부감염에대한경험적항생제를선택할때에는과거균배양결과, 최근의항생제사용력, 입원력, 감염의중증도등을고려해서결정해야한다. 당뇨병성족부감염의가장흔한원인균은호기성그람양성알균이며, 경도또는중등도감염증은그람양성알균에의한단독감염인경우가많다. 그러므로, 과거치료경험이없는경도또는중등도급성당뇨병성족부감염에대해서는비교적좁은항균범위의 1 세대 cephalosporin 또는 nafcillin 이적절한경험적항생제라고할수있다. 지역사회 MRSA 유병률이높은지역에서는 fluoroquinolone, trimethoprimsulfamethoxazole, clindamycin 등의항생제사용을고려해야하며, 원내감염또는의료관련감염의경우는배양결과확인전까지 glycopeptide 계열의항생제를경험적으로투여할수있다. 항생제치료경험이있는만성당뇨병성족부감염인경우는그람음성막대균을포함한여러균감염가능성을염두에두고경험적항생제를선택해야하고, 상처부위의괴사또는괴저가 Table 3. Empirical antibiotic regimens for diabetic foot infections Type Clinical setting Probable pathogens Antibiotic agents Acute, Antibiotic-naïve (low-risk MRSA) MSSA, β-haemolytic streptococci Nafcillin, first-generation cephalosporins mild to Healthcare-associated MRSA Glycopeptides (vancomycin, teicoplanin), linezolid moderate High local community rates of MRSA MRSA Glycopeptides, linezolid, fluoroquinolone, infections trimethoprim-sulfamethoxazole, doxycycline, clindamycin Chronic, Chronic, previous antibiotic treatment S. aureus, β-haemolytic streptococi β-lactam + β-lactamase inhibitor, second- or thirdsevere and Enterobacteriaceae ± anaerobes generation cephalosporin, carbapenem, fluoroquinolone infections Necrotic, gangrenous ischaemic limb, S. aureus, β-haemolytic streptococi Clindamycin + fluoroquinolone, metronidazole + foul odour and Enterobacteriaceae + obligate fluoroquinolone, β-lactam + β-lactamase inhibitor, anaerobes carbapenem Hydrotherapy, green-blue-coloured Pseudomonas aeruginosa Anti-pseudomonal fluoroquinolone, penicillin drainage or cephalosporin MSSA, methicillin-susceptible Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus aureus.

5 있고악취가나는경우는혐기균감염가능성을고려해야한다. 균동정이후에는감수성결과에따른조절이필요하며, 당뇨병성족부감염의항생제치료기간은감염의중증도, 골수염동반여부, 수술후잔여감염조직의범위에따라서결정해야한다. 참고문헌 01. K Boulton AJ. The diabetic foot: a global view. Diabetes Metab Res Rev 2000;16 Suppl 1:S K Senneville E. Antimicrobial interventions for the management of diabetic foot infections. Expert Opin Pharmacother 2005;6: K Byren I, Peters EJ, Hoey C, Berendt A, Lipsky BA. Pharmacotherapy of diabetic foot osteomyelitis. Expert Opin Pharmacother 2009;10: K Grayson ML. Diabetic foot infections. Antimicrobial therapy. Infect Dis Clin North Am 1995;9: K Lipsky BA, Berendt AR, Deery HG, Embil JM, Joseph WS, Karchmer AW, LeFrock JL, Lew DP, Mader JT, Norden C, Tan JS; Infectious Diseases Society of America. Diagnosis and treatment of diabetic foot infections. Clin Infect Dis 2004;39: K Rao N, Lipsky BA. Optimising antimicrobial therapy in diabetic foot infections. Drugs 2007;67: K C h o i S R, L e e C K, K i m DW, H a n S K, K i m W K. Bacteriology and antibiotic sensitivity for diabetic foot ulcer. J Korean Soc Plast Reconstr Surg 2006;33: K Park SJ, Jung HJ, Shin HK, Kim E, Lim JJ, Yoon JW. Microbiology and antibiotic selection for diabetic foot infections. J Korean Foot Ankle Soc 2009;13: K Seo YB, Noh JY, Huh JY, Lee J, Song JY, Han SK, Kim WJ, Cheong HJ. Diabetic foot infection: microbiologic analysis based on deep tissue biopsy. Infect Chemother 2007;39: K Lipsky BA. Empirical therapy for diabetic foot infections: are there clinical clues to guide antibiotic selection? Clin Microbiol Infect 2007;13: K Dang CN, Prasad YD, Boulton AJ, Jude EB. Methicillinresistant Staphylococcus aureus in the diabetic foot clinic: a worsening problem. Diabet Med 2003;20: K Tentolouris N, Jude EB, Smirnof I, Knowles EA, Boulton AJ. Methicillin-resistant Staphylococcus aureus: an increasing problem in a diabetic foot clinic. Diabet Med 1999;16: K Tentolouris N, Petrikkos G, Vallianou N, Zachos C, Daikos GL, Tsapogas P, Markou G, Katsilambros N. Prevalence of methicillin-resistant Staphylococcus aureus in infected and uninfected diabetic foot ulcers. Clin Microbiol Infect 2006;12: K Lipsky BA; International consensus group on diagnosing and treating the infected diabetic foot. A report from the international consensus on diagnosing and treating the infected diabetic foot. Diabetes Metab Res Rev 2004;20 Suppl 1:S K Chantelau E, Tanudjaja T, Altenhöfer F, Ersanli Z, Lacigova S, Metzger C. Antibiotic treatment for uncomplicated neuropathic forefoot ulcers in diabetes: a controlled trial. Diabet Med 1996;13: K Hirschl M, Hirschl AM. Bacterial flora in mal perforant and antimicrobial treatment with ceftriaxone. Chemotherapy 1992;38: K Shankar EM, Mohan V, Premalatha G, Srinivasan RS, Usha AR. Bacterial etiology of diabetic foot infections in South India. Eur J Intern Med 2005;16: K Fierer J, Daniel D, Davis C. The fetid foot: lowerextremity infections in patients with diabetes mellitus. Rev Infect Dis 1979;1:

2 - ceftazidime-clavulanate 디스크를이용하여 ESBL 생성균주를확인하였다. 또한 2009년도에수집된균주인 P. aeruginosa(386주 ), A. baumannii(349주 ) 를대상으로 imipenem에대한감수성을확인하였고 imipenem-h

2 - ceftazidime-clavulanate 디스크를이용하여 ESBL 생성균주를확인하였다. 또한 2009년도에수집된균주인 P. aeruginosa(386주 ), A. baumannii(349주 ) 를대상으로 imipenem에대한감수성을확인하였고 imipenem-h 1 - 국내종합병원을대상으로한항균제내성모니터링 Monitoring of antimicrobial resistance on general hospitals in Korea 질병관리본부국립보건연구원감염병센터약제내성과 연세대학교의과대학진단검사의학교실, 세균내성연구소 Ⅰ. 들어가는말 항균제내성세균의출현과확산으로인하여세균감염증치료는점점어려워지고있다 [1-4]. 항균제내성률은흔히국가간,