J Korean Soc Transplant 2013;27:81-86 http://dx.doi.org/10.4285/jkstn.2013.27.3.81 Review Article 다제내성세균의시대에세균성감염질환에대한항생제치료의최근발전들 성균관대학교의과대학삼성서울병원감염내과 강철인 What s New in the Management of Bacterial Infections in the Era of Multidrug-Resistant Bacteria? Cheol-In Kang, M.D. Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Bacterial infection is an increasingly important diagnosis following successful organ transplantation in humans. This is notwithstanding the fact that opportunistic infections such as those of fungal and viral origin can occur frequently in this population. Infections due to multidrug resistant bacteria have been on the rise since the past decade and not surprisingly continue to challenge physicians. Recent studies show that rapidly increasing rates of infections in such population are due to methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococci (VRE), and multidrug-resistant gram-negative bacilli. Furthermore, pan-drug-resistant infections are now on the rise, especially in gram-negative bacilli. Regrettably, our therapeutic options for these pathogens are currently extremely limited. Very recently, it has been shown that infections due to Clostridium difficile spp. have been the leading cause of antibiotic-associated diarrhea. It is a well-known fact that infections due to antimicrobial-resistant bacteria were associated with a greater likelihood of inappropriate antimicrobial therapy. Therefore, it is very clear that inappropriate antimicrobial therapy has an adverse effect on survival rate in patients with serious infections. This is especially true in immunocompromised hosts. Hence, in the light of the above, it is very essential that physicians who are treating immunocompromised patients should be aware of not only current epidemiological status of antimicrobial resistance but also proper clinical practice guidelines to be followed while diagnosing infections due to such antimicrobial agents. The objective of this review is, therefore, to provide a recent update of currently available antimicrobial therapeutic strategies for life-threatening infections due to antimicrobial-resistant pathogens. Key Words: Bacterial infections, Antimicrobial resistance, Antimicrobial agents 중심단어 : 세균감염, 항균제내성, 항균제 서론 간, 신장등의고형장기이식후발생하는감염증에대해서생각할때바이러스감염, 진균감염같은기회감염증을흔히떠올리지만실제로가장흔하게발생하는감염증은세균감염이다. 특히이식수술후 1개월이내 책임저자 : 강철인, 서울시강남구일원로 81 성균관대학교의과대학삼성서울병원감염내과, 135-710 Tel: 02-3410-0324, Fax: 02-3410-0064 E-mail: collacin@hotmail.com 접수일 : 2013 년 8 월 22 일, 심사일 : 2013 년 8 월 27 일게재승인일 : 2013 년 8 월 29 일 이논문은교육과학기술부의재원으로한국연구재단의지원을받아수행된기초연구사업임 (No. 2010-0021572). 에는수술합병증과관련된세균감염, 이식전기저질환과관련된세균감염이매우흔하게발생한다. 간이식환자의경우이식전간기능부전으로장내세균감염에취약한상태이고이식후담도염발생위험이높아서다제내성그람음성균에의한감염이잘발생할수있다. 수술후창상감염의중요한원인균으로서메티실린내성황색포도알균 (Methicillin-resistant Staphylococcus aureus, MRSA) 이있으며 MRSA에의한폐렴도흔하게발생할수있다. 과거에는비교적쉽게치료될수있었던세균성감염질환이었으나최근에는다제내성균주의출현으로인해적절한항생제치료가점점더어려워지고있다 (1). 항생제는임상의사들이가장많이처방하는약중한가지이며항생제를처방할때에도항생제내성균감염에대 J Korean Soc Transplant www.ksot.org 81 September 2013 Volume 27 Issue 3
한지식이필수적인시대가되었다. 그람양성균중임상적으로중요한세균인황색포도알균에서메티실린내성균주인 MRSA의빈도가점점증가하고있고, vancomycin에도내성을보이는균주인 vancomycin-resistant enterococci (VRE) 가출현하고있다. 그람음성균중가장흔하게감염을유발하는대장균 (Escherichia coli) 과폐렴간균 (Klebsiella pneumoniae) 에서 extended-spectrum β-lactamase (ESBL) 을생성하는균주가증가하고있고, 최근에는 carbapenem에도내성을보이는 carbapenemresistant Enterobacteriaceae 도출현하였다 (2). Carbapenem 내성녹농균 (Pseudomonas aeruginosa) 과아시네토박터균 (Acinetobacter) 에의한감염증또한중환자실을중심으로꾸준하게발생하고있다. 그외에도광범위항생제사용의증가로인해난치성 Clostridium difficile 장염의발생이증가하고있는실정이다. 본논문에서는고형장기이식환자에서최근임상적으로문제가되고있는다제내성세균감염에대한적절한항생제치료에대하여간략히기술하고자한다. 다제내성세균감염의항생제치료 1) 메티실린내성황색포도알균 (Methicillin-resistant Staphylococcus aureus, MRSA) MRSA 감염증에사용할수있는항생제들을 Table 1에기술하였다. MRSA에의한중증감염증에서가장효과적으로사용할수있는항생제는 vancomycin이며가장우 선적으로추천되는항생제이다. 항생제의약동학적, 약력학적인지표중치료효과에관련성이있는지표로서 time > minimum inhibitory concentration (MIC), peak/ MIC, area under curve (AUC)/MIC가있다. 에서는이중 AUC/MIC가가장중요한지표인것으로알려져있고 AUC/MIC를최소 400 이상으로유지해야가장좋은치료효과를기대할수있다 (3). AUC/MIC를높게유지하기위해서는혈중약물농도중 trough level를높게유지하는것이중요하며원인균의 MIC가상승하면 AUC 또한상승되어야한다. 과거에는 MRSA 균주들의대부분이 MIC <1 μg/ml 로낮아서 AUC/MIC가 400 이하로감소하는경우가적었으나, 최근에분리되는 MRSA 균주들의 MIC는 1 또는 2 μg/ml로증가되어있는경우가많아서 AUC/MIC를 400 이상으로유지하기가어려운경우가흔하며이로인한 vancomycin 치료실패의위험성이증가하고있다. 국내한대학병원에서분리된 MRSA 균주중 10% 미만에서 MIC <1 μg/ml 이었고 vancomycin에대한 MIC 증가가심각한문제임이확인된바있다 (4). 에대한 MIC의증가가사망률의증가와관련이있음이최근한 meta-analysis 연구에서보고되었다 (5). MIC 1.5 μg/ml 군의 MIC <1.5 μg/ml 군에대한사망의 odds ratio가 1.64로유의하게상승되었다 (5). MIC의증가와치료실패와의관련성또한확인되었으며 MIC 1.5 μg/ml 군의 MIC <1.5 μg/ml 군에대한치료실패의 odds ra- Table 1. Recommendations for the antimicrobial treatment of MRSA infections Manifestation Treatment Adult dose Skin and soft tissue infection (SSTI) Purulent cellulitis Complicated SSTI Bacteremia and infective endocarditis Pneumonia Bone and joint infections TMP-SMX Doxycycline or minocycline Linezolid Linezolid Linezolid TMP-SMX 300 450 mg PO TID 2 4 T PO BID 100 mg PO BID 600 mg PO/IV BID 600 mg IV TID 600 mg PO/IV BID 600 mg IV TID 600 mg PO/IV BID 600 mg IV TID 5 mg/kg/dose PO/IV every 8 12 hr Abbreviations: MRSA, Methicillin-resistant Staphylococcus aureus ; TMP-SMX, Trimethoprim/sulfamethoxazol; BID, twice a day; TID, three times a day; IV, intravenous; PO, per os. Adapted from Table 3 of reference [3]. J Korean Soc Transplant www.ksot.org 82 September 2013 Volume 27 Issue 3
tio가 2.69로유의하게상승되었다 (5). 따라서최근에는 MRSA에대한중증감염의경우 vancomycin의 trough level을 15 20 μg/ml 로높게유지할것을권고하고있다. 중증감염의예로서균혈증을동반한경우, 감염성심내막염, 골수염, 뇌수막염, 폐렴, 중증피부및연조직감염을들수있다. trough level를높이기위해서투여용량을증가시켜야하는데, 그결과필연적으로 vancomycin에의한신독성이증가하고있다 (6). 을투여하는경우 therapeutic drug monitoring (TMD) 을철저히해서용량을조절하는것이필요하며, 신독성발생에주의를기울여야한다. 신독성발생에대한걱정으로 vancomycin 대신 teicoplanin을투여하는경우가있는데, 국내대부분의병원에서는 teicoplanin에대한 TDM이시행되지않으므로적절한용량을결정하기어려워서중증감염증에서 teicoplanin을사용할경우주의를요한다. 최근 MRSA 감염증의치료제로서새롭게개발되어사용가능한항생제는 linezolid이다. 고가의약제이며 1차치료제로국내건강보험적용이되지않아사용에제한이있으나, vancomycin, teicoplanin에치료실패한경우또는부작용이발생한경우사용가능한항생제이다. 특히 MRSA 폐렴에대해서 vancomycin보다우월한치료효과를보고한연구들이있어 vancomycin 신독성등의부작용을고려한다면 MRSA 폐렴에서적극적으로 linezolid의사용을고려해볼수있겠다 (7,8). 하지만 2주이상장기간투여하는경우호중구감소증, 혈소판감소증등의혈액학적부작용이흔하며말초신경염등의신경학적인부작용이발생할수있다. 2) 반코마이신내성장알균 (-resistant enterococcus, VRE) 장알균은장내상재균으로서병독력 (virulence) 이낮아서침습성감염증을유발하는경우가드물지만복강수술후환자, 면역억제환자등에서는복강내감염, 요로감염등을유발할수있다. 또한감염성심내막염의중요한원인균이다. 최근 vancomycin에내성을보이는 VRE 가증가추세로서병원감염에서큰문제를일으키고있다. 특히간이식을받은환자에서 VRE에의한담도감염, 복강내감염이발생하는경우가흔하다. 치료항생제로서 linezolid가대표적이며, 다른그람음성균, 혐기균과혼합감염인경우 tigecycline의사용이추천된다 (9). 3) 다제내성 Enterobacteriaceae 대장균, 폐렴간균등 Enterobacteriaceae에서광범위 cephalosporin에내성을나타내는가장중요한기전은 ESBL 생성이며 ESBL 생성균인경우 cephalosporin으로치료할수없다 (10). Imipenem, meropenem, doripenem, ertapenem 같은 carbapenem이가장효과적인치료항생제이며이중 ertapenem은반감기가길어서 1일 1회투여할수있다는장점이있다 (10,11). 하지만 ertapenem은다른 carbapenem 계열항생제와달리녹농균와아시네토박터균에항균력이없다. Carbapenem에내성이발생하는경우안전하고효과적으로치료할수있는항생제가실제적으로없는상황이므로 carbapenem 내성균발생을억제하는것이필요하며 carbapenem의오남용을막는것이매우중요하다. ESBL 생성균에의한감염에서도 carbapenem 외감수성있는다른항생제를사용해볼수있는데, 이중가장중요한것이 piperacillin/tazobactam과 amikacin이다. 국내 ESBL 생성균의 piperacillin/tazobactam에대한감수성은약 70% 가량이며 amikacin에대한감수성은 90% 이상으로보고된다 (12). 감수성있는 piperacillin/tazobactam의 ESBL 생성균에대한치료효과는우수한것으로알려져있다 (13,14). 높은내성률로인해경험적인사용은어렵지만 ciprofloxacin에감수성이확인된경우 ciprofloxacin 또는 levofloxacin을사용할수있다. 최근 carbapenem-resistant Enterobacteriaceae (CRE) 가출현하여증가추세이며이는전세계적인문제가되고있다. 이균주에대해서 colistin과 tigecycline이사용가능한약제이다 (11). Colistin은 40여년전개발되었으나부작용으로인하여시장에서퇴출된약으로서최근다제내성그람음성균감염이증가하면서다시생산을시작한약제이다. Carbapenem을포함한모든항생제에내성을보이는경우사용을고려할수있는항생제이다. 신독성과신경독성이문제가되므로혈청크레아티닌의모니터링이필요하다. 최근에개발된약제로서사용을고려해볼수있는항생제는 tigecycline이다. Tigecycline은간에서대사되어담도를통해배설되기때문에혈중농도의 100배이상의약물농도가담즙액에서검출되며대장상피세포에서도높은농도를유지한다. 따라서복강내감염에서사용가능한항생제로승인받았다. 그람양성균, 그람음성균, 혐기균에대해항균력이있는광범위항생제이며병원내감염에서문제가되고있는 MRSA, VRE, ESBL 생성균주에도항균력이있어 tigecycline은단일요법만으로도여러가지내성균주들을치료할수있다. 하지만 tigecycline은녹농균, Proteus균에항균력이부족하므로이들균주감염에대해서사용해서는안되고혈중농도가낮기때문에균혈증을동반한경우에 J Korean Soc Transplant www.ksot.org 83 September 2013 Volume 27 Issue 3
는주의해서투여해야한다. Tigecycline 치료효과에대한최근 meta-analysis 연구에서다른비교항생제에비해다소떨어지는치료효과를보고한바있어, 중증감염에서 tigecycline 단독요법을시행할때주의를요한다 (15). 다제내성 Enterobacteriaceae 감염증에사용가능한항생제를 Table 2에기술하였다 (11). 4) 다제내성녹농균, 아시네토박터균녹농균, 아시네토박터균감염증에서사용을고려할수있는항생제는 cephalosporin 계열항생제중 ceftazidime, cefoperazone, cefepime이며 penicillin 계열항생제중 piperacillin 또는 piperacillin/tazobactam이다. 이들항생제에부작용이있는경우 aztreonam 사용을고려할수있으며, 다제내성인경우 imipenem, meropenem, doripenem 등의사용을고려한다 (11). 과거에는항생제병합요법을고려하는경우가많았으나초기에적절한항생제가적절한용량으로투여된다면병합요법이단일요법에비해우월한치료효과를보인다는근거는부족하다 (16). 하지만패혈증발생초기에원인균을알지못할때두가지항생제를병합해서투여함으로써항균범위를넓힐수있으므로다제내성균감염의위험성이높은환자에서초기경험적항균제치료로서병합요법을고려할수있다. Carbapenem 내성녹농균, 아시네토박터균은다른계열항생제에도내성을보이는경우가흔하여사용가능한항생제에제한이있다. 일부균주들은 cefepime, aztreonam, ciprofloxacin 등에감수성을보이는경우가있어감수성인항생제를사용할수있다. 하지만대부분의 carbapenem 내성균은다른항생제에모두내성을보이는경우가흔하므로이경우 colistin을투여해야한다 (11). Amikacin, tobramycin에감수성을보이는균주라면다른항생제와병합해서 aminoglycoside 투여를고려할수있다. 녹농균과달리아시네토박터균은 tigecycline에감수성이있다. Tigecycline은 tetracycline 계열항생제이므로 minocycline의감수성으로 tigecycline의감수성을추정해볼수있다. 다제내성녹농균, 아시네토박터균감염증에사용가능한항생제를 Table 3에기술하였다. 5) Clostridium difficile 감염장염을유발하는 Clostridium difficile균은주로항생제를장기간투여받은환자에서감염을유발하지만, 복강내수술을받은환자, 항암치료를받은환자에서도장염을유발할수있다. 최근발생빈도와중증도가증가추세이며특히북미지역에서는 NAP-1/027 (North America Pulsed Field type 1 and PCR ribotype 027) 이라는특정균주가폭발적으로증가하고있다 (17). 이균주가 quinolone, metronidazole에내성인경우가흔하여서구에서시행된연구에서는 metronidazole이 vancomycin에비해치료효과가떨어지고재발률이높다고보고된다 (17). 국내에서는아직까지 NAP-1/027 균주가흔하게발견되지는않지만최근보고에따르면국내에서도 C. difficile 감염증의발생빈도및중증도가증가추세이다 Table 2. Antimicrobial therapy for serious infections caused by MDR-Klebsiella pneumoniae or Escherichia coli Antimicrobial agents Dose Adverse drug reaction Commentary For ESBL or AmpC producers Imipenem/cilastatin Meropenem Doripenem Ertapenem For carbapenem-resistant Enterobacteriaceae Colistin (polymyxin E) Tigecycline 0.5 g IV q 6 hr 1 g IV q 8 hr 0.5 g IV q 8 hr 1 g IV q 24 hr Mild infection: 5 mg/kg per day, divided into 2 doses Severe infection: 3.5 [(1.5 CrCln)+30]=total daily dose After 100 mg IV loading, 50 mg IV q 12 hr CNS toxicity Nephrotoxicity, neurotoxicity Nausea, vomiting, hepatotoxicity Preferred in patients with neurologic disorder Long half-life Available in colistimethate sodium salt The maximum suggested daily dose is 475 mg Approved for complicated intraabdominal infection and soft tissue infections Abbreviations: MDR, multidrug-resistant; ESBL, extended-spectrum β-lactamase; CNS, central nervous system; CrCln, creatinine clearance normalized for body surface area; IV, intravenous. Adapted from Table 1 of reference [11]. J Korean Soc Transplant www.ksot.org 84 September 2013 Volume 27 Issue 3
Table 3. Antimicrobial therapy for serious infections caused by carbapenem-resistant-pseudomonas aeruginosa or Acinetobacter baumannii a Antimicrobial agents Dose Adverse drug reaction Commentary Colistin (polymyxin E) Aztreonam Amikacin Tobramycin Mild infection: 5 mg/kg per day, divided into 2 doses Severe infection: 3.5 [(1.5 CrCln)+30]=total daily dose 2 g IV q 8 6 hr 7.5 mg/kg IV q 12 hr 1.7 mg/kg IV q 8 hr Nephrotoxicity, neurotoxicity Nephrotoxicity, ototoxicity Nephrotoxicity, ototoxicity Available in colistimethate sodium salt The maximum suggested daily dose is 475 mg Some isolates may be susceptible to aztreonam Combination with other susceptible antibiotics Combination with other susceptible antibiotics Adapted from Table 2 of reference [11]. a Carbapenem-resistant-Pseudomonas aeruginosa or Acinetobacter baumannii isolates might be susceptible to other classes of antibiotics (e.g., cefepime, piperacillin/tazobactam, and ciprofloxacin), particularly in isolates with porinmutation as the main mechanism of carbapenem resistance. In such cases, those antibiotics susceptible in vitro can be used. Table 4. Suggested approaches to therapy for Clostridium difficile infection Category Initial episode Mild-to-moderate infection Severe infection or unresponsiveness to or intolerance of metronidazole First recurrence Mild-to-moderate infection Severe infection or unresponsiveness to or intolerance of metronidazole Second recurrence Third recurrence Other options for recurrent infection Antimicrobial therapy Metronidazole at a dose of 500 mg orally 3 times daily for 10 14 days at a dose of 125 mg orally 4 times daily for 10 14 days Metronidazole at a dose of 500 mg orally 3 times daily for 10 14 days at a dose of 125 mg orally 4 times daily for 10 14 days in tapered and pulsed doses at a dose of 125 mg orally 4 times daily for 14 days, followed by rifaximinat a dose of 400 mg twice daily for 14 days Intravenous immune globulin at a dose of 400 mg per kg of body weight once every 3 weeks for a total of 2 or 3 doses Therapy with other microorganisms, including fecal transplantation Adapted from Table 2 of reference [17]. (18). 경구용또는주사용 metronidazole과경구용 vancomycin이치료항생제이다. 최근 fidaxomicin이개발되었다. C. difficile 장염의치료원칙을 Table 4에기술하였다. 장내정상세균총을복원해서중증, 불응성 C. difficile 장염을치료하려는시도가이루어졌는데, 배우자나가까운가족의대변을튜브를통해주입하는방법을사용하였다. 최근 vancomycin 치료와비교하는임상연구가수행되었는데, 93.8% vs. 30.8% 라는뛰어난치료효과가보고된바있다 (19). Metronidazole, vancomycin 치료에도불구하고치료불응성이거나자주재발하는경우대변주입치료를고려해볼수있겠다 (20). 결론세균의항생제내성은의료현장에서뿐만아니라공중보건학적으로도큰문제를야기하고있으며장기이식분야에서도예외는아니다. 항생제사용에따른세균의내성획득으로인해세균성감염질환의치료가점점더어려워지고있으며항생제를처방할때에도항생제내성균감염에대한지식이필수적인시대가되었다. 환자를진료하는임상의사들은항생제내성문제의심각성에대해잘인지해야하며서구와다른국내현실의독특한상황을잘파악하고있는것이중요하다. J Korean Soc Transplant www.ksot.org 85 September 2013 Volume 27 Issue 3
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