C.difficle 관련 설사, CDAD(Clostridium difficile-Associated Disease) 치료의 변화: metronidazole에서 vancomycin

감염성 설사의 원인에는 enterohemorrhagic E. coli, Shigella species, Salmonella species, C. jejuni, C. difficile 등이 있다.

그중에서연관 설사에 대해 알아보자!

 

C. difficile 관련 설사의 병태생리

• 독소에 의한 염증성 설사를 일으킴
• 독소가 장의 상피에 부착한 후 세표 내로 유입되어 단백합성을 저해하고 세포괴사 유발
• IL-1β, TNF, IL-8 등이 증가됨
• 항생제 복용 후 후 C. difficile에 노출되면 염증성 설사가 발생할 수 있음. 항생제 관련 설사를 일으키는 것이 C. difficile만이 원인은 아니지만 임상적으로 의미있는 정도의 설사와 WBC 증가의 원인은 대개 C.difficile의 독성로 발생함

 

C. difficile 관련 설사의 치료(2009 소화기계 감염 진료지침 권고안)

1. 장운동 억제제는 가능하면 사용하지 않는다. 증상이 불명확해지고 독성큰결장증을 촉진할 수 있다(C-III).
2. 경증-증등도 C. difficile 관련 설사는 초치료로 metronidazole (500 mg 경구, 일일 3회, 10-14일)을 권장하고(A-I), 중증 C.difficile 관련 설사 초치료로 vancomycin (125 mg 경구, 1일 4회, 10-14일)을 고려한다(B-I).
3. 중증 및 합병증이 동반된 C. difficile 관련 설사는 경구 vancomycin (장폐색증이 있으면 직장으로 투여)±주사용 metronidazole을 고려하나 권장 근거가 부족하다. Vancomycin의 용량은 500 mg 경구 혹은 코 위 영양관으로6시간마다, 직장내 투여의 경우 500 mg (생리식염수 약 100 mL과 혼합)을 6시간마다 투여하고, metronidazole은 500 mg을 정맥내로 8시간마다투여한다(C-III).
4. C. difficile 관련 설사 첫 재발은 통상적으로 초치료와 같은 항생제 사용을 권장하지만(A-II), 초치료 때와 마찬가지로 증증도에 따라 접근한다(C-III).
5. 2회 이상의 재발이나 장기간 치료가 필요할 때 metronidazole은 신경독성 가능성이 있어 고려하지 않는다(B-II).
6. 2회 이상 재발의 경우 다양한 용법, 용량의 vancomycin 사용을 고려한다(B-III).

 

1995년 CMC에서 VRE 출혈을 감소시키기 위해 병원 내 vancomycin 사용을 줄일 것을 권장한 이후 CDAD 초치료로 metronidazole을 주로 사용하였고 경구 vancomycin은 metronidazole에 효과가 없는 환자에 한해서 사용되었다. 그러나 한 임상연구에서 metronidazole의 치료 실패율이 평균 18.2%까지 보고되었고 후향적 연구에서 metronidazole이 vancomycin을 사용하였을 때보다 설사 증상 소실되는 데까지 걸리는 시간이 더 길었다는 보고가 있었다.

이에 2017년 IDSA guideline에서 PO vancomycin의 사용을 좀 더 권장하고 있다.

 

 

C. difficile 관련 설사의 치료(2017 IDSA guideline)

What are important ancillary treatment strategies for CDI? (CID에 대한 중요한 보조 치료 전략은?)

1. Discontinue therapy with the inciting antibiotic agent(s) as soon as possible, as this may influence the risk of CDI recurrence (strong recommendation, moderate quality of evidence).
2. Antibiotic therapy for CDI should be started empirically for situations where a substantial delay in laboratory confirmation is expected, or for fulminant CDI (described in section XXX) (weak recommendation, low quality of evidence).

What are the best treatments of an initial CDI episode to ensure resolution of symptoms and sustained resolution 1 month after treatment? (초기 CDI 증상 해결과 치료 한 달 후 지속적인 효과를 보장할 수 있는 가장 좋은 치료는?)

1. Either vancomycin or fidaxomicin is recommended over metronidazole for an initial episode of CDI. The dosage is vancomycin 125 mg orally 4 times per day or fidaxomicin 200 mg twice daily for 10 days (strong recommendation, high quality of evidence) (Table 1).
2. In settings where access to vancomycin or fidaxomicin is limited, we suggest using metronidazole for an initial episode of nonsevere CDI only (weak recommendation, high quality of evidence). The suggested dosage is metronidazole 500 mg orally 3 times per day for 10 days. Avoid repeated or prolonged courses due to risk of cumulative and potentially irreversible neurotoxicity (strong recommendation, moderate quality of evidence). (See Treatment section for definition of CDI severity.)

😁 이전의 권고안과 달라진 점은 중증도에 상관없이 vancomycin을 우선 권고하고 있다는 점이다! 😁 

 

What are the best treatments of fulminant CDI?

1. For fulminant CDI*, vancomycin administered orally is the regimen of choice (strong recommendation, moderate quality of evidence). If ileus is present, vancomycin can also be administered per rectum (weak recommendation, low quality of evidence). The vancomycin dosage is 500 mg orally 4 times per day and 500 mg in approximately 100 mL normal saline per rectum every 6 hours as a retention enema. Intravenously administered metronidazole should be administered together with oral or rectal vancomycin, particularly if ileus is present (strong recommendation, moderate quality of evidence). The metronidazole dosage is 500 mg intravenously every 8 hours.*
2. If surgical management is necessary for severely ill patients, perform subtotal colectomy with preservation of the rectum (strong recommendation, moderate quality of evidence). Diverting loop ileostomy with colonic lavage followed by antegrade vancomycin flushes is an alternative approach that may lead to improved outcomes (weak recommendation, low quality of evidence).

*Fulminant CDI, previously referred to as severe, complicated CDI, may be characterized by hypotension or shock, ileus, or megacolon.

 

What are the best treatments for recurrent CDI?

1. Treat a first recurrence of CDI with oral vancomycin as a tapered and pulsed regimen rather than a second standard 10-day course of vancomycin (weak recommendation, low quality of evidence), OR
2. Treat a first recurrence of CDI with a 10-day course of fidaxomicin rather than a standard 10-day course of vancomycin (weak recommendation, moderate quality of evidence), OR
3. Treat a first recurrence of CDI with a standard 10-day course of vancomycin rather than a second course of metronidazole if metronidazole was used for the primary episode (weak recommendation, low quality of evidence).
4. Antibiotic treatment options for patients with >1 recurrence of CDI include oral vancomycin therapy using a tapered and pulsed regimen (weak recommendation, low quality of evidence), a standard course of oral vancomycin followed by rifaximin (weak recommendation, low quality of evidence), or fidaxomicin (weak recommendation, low quality of evidence).
5. Fecal microbiota transplantation is recommended for patients with multiple recurrences of CDI who have failed appropriate antibiotic treatments (strong recommendation, moderate quality of evidence).
6. There are insufficient data at this time to recommend extending the length of anti–C. difficile treatment beyond the recommended treatment course or restarting an anti–C. difficile agent empirically for patients who require continued antibiotic therapy directed against the underlying infection or who require retreatment with antibiotics shortly after completion of CDI treatment, respectively (no recommendation).

 

reference:

1) 소화기계 감염 진료지침 권고안, Infect Chemother. 2010 Dec;42(6):323-361. Korean.

2) McDonald, L. Clifford, et al. "Clinical practice guidelines for Clostridium difficile infection in adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA)." Clinical Infectious Diseases 66.7 (2018): e1-e48.