병원에서 환자를 보다보면 감염 관련하여 ESBL 이라는 단어를 마주치게 됩니다.
오늘은 ESBL이 무엇이고, 어떤 종류가 있는지, 어떻게 검사하고 해석하는지, 어떻게 치료하는지에 대해서 자세히 알아보도록 하겠습니다.
ESBL의 정의
ESBL은 Extended-spectrum beta-lactamase의 약자입니다. 그렇다면, 먼저 beta-lactamase에 대한 이해가 필요합니다. 세균 감염에 사용되는 항생제 중에서 베타락탐 계열의 항생제는 베타락탐링(beta-lactam ring)의 구조를 가집니다.
위는 베타락탐 계열의 항균제의 베타락탐 링의 구조를 나타난 그림입니다. 그림의 1번은 페니실린 (penicillin), 2번은 세팔로스포린(cephalosporin), 3번은 카바페넴(carbapenem), 4번은 모노박탐(monobactam)입니다. 세균이 분비하는 Beta-lactamase는 이러한 베타락탐링을 분해하는 효소입니다.
3세대 세팔로스포린계 항생제가 개발되면서 이에 대해 내성을 보이는 효소를 세균이 생성하게 시작하게 되면서 ESBL이라는 개념이 등장하였습니다. ESBL은 beta-lactamase 중에서도 broad-spectrum cephalosporin 및 monobactam을 분해할 수 있는 특징을 가진 것으로 정의합니다.
그렇지만, 이러한 ESBL은 clavulanic acid라는 약물에 의해 억제 되는 경우가 많이 있습니다. 최근에는 clavulanic acid에 의해 억제되는 beta-lactamase를 ESBL로 한정하여 정의하고 있습니다.
ESBL의 종류
특징적인 ESBL은 TEM-derived ESBL, SHV-derived ESBL, CTX-M derived ESBL 등이 있습니다.
1960년대에 그람 음성 세균의 ampicillin 내성 증가는 그리스 환자인 Temoniera의 이름을 따서 명명된 plasmid-encoded beta-lactamase인 TEM-1의 출현에 기인합니다. TEM-1은 그람 음성세균에서 most common한 beta-lactamse로서, Enterobacteriaceae, N.gonorrhoeae, H. influenzae에서 페니실린과 narrow-spectrum의 세팔로스포린을 분해합니다. 이러한 TEM에서 유래한 ESBL은 몇 개의 아미노산 변화를 통해 일어납니다. 이러한 아미노산 변화는 3세대 세팔로스포린계 항균제 및 monobactam에 대한 접근을 용이하게 함으로써, 광범위 항생제를 저해하는 extended spectrum이 나타나게 되는 것입니다.
위의 그림을 보면 SHV-1 beta-lactamase 또한 TEM-1과 유사한 구조를 가지고 있음을 알수 있으며, active site의 point mutation에 의해 ESBL이 됩니다.
CTX-M-derived ESBL은 TEM 및 SHV계열과는 진화적으로 관련이 없습니다. CTX-M-derived ESBL은 특히 community onset infection에서 많이 나타나는 것으로 보고되고 있습니다.
ESBL 검사 방법 및 해석
흔히 볼 수 있는 세균 동정 결과 및 항생제 감수성 결과로, ESBL 양성으로 확인되는 균을 보여주고 있습니다. 그렇다면, 병원에서 흔히 사용하는 자동화장비를 이용한 항균제 감수성검사는 어떻게 이루어질까요?
흔히 사용되는 검사 장비로는 MicroScan WalkAway와 Vitek 장비가 있습니다.
Vitek 장비의 ESBL test를 살펴보면, 검사 패널 안에는 ceftazidime과 cefotaxime이 들어가 있는 well이 있고, 여기에 clavulanic acid가 각각 첨가되어, ceftazidime+clavulanic acid, cefotaxime+clavulanic acid 있는 well이 존재하여 총 4개의 well로 ESBL을 검출하게 됩니다.
Ceftazidime과 cefotaxime만 들어있는 well에 비하여 clavulanic acid가 첨가된 well에서 균 증식률이 50%이상 감소하게 되면 ESBL 양성으로 보고하게 됩니다. 이때, ceftazidime과 cefotaxime 둘 중 하나에서라도 균 증식이 감소하면 양성으로 보고하게 됩니다.
따라서, 자동화장비에서 ESBL이 양성으로 보고되었을 경우, 이 균은 clavulanic acid에 의해서는 in vitro에서 억제되는 양상을 보인 균인 것입니다.
ESBL의 치료
국내에서 분리되는 ESBL 생성 장내세균은 piperacillin/tazobactam에 감수성인 경우가 60-70%에 달하기 때문에, ESBL 생성균이라고 하더라도 piperacillin/tazobactam 감수성 균인 경우에는 이를 먼저 사용해 볼 수 있겠습니다.
그렇지만, 균주 수가 100배 이상 증가하면 MIC가 8배 이상 증가하는 inoculum effect가 나타날 수 있으므로 중증 감염에서는 주의가 필요합니다. high inoculum이 예상되는 감염증 (농양을 동반한 복강 내 감염, 중증 폐렴 등) 에서는 piperacillin/tazobactam에 감수성균이라도 ESBL 생성균이라면 carbapenem 계열 항생제를 투여하는 것이 안전하겠습니다.
국내에서 분리되는 ESBL 생성균에서는 amikacin에 대한 감수성이 90% 이상 매우 높은 것으로 알려져 있어, ESBL 생성균 감염의 위험이 높은 환자에서 경험적으로 piperacillin/tazobactam과 amikacin의 병합요법을 고려해 볼 수 있습니다.
또한 ESBL 생성균 중 ciprofloxacin 또는 trimethoprim/sulfamethoxazole에 감수성을 나타내는 경우가 있는데, 이들 항생제는 요로 감염에서 효과적으로 사용 가능하기 때문에, 이들에 감수성이라면 투여를 고려할 수 있겠습니다.
ESBL 생성균에서 가장 효과적인 항생제는 carbapanem계열 항생제(ertapenem, imipenem, meropenem, doripenem) 입니다. 그렇지만, 최근 carbapenem 항생제 사용이 증가하면서 CRE (carbapenem resistant Enterobacterales)가 많이 증가하고 있는 추세로, 적정기간 동안 적정 용량으로 사용해야 하겠습니다.
Reference : 대한임상미생물학회지 : 제6권 제1호 2003, 대한내과학회지: 제 88 권 제 5 호 2015
몇개의 아미노산 변화로 인한 차이가 흥미롭네요
아미노산 변화가 중요한 위치에 발생한다면 구조 전체가 바뀌어버리니 아주 중요하다고 할 수 있겠습니다.
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